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Diverse Evolutionary Histories for β-adrenoreceptor Genes in Humans
Abstract
In humans, three genes--ADRB1, ADRB2 and ADRB3--encode beta-adrenoreceptors (ADRB); these molecules mediate the action of catecholamines in multiple tissues and play pivotal roles in cardiovascular, respiratory, metabolic, and immunological functions. Genetic variants in ADRB genes have been associated with widespread diseases and conditions, but inconsistent results have often been obtained. Here, we addressed the recent evolutionary history of ADRB genes in human populations. Although ADRB1 is neutrally evolving, most tests rejected neutral evolution for ADRB2 in European, African, and Asian population samples. Analysis of inferred haplotypes for ADRB2 revealed three major clades with a coalescence time of 1-1.5 million years, suggesting that the gene is either subjected to balancing selection or undergoing a selective sweep. Haplotype analysis also revealed ethnicity-specific differences. Additionally, we observed significant deviations from Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct European cohorts; HWE deviation depends on sex (only females are in disequilibrium), and genotypes displaying maximum and minimum relative fitness differ across population samples, suggesting a complex situation possibly involving epistasis or maternal selection. Overall, our data indicate that future association studies involving ADRB2 will benefit from taking into account ethnicity-specific haplotype distributions and sex-based effects. With respect to ADRB3, our data indicate that the gene has been subjected to a selective sweep in African populations, the Trp64 variant possibly representing the selection target. Given the previous association of the ancestral ADRB3 Arg64 allele with obesity and type 2 diabetes, dietary adaptations might represent the underlying selective force.
... ADRB2 is an intron-less gene located on chromosome 5q31-32, which is of particular interest due to its impact on the genetic risk for several common illnesses, including obesity, asthma, and cardiovascular disease [13][14][15]. Notably, ADRB2 shows great interpopulation variability in allele frequencies [16,17]. Since ADRB2 may have been subjected to balancing selection during human evolution, it is a particularly interesting candidate for evaluating how the genetic structure of a population affects the inter-individual differences in susceptibility to chronic degenerative diseases and response to therapeutic drugs [17,18]. ...
... Notably, ADRB2 shows great interpopulation variability in allele frequencies [16,17]. Since ADRB2 may have been subjected to balancing selection during human evolution, it is a particularly interesting candidate for evaluating how the genetic structure of a population affects the inter-individual differences in susceptibility to chronic degenerative diseases and response to therapeutic drugs [17,18]. ...
... It is well known that MA individuals have contributed along with Caucasian and, to a lesser extent, African individual towards the generation of the current MEZ population in Mexico, with a gradient of Caucasian ancestry decreasing from North to South [3,4]. Many reports of European, African, and Asian populations suggest that ADRB2 has been subjected to either balancing selection or a selective sweep [17,18]. However, the Glu27 (G) allele of rs1042714, which is almost absent among MAs but carried at a high frequency among Europeans, may have been enriched in our population at the time that Spanish people colonized Mexico. ...
The Mexican population is characterized by high and particular admixture, and the picture of variants associated with disease remains unclear. Here we investigated the distribution of single nucleotide polymorphisms (SNPs) in the Mexican population. We focused on two non-synonymous and three synonymous SNPs in the beta-2 adrenergic receptor gene (ADRB2), which plays key roles in energy balance regulation. These SNPs were genotyped in 2,011 Mexican Amerindians (MAs) belonging to 62 ethnic groups and in 1,980 geographically matched Mexican Mestizos (MEZs). The frequency distribution of all five ADRB2 variants significantly differed between MAs, MEZs, and other continental populations (CPs) from the 1000 Genomes database. Allele frequencies of the three synonymous SNPs rs1042717A, rs1042718A, and rs1042719C were significantly higher in Mexican individuals, particularly among MAs, compared to in the other analyzed populations (P
... From the analysis of nucleotide sequences of a chimpanzee and haplotypes of ADRB2 and ADRB3 in humans, it was proved that Gly16, Glu27, and Thr164 in ADRB2 and Arg64 in ADRB3 are ancient types. In ADRB2, substitution of the energy-expense type, Gly16:Gln27 (GC haplotype), for Gly16:Glu27 (GG haplotype) occurred first 1.9 million years ago (Ma), then substitution Arg16:Gln27 (AC haplotype) occurred, and then there was recombination between some GG and AC haplotypes [27,28]. Little information has been accumulated about alleles of ADRB2 or ADRB3 in NHP, except for the determination of the Arg64 type in fifteen obese M. mulatta [29]. ...
... As the Gln27 allele of ADRB2 and the Trp64 allele of ADRB3 are found all over the world in human populations, these alleles might have appeared before the migration out of Africa and now be present in many populations. Cagliani et al. [27,28] and Wilson et al. [28] speculated that the divergence occurred around 1.9 MYA and that, from Fisher's exact test of ADRB2, this gene may be associated with balancing selection or relaxed constraint. The lipolysis activity of ADRB3 with the Trp64 allele is higher than that with Arg64. ...
... The brown adipose tissue expresses UCP1 and might be able to produce heat. Fortunately, there was a mutation of ADRB2 from a thrifty type to an energy expense type 1.9 MYA [27,28] . Noradrenaline from the sympathetic nervous system is secreted by cold stimulation and produces much more heat through the Gln27 allele of ADRB2 and the Trp64 allele of ADRB3, which helps maintenance of body temperature of Homo erectus more than the Glu27 allele or the Arg64 allele. ...
Adrenergic-receptor beta2 (ADRB2) and beta3 (ADRB3) are obesity genes that play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. The Glu27 allele in ADRB2 and the Arg64 allele in ADRB3 are associated with abdominal obesity and early onset of non-insulin-dependent diabetes mellitus (NIDDM) in many ethnic groups. Peroxisome proliferator-activated receptor γ (PPARG) is required for adipocyte differentiation. Pro12Ala mutation decreases PPARG activity and resistance to NIDDM. In humans, energy-expense alleles, Gln27 in ADRB2 and Trp64 in ADRB3, are at higher frequencies than Glu27 and Arg64, respectively, but Ala12 in PPARG is at lower frequency than Pro12. Adaptation of humans for lipolysis, thermogenesis, and reduction of fat accumulation could be considered by examining which alleles in these genes are dominant in non-human primates (NHP). All NHP (P. troglodytes, G. gorilla, P. pygmaeus, H. agilis and macaques) had energy-thrifty alleles, Gly16 and Glu27 in ADRB2, and Arg64 in ADRB3, but did not have energy-expense alleles, Arg16, Gln27 and Trp64 alleles. In PPARG gene, all NHP had large adipocyte accumulating type, the Pro12 allele.
Conclusions
These results indicate that a tendency to produce much more heat through the energy-expense alleles developed only in humans, who left tropical rainforests for savanna and developed new features in their heat-regulation systems, such as reduction of body hair and increased evaporation of water, and might have helped the protection of entrails from cold at night, especially in glacial periods.
... Cagliani et al. [40] concluded that the structure of the ADRB2 haplotypes warranted the need for association studies and that these studies would benefit from identification of an ethnic-specific haplotype. This recommendation was based on evidence for ethnic-specific differences among five human populations from the National Institute of Environmental Health Sciences (NIEHS) SNPs Program [40]. ...
... Cagliani et al. [40] concluded that the structure of the ADRB2 haplotypes warranted the need for association studies and that these studies would benefit from identification of an ethnic-specific haplotype. This recommendation was based on evidence for ethnic-specific differences among five human populations from the National Institute of Environmental Health Sciences (NIEHS) SNPs Program [40]. Subsequently, we constructed haplotypes and tested associations and modifications of breast cancer risk and found ethnic differences. ...
... Subsequently, we constructed haplotypes and tested associations and modifications of breast cancer risk and found ethnic differences. The complexity of the ADRB2-inferred haplotypes could be attributed to either the gene having been subjected to balancing selection or having undergone a selective sweep [40]. ...
Polymorphisms in the beta-2-adrenergic receptor (ADRB2) gene have been studied in relation to risk of type 2 diabetes and obesity, risk factors that have received increased attention in relation to breast cancer. We evaluated the hypothesis that ADRB2 variants (rs1042713, rs1042714) are associated with breast cancer risk in non-Hispanic white (NHW) and Hispanic (H) women using data from a population-based case-control study conducted in the southwestern United States.
Data on lifestyle and medical history, and blood samples, were collected during in-person interviews for incident primary breast cancer cases (1,244 NHW, 606 H) and controls (1,330 NHW, 728 H). ADRB2 genotypes for rs1042713(G/A) and rs1042714(G/C) were determined using TaqMan assays. The associations of each variant and corresponding haplotypes with breast cancer were estimated using multivariable logistic regression.
Two copies compared to one or zero copies of the ADRB2 G-G haplotype were associated with increased breast cancer risk for NHW women [odds ratio (OR), 1.95; 95 % confidence interval (95 % CI), 1.26-3.01], but with reduced risk for H women [OR, 0.74; 95 % CI, 0.50-1.09]. Effect estimates were strengthened for women with a body mass index (BMI) ≥25 kg/m(2) [H: OR, 0.50; 95 % CI, 0.31-0.82; NHW: OR, 3.85; 95 % CI, 1.88-7.88] and for H women with a history of diabetes [H: OR, 0.32; 95 % CI, 0.12-0.89].
These data suggest that ethnicity modifies the association between the ADRB2 G-G haplotype and breast cancer risk, and being overweight or obese enhances the divergence of risk between H and NHW women.
... There is also evidence of favorable selection of ADRB2 variants due to the effect on Plasmodium falciparum infection, which has strong selective pressures on humans. 4 Genetic factors are essential for both asthma and obesity. Family and twin studies confirmed that body-mass index (BMI) is heritable in 40%-70% of individuals. ...
... According to the study by Wang et al., 28 the most common haplotypes are Arg19/Gly16/Glu27, Cys19/Gly16/Gln27, and Cys19/Arg16/Gln27. In a study by Cagliani et al., 4 dominant clades were indentified: Gly16/Gln27 Ha, Arg16Gln27 Hb, Arg16Gln27 Hc1, and Gly16/Glu27 Hc2. In a HuGE 29 review, Arg16/Gln27 was the most common haplotype in both the control and asthma group. ...
The goal of this review was to evaluate the association of β2-adrenergic receptor (ADRB2) gene polymorphisms with asthma and obesity. Asthma is the most common pediatric inflammatory disorder. The prevalence, severity, and hospitalization index for asthma have increased markedly in the last several decades. Interestingly, asthma is often diagnosed along with obesity. Genetic factors are essential for both conditions, and some of the candidate pleiotropic genes thought to be involved in the development of these diseases are ADRB2, vitamin D receptor (VDR), leptin (LEP), protein kinase C alpha (PRKCA), and tumor necrosis factor alpha (TNFα). The ADRB2 has been studied in multiple populations and more than 80 polymorphisms, mainly single-nucleotide polymorphisms, have been identified. For nonsynonymous Arg16Gly, Gln27Glu, and Thr164Ile, functional effects have been shown. In vivo, these polymorphisms have been evaluated to determine their association with both obesity and asthma, but the results are inconsistent and depend on the population studied or how the disease was defined. Currently, there are only few reports describing the genetic background for the comorbidity of asthma and obesity.
... There are nonsynonymous polymorphisms within ADRB2. Three such examples are found at nucleotide 46 G/A in the coding region, which alters Gly16Arg, at nucleotide 79 C/G, which alters Gln27Glu, and at nucleotide 491 C/T, which alters Thr164Ile [18][19][20]. Nucleotide 46 G/A corresponds to amino acid 16 Gly/Arg, and nucleotide 79 C/G corresponds to amino acid 27 Gln/Glu (Table 1). ...
Background
Upon activation, helper T (Th) cells produce cytokines such as IL-17A and IFNγ, which may exacerbate inflammatory disease and disorders. Adrenergic drugs are emerging as immunomodulatory agents to treat pro-inflammatory diseases, but their function is not completely understood. Th Cells express the β2-adrenergic receptor (β2AR) that is encoded by ADRB2. Agonists of the β2AR decrease IFNγ but can increase IL-17A from Th cells. We compared a β2AR agonist to an inverse-agonist, and assessed the influence of ADRB2 polymorphisms on IL-17A and IFNγ responses.
Methods
Peripheral blood mononuclear cells (PBMCs) from venous blood of healthy human participants were cultured with T cell activators anti-CD3 and anti-CD28 antibodies. Terbutaline, a β2AR agonist or nebivolol, a β1AR antagonist and β2AR inverse-agonist, were added in vitro. Cytokines IL-17A and IFNγ were measured using enzyme-linked immunosorbent assay. Genomic ADRB2 and its immediate upstream region were sequenced using Sanger's method. Cytokine response to drug was analyzed based on ADRB2 polymorphisms.
Results
Terbutaline consistently inhibited IFNγ from activated PBMC samples. In contrast, it increased IL-17A in PBMC homozygous for Gly16 codon of ADRB2. Nebivolol inhibited IL-17A and IFNγ from activated Th cells. When applied to activated-PBMCs, nebivolol inhibited IL-17A but did not significantly inhibit IFNγ although a trend was observed. The ability of nebivolol to inhibit IL-17A was attenuated by a β2AR-specific antagonist. Cellular proliferation and viability was not significantly changed by nebivolol. Nebivolol suppressed IL-17A in all of the samples regardless of ADRB2 polymorphisms.
Conclusions
This data demonstrates that terbutaline inhibited IFNγ, however, it increased IL-17A in samples with the common Gly16 polymorphism of ADRB2. Nebivolol inhibited IL-17A regardless of ADRB2 polymorphisms. Thus, nebivolol is a strong candidate for treating inflammatory diseases or disorders where IL-17A exacerbates symptoms.
... Of these, the polymorphisms in the beta adrenergic receptor (ADRB) might be one of the most promising connections. This is because genetic polymorphisms in ADRB genes have been linked to asthma [91], but there are a lot of variations between different populations [92]. Further mechanisms involved in this complex interplay among maternal asthma, risk of TTN and the subsequent development of asthma later in life in children needs to be explored further. ...
Transient tachypnea of newborn (TTN) results from failure of the newborn to effectively clear the fetal lung fluid soon after birth. TTN represents the most common etiology of respiratory distress in term gestation newborns and sometimes requires admission to the neonatal intensive care unit. TTN can lead to maternal-infant separation, the need for respiratory support, extended unnecessary exposure to antibiotics and prolonged hospital stays. Recent evidence also suggests that TTN may be associated with wheezing syndromes later in childhood. New imaging modalities such as lung ultrasound can help in the diagnosis of TTN and early management with distending pressure using continuous positive airway pressure may prevent exacerbation of respiratory distress.
... Yes (Cagliani et al. 2009) Content courtesy of Springer Nature, terms of use apply. Rights reserved. ...
Between the 1930s and 1950s, scientists developed key principles of population genetics to try and explain the aging process. Almost a century later, these aging theories, including antagonistic pleiotropy and mutation accumulation, have been experimentally validated in animals. Although the theories have been much harder to test in humans despite research dating back to the 1970s, recent research is closing this evidence gap. Here we examine the strength of evidence for antagonistic pleiotropy in humans, one of the leading evolutionary explanations for the retention of genetic risk variation for non-communicable diseases. We discuss the analytical tools and types of data that are used to test for patterns of antagonistic pleiotropy and provide a primer of evolutionary theory on types of selection as a guide for understanding this mechanism and how it may manifest in other diseases. We find an abundance of non-experimental evidence for antagonistic pleiotropy in many diseases. In some cases, several studies have independently found corroborating evidence for this mechanism in the same or related sets of diseases including cancer and neurodegenerative diseases. Recent studies also suggest antagonistic pleiotropy may be involved in cardiovascular disease and diabetes. There are also compelling examples of disease risk variants that confer fitness benefits ranging from resistance to other diseases or survival in extreme environments. This provides increasingly strong support for the theory that antagonistic pleiotropic variants have enabled improved fitness but have been traded for higher burden of disease later in life. Future research in this field is required to better understand how this mechanism influences contemporary disease and possible consequences for their treatment.
... 52 In particular, it has been suggested that alleles responsible for T2DM might have evolved as ''thrifty'' variants in ancient populations. 52 In this context, Cagliani et al. 53 showed that the ADRB3 gene has been subjected to a significant selective sweep in African populations and that the Trp64 allele probably represents the selection target. Therefore, we hypothesized that the association between the ADRB3 Trp64Arg polymorphism and overweight/obesity might also be explained by the ''thrifty genotype'' theory, with the Trp64 allele possibly being a thrifty variant associated with increased fat accumulation during human evolution. ...
Background:
We investigated whether the -3826A/G polymorphism (rs1800592) of the uncoupling protein 1 gene (UCP1) and the Trp64Arg polymorphism (rs4994) of the β3-adrenergic receptor gene (ADRB3) are associated with type 2 diabetes mellitus (T2DM) and features of metabolic syndrome in a Brazilian-Caucasian population.
Methods:
Both polymorphisms were genotyped in 1015 T2DM patients and 561 nondiabetic subjects. The combined effect of both polymorphisms on T2DM and metabolic syndrome-related parameters was analyzed according to a triallelic inheritance pattern, by which at least three minor alleles from two loci are necessary for trait manifestation.
Results:
UCP1 -3826A/G and ADRB3 Trp64Arg polymorphisms were not associated with T2DM (P>0.05). Patients carrying the ADRB3 64Arg allele had higher fasting plasma glucose and high-density lipoprotein cholesterol (HDL-C) than patients with the Trp64Trp genotype (P=0.0001 and P=0.015, respectively). The 64Arg allele was also associated with protection against overweight/obesity (body mass index ≥ 25 kg/m(2); odds ratio [OR]=0.598; P=0.014). Interestingly, prevalence of overweight/obesity was lower among carriers of at least three minor alleles of the -3826A/G and ADRB3 Trp64Arg polymorphisms than among patients with fewer than three minor alleles (54.5% vs. 79.1%; OR=0.288; P=0.007, respectively). Subjects with at least three minor alleles also had higher HDL-C levels (P=0.018).
Conclusions:
UCP1 -3826A/G and ADRB3 Trp64Arg polymorphisms may have a combined effect in the modulation of overweight/obesity and HDL-C levels in type 2 diabetes mellitus (T2DM) Caucasian-Brazilian patients.
... 16 However, it has been demonstrated that this typically occurs in several European populations, suggesting this variant is subject to selective forces, such as parental selection or epistasis, leading to oscillations in genotype frequencies. 36 Therefore, considering all the above explanations, although preliminary, this result should be taken into account and be further validated in an independent sample. ...
The variability in the antipsychotic response is, to some extent, genetically determined. Several studies have attempted to establish a role for genetic variation in genes coding pharmacokinetic and pharmacodynamic targets, but to date, no definite genetic predictive marker has been identified. We aimed to explore the putative role of 19 genetic variants and risperidone clinical improvement in 76 White schizophrenic inpatients, measured as change in Positive and Negative Syndrome Scale (PANSS). CYP2D6 poor metabolism was significantly associated with greater clinical improvement in total PANSS and a trend was also found for MDR1 3435C>T to higher total PANSS scores in 3435T carriers. This study suggests the importance that genetic variability on pharmacokinetic factors may have in risperidone response and gives evidence for the need for further investigation in order to establish the actual predictive value and clinical utility that CYP2D6 genotyping might have in risperidone therapy management.
... The adrenergic b-2 receptor gene (ADRB2) is widely expressed in the brain where it plays many roles including signal transduction of adrenaline, noradrenaline and to a lesser extent dopamine (Brodde 2008; Dohlman et al. 1991). Two single nucleotide polymorphisms (SNPs), rs1042713 which causes an arg16gly amino acid substitution , and rs1042714 which causes a gln27glu amino acid substitution, affect adrenergic receptor sensitivity (Cagliani et al. 2009). Arg16gly and gln27glu polymorphisms have been significantly associated at p \ 0.05 (hereafter simply 'associated') with increased risk of neurodevelopmental disorder (Cheslack-Postova et al. 2007) and, separately, with differences in cardiovascular phenotypes such as diastolic blood pressure (Snieder et al. 2002). ...
The non-synonymous mutations arg16gly (rs1042713) and gln27glu (rs1042714) in the adrenergic β-2 receptor gene (ADRB2) have been associated with cognitive function and brain white matter integrity. The current study aimed to replicate these findings and expand them to a broader range of cognitive and brain phenotypes. The sample used is a community-dwelling group of older people, the Lothian Birth Cohort 1936. They had been assessed cognitively at age 11 years, and undertook further cognitive assessments and brain diffusion MRI tractography in older age. The sample size range for cognitive function variables was N = 686-765, and for neuroimaging variables was N = 488-587. Previously-reported findings with these genetic variants did not replicate in this cohort. Novel, nominally significant associations were observed; notably, the integrity of the left arcuate fasciculus mediated the association between rs1042714 and the Digit Symbol Coding test of information processing speed. No significant associations of cognitive and brain phenotypes with ADRB2 variants survived correction for false discovery rate. Previous findings may therefore have been subject to type 1 error. Further study into links between ADRB2, cognitive function and brain white matter integrity is required.
... However, such antagonistic pleiotropic trade-offs tend to be evolutionarily unstable in the long run (Roff and Fairbairn 2007), and this might imply that the effects of the rs1042714 polymorphism that we found in a Scottish population do not replicate in other populations because this locus might already be close to fixation in some (see Penke et al. 2007a, b). This is also in line with a recent molecular population genetic study that suggests ADRB2 is either under balancing selection or in the midst of a recent selective sweep (Cagliani et al. 2009). Indeed, Bochdanovits et al. (2009) found the rs1042714 SNP to be out of Hardy-Weinberg equilibrium in two Dutch populations, and the derived C allele has already reached 88.2% prevalence in Han Chinese, 91.0% prevalence in North American Na-Dene Indians, and fixation in South American Quechua people (Kidd 2009). ...
It has recently been reported that the evolu-tionarily ancestral alleles of two functional polymorphisms in the b 2 -adrenergic receptor gene (ADRB2) were related to higher cognitive ability in the 70 year old participants of the Lothian Birth Cohort 1936 (LBC1936). One emerging important factor in cognitive aging is the integrity of white matter tracts in the brain. Here, we used diffusion tensor MRI-based tractography to assess the integrity of eight white matter tracts in a subsample of the LBC1936. Higher integrity of the splenium of the corpus callosum predicted better cognitive ability in old age, even after controlling for IQ at age 11. Also, the ancestral allele of one ADRB2 SNP was associated with both splenium integrity and better cognitive aging. While the effects of the SNP and splenium integrity on cognitive aging were largely independent, there was some evidence for a partial mediation effect of ADRB2 status via splenium integrity.
... Polymorphisms in several well-studied human genes provide putative examples of evolutionary genetic tradeoffs involving risk of polygenic disease. For example, (i) the Arg72Pro polymorphism in the tumor suppressor gene TP53 engenders lower fertility, but enhanced survival of individuals with the Pro allele (Ørsted et al. 2007;Kang et al. 2009); (ii) APOE gene E4 carriers have been shown in replicated studies to exhibit better verbal skills than individuals with alleles E3 or E2 when young, but higher risk of Alzheimer's and schizophrenia when older (Xu et al. 2006;Alexander et al. 2007;Akanji et al. 2009); and (iii) antagonistically pleiotropic, age-related effects of the Arg16Gly and Gln27Glu polymorphisms of the ADRB2 gene have been demonstrated for measures of cognition and age-related disease (Bochdanovits et al. 2009;Cagliani et al. 2009;Kulminski et al. 2010). These studies suggest that balanced polymorphisms may commonly be maintained under life history tradeoffs, with each allele providing benefits in the context of one component of fitness but costs, often expressed as disease, in the context of another. ...
In this review, I describe how evolutionary genomics is uniquely suited to spearhead advances in understanding human disease risk, owing to the privileged position of genes as fundamental causes of phenotypic variation, and the ability of population genetic and phylogenetic methods to robustly infer processes of natural selection, drift, and mutation from genetic variation at the levels of family, population, species, and clade. I first provide an overview of models for the origins and maintenance of genetically based disease risk in humans. I then discuss how analyses of genetic disease risk can be dovetailed with studies of positive and balancing selection, to evaluate the degree to which the ‘genes that make us human’ also represent the genes that mediate risk of polygenic disease. Finally, I present four basic principles for the nascent field of human evolutionary medical genomics, each of which represents a process that is nonintuitive from a proximate perspective. Joint consideration of these principles compels novel forms of interdisciplinary analyses, most notably studies that (i) analyze tradeoffs at the level of molecular genetics, and (ii) identify genetic variants that are derived in the human lineage or in specific populations, and then compare individuals with derived versus ancestral alleles.
... The multilocus Hudson-Kreitman-Aguade (HKA) test was performed using the ''HKA'' software distributed by Jody Hey, as previously proposed (Cagliani et al. 2009). Briefly, 16 reference loci were randomly selected among NIEHS loci shorter than 20 kb that have been resequenced in the three populations; the only criterion was that Tajima's D did not suggest the action of natural selection (i.e., Tajima's D is higher than the 5th and lower than the 95th percentiles in the distribution of NIEHS genes). ...
The CPB2 gene encodes thrombin-activatable fibrinolysis inhibitor (TAFI), a hepatically secreted zymogen acting as a molecular link among coagulation, fibrinolysis, and inflammation. Variants in CPB2 have been associated with several human conditions. We resequenced and analyzed the two regions carrying previously known nonsynonimous single-nucleotide polymorphisms (Ala147Thr and Ile325Thr) and variants affecting transcript stability. Our data indicate that whereas the gene portion extending from exon 9 to the 3′ untranslated region fits a model of neutral evolution, variants in the region encompassing exons 6–7 have been maintained by balancing selection. Indeed, we verified that the region displays high nucleotide diversity, many intermediate frequency variants, and an excess of polymorphism compared with interspecific divergence. Consistently, haplotype analysis indicated the presence of two major haplotype clades separated by deep branches. Transcript analysis revealed that in both HepG2 cells and human liver samples, CPB2 exon 7 undergoes haplotype-preferential skipping. Therefore, we indicate that balancing selection has been maintaining functional variants that promote alternative exon 7 splicing. Although transcripts lacking exon 7 represent a minority of total CPB2 products, the effect on antifibrinolytic activity might be much greater as the intrinsic instability of TAFI is a major determinant of its antifibrinolytic potential.
These data highlight the contribution of population genetics approaches to the analysis of functional genetic variation and may orient further biochemical and genetics studies on the pathophysiolgic role of CPB2 gene products.
... However, such antagonistic pleiotropic trade-offs tend to be evolutionarily unstable in the long run (Roff and Fairbairn 2007), and this might imply that the effects of the rs1042714 polymorphism that we found in a Scottish population do not replicate in other populations because this locus might already be close to fixation in some (see Penke et al. 2007a, b). This is also in line with a recent molecular population genetic study that suggests ADRB2 is either under balancing selection or in the midst of a recent selective sweep (Cagliani et al. 2009). Indeed, Bochdanovits et al. (2009) found the rs1042714 SNP to be out of Hardy-Weinberg equilibrium in two Dutch populations, and the derived C allele has already reached 88.2% prevalence in Han Chinese, 91.0% prevalence in North American Na-Dene Indians, and fixation in South American Quechua people (Kidd 2009). ...
It has recently been reported that the evolutionarily ancestral alleles of two functional polymorphisms in the beta(2)-adrenergic receptor gene (ADRB2) were related to higher cognitive ability in the 70 year old participants of the Lothian Birth Cohort 1936 (LBC1936). One emerging important factor in cognitive aging is the integrity of white matter tracts in the brain. Here, we used diffusion tensor MRI-based tractography to assess the integrity of eight white matter tracts in a subsample of the LBC1936. Higher integrity of the splenium of the corpus callosum predicted better cognitive ability in old age, even after controlling for IQ at age 11. Also, the ancestral allele of one ADRB2 SNP was associated with both splenium integrity and better cognitive aging. While the effects of the SNP and splenium integrity on cognitive aging were largely independent, there was some evidence for a partial mediation effect of ADRB2 status via splenium integrity.
... Furthermore, these associations may also be specific to certain ethnicities and subject to sex effects. Cagliani et al. described ethnicity-specific and sex-based haplotype distributions of the ADRB2 variants [68]. Similar findings were reported in a meta-analysis by Jalba et al. which resulted in differences in association across populations [44]. ...
The beta2-adrenergic receptor (beta2-AR) is a member of the G-protein-coupled adrenergic receptor family with seven transmembrane segments. Similar to other members of this receptor family, beta2-AR specifically binds and is activated by the endogenous class of ligands known as catecholamines, and epinephrine in particular. The gene encoding this receptor, ADRB2, was cloned by Kobilka et al. in 1987 and is localized to chromosome 5q31–q32, a region that has been linked with asthma and asthma related phenotypes [1,2]. ADRB2 consists of a single exon of 2015 nucleotides, which encodes a 413 amino acid protein. This review highlights the genetic polymorphisms in ADRB2 and the pivotal role of beta2- AR in the regulation of the cardiac, pulmonary, vascular, endocrine, and central nervous systems.
ADRB2 is abundantly expressed in bronchial smooth muscle cells and activation of the resulting receptor leads to bronchodilation. In addition, this gene is expressed in cardiac myocytes and vascular smooth muscle cells. Activation of beta2-AR in these cells causes an increase in the rate and force of heart contractions. Intracellular signaling upon beta2-AR activation is largely affected through a trimer of G proteins coupled to adenylate cyclase, to produce cyclic adenosine monophosphate. This, in turn, activates protein kinase A, leading to the phosphorylation and down-regulation of proteins including beta2-AR itself (please refer to PharmGKB β-agonist and β-blocker Pathway for further details: https://www.pharmgkb.org/do/serve?objId=PA2024&objCls=Pathway#).
Beta2-AR is the target of clinically important drugs for asthma and cardiovascular conditions including hypertension and congestive heart failure (CHF). Beta-receptor agonists (e.g. albuterol, salmeterol) and antagonists (e.g. carvedilol and propranolol) are among the most commonly prescribed medications in the treatment of asthma and cardiovascular disease, respectively. Although some beta-blockers are ‘selective’ for the beta1-AR (e.g. metoprolol and atenolol), these also antagonize the beta2-AR at higher concentrations. A number of genetic polymorphisms in the ADRB2 gene have been described which affect gene expression, the function of the resulting receptor, and response to beta2-agonists.
Adrenaline and noradrenaline, released as hormones and/or neurotransmitters, exert diverse physiological functions in vertebrates, and teleost fishes are widely used as model organisms to study adrenergic regulation; however, such investigations often rely on receptor subtype-specific pharmacological agents (agonists and antagonists; see Glossary) developed and validated in mammals. Meanwhile, evolutionary (phylogenetic and comparative genomic) studies have begun to unravel the diversification of adrenergic receptors (ARs) and reveal that whole-genome duplications and pseudogenization events in fishes results in notable distinctions from mammals in their genomic repertoire of ARs, while lineage-specific gene losses within teleosts have generated significant interspecific variability. In this Review, we visit the evolutionary history of ARs (including α1-, α2- and β-ARs) to highlight the prominent interspecific differences in teleosts, as well as between teleosts and other vertebrates. We also show that structural modelling of teleost ARs predicts differences in ligand binding affinity compared with mammalian orthologs. To emphasize the difficulty of studying the roles of different AR subtypes in fish, we collate examples from the literature of fish ARs behaving atypically compared with standard mammalian pharmacology. Thereafter, we focus on specific case studies of the liver, heart and red blood cells, where our understanding of AR expression has benefited from combining pharmacological approaches with molecular genetics. Finally, we briefly discuss the ongoing advances in ‘omics’ technologies that, alongside classical pharmacology, will provide abundant opportunities to further explore adrenergic signalling in teleosts.
Background:
Technical capabilities have significant discriminative and prognostic power in youth football. Although, many factors influence technical performance, no research has explored the genetic contribution. As such, the purpose of this study was to examine the association of several single nucleotide polymorphisms (SNPs) with technical assessments in youth football players.
Methods:
Fifty-three male under-13 to under-18 outfield football players from two Category 3 English academies were genotyped for eight SNPs. Objective and subjective technical performance scores in dribbling, passing, and shooting were collated. Simple linear regression was used to analyse individual SNP associations each variable, whereas both unweighted and weighted total genotype scores (TGSs; TWGSs) were computed to measure the combined influence of all SNPs.
Results:
In isolation, the ADBR2 (rs1042714) C allele, BDNF (rs6265) C/C genotype, DBH (rs1611115) C/C genotype, and DRD1 (rs4532) C allele were associated with superior (8-10%) objective dribbling and/or shooting performance. The TGSs and/or TWGSs were significantly correlated with each technical assessment (except subjective passing), explaining up to 36% and 40% of the variance in the objective and subjective assessments, respectively.
Conclusions:
The results of this study suggest inter-individual genetic variation may influence the technical capabilities of youth football players and proposes several candidate SNPs that warrant further investigation.
This article discusses issues related to the role of polymorphism of the ADRB2 gene encoding β2-adrenergic receptor in preterm labor and tocolysis. Information is provided on scientific studies related to the search for associations of the carriage of alleles and genotypes of ADRB2 with the preterm labor, as well as with the pharmacological response to tocolytic therapy using β2-adrenergic agonists. The history of the discovery of the relationship of ADRB2 gene polymorphisms with preterm labor is presented in chronological order. As scientific facts emerge, researchers are faced with the question: how can ADRB2 gene polymorphisms affect physiological processes? That is, whether they affect by changing the primary structure of the receptor or by changing the level of expression. Depending on the answer to this question, pharmacogenetics are faced with a further task: what to study - individual polymorphisms or haplotypes?
Das Kapitel soll einen Überblick über die Genetik gesundheitsbezogener Fitness einschließlich körperlicher Leistungsfähigkeit und Training aufzeigen. Hierbei werden die neuesten und wichtigsten Erkenntnisse zusammengefasst und ein Ausblick in die Zukunft geben. Ein Großteil der genetischen Daten basiert auf Forschungsergebnissen aus Untersuchungen zu Volkskrankheiten wie Adipositas und Diabetes mellitus Typ 2. Zusätzlich werden die Daten aus den leistungssportassoziierten Untersuchungen zusammengefasst und gewertet. Zahlreiche autosomale mitochondriale Gene mit Assoziation zur körperlichen Leistungsfähigkeit und gesundheitsbezogenen Fitness werden diskutiert. Allerdings muss berücksichtigt werden, dass die Mehrzahl der genetischen Erkenntnisse aktuell noch auf relativ kleinen Stichproben basiert und daher differenziert zu interpretieren ist.
Severe forms of malaria in humans is caused by Plasmodium falciparum and Plasmodium vivax.Malaria infection is the results of complex membrane sorting and signaling. Erythrocyte membrane lipid rafts proteins regulate membrane sorting and signaling processes and hence lipid raft proteins (Gαs and β2AR) and the interacting proteins (ADORA2A and GRK5) can influence pathogen entry and consequently the erythrocyte phase of the infection that is crucial to the pathogenesis of malaria. It is also known that the entry of malaria parasite in patients induces the synthesis of inflammatory cytokines such as TNF-a, IL-1, IL-6 and IL-10 and altered gene expression known to be regulated by epigenetic mechanisms. We demonstrated that malaria susceptibility or its severity may be influenced by the SNPs in GNAS, ADRB2, ADORA2A, GRK5and ABCB1genes; and epigenetic changes at the critical CpG sites in the promoter region of ABCB1and ADRB2genes. We also showed that global DNA methylation variants could discriminate the malaria phenotypes. Our study provides evidence for the proposed role of host genes mediated mechanisms in the etiology of malaria susceptibility. For the effective control of malaria, the development of sensitive, accurate and rapid assay is essential. We developed the single-step amplification and non-amplification based assays with better sensitivity than existing assays.
Thesis link: http://hdl.handle.net/10603/148259
β2-Adrenergic receptor (β2-AR) plays a crucial role in asthma pathophysiology by regulating, processes of the lung function, and clinical response to bronchodilators. The +46G>A- Gly16Arg polymorphism in the gene encoding β2 adrenergic receptor (ADRB2) has been associated with receptor non-responsiveness after β2-agonist exposure. In the present study, we sought to evaluate the possible association of Gly16Arg polymorphism with asthma susceptibility, pharmacogenetic response to Salbutamol, and varying degrees of disease severity. Three hundred ninety-eight clinically diagnosed patients and 456 healthy controls were enrolled for the study. Patients were classified into severity classes according to Global Initiative for Asthma guidelines. To assess bronchodilator response, spirometry was performed before and 15 min after Salbutamol (200 μg) delivery. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12 % in them, while those showing reversibility less than 12 % were classified as non-responders. Genotyping was carried out by ARMS-PCR technique. Statistical methods were applied to test for the significance of the results. In the present study, there was lack of significant association of polymorphism with disease susceptibility as well as with bronchodilator response. The polymorphism was not associated with mild and moderate asthma subtypes; however, there was a notable association with severe asthma subtype. In addition, the polymorphism was associated with severe asthma compared to subtypes of mild and moderate asthma combined. In a South Indian population, the ADRB2 Arg/Gly may not form a susceptible variant to develop asthma nor can be a standard predictive marker to bronchodilator response; nevertheless, the patterns in asthma severity can be predicted by analyzing this variant.
Background and objectives:
Polymorphisms of beta2-adrenergic receptor gene (ADRB2) are clinically relevant for several reasons, including as a risk factor for asthma development/severity and predicting the effectiveness of treatment with beta2-agonists in reducing asthma symptoms. The aim of this study was to examine the association between ADRB2 gene polymorphisms and asthma in the Serbian population, and to evaluate the therapeutic response in relation to the ADRB2 genotype.
Methods:
The study included 171 patients with asthma and 101 healthy subjects as the control group. Genotyping of Arg16Gly and Gln27Glu polymorphisms was performed by direct sequencing of polymerase chain reaction (PCR) products.
Results:
In Serbian adults, carriers of the 27Gln allele and 27Gln/Gln genotype were at higher risk of asthma [odds ratio (OR) 2.5, 95% confidence interval (CI) 1.6-3.8, and OR 3.00, 95% CI 1.7-5.3, respectively], while the presence of the 27Glu allele and 27Gln/Glu genotype were found to be protective of asthma (OR 0.4, 95% CI 0.3-0.6, and OR 0.3, 95% CI 0.1-0.7, respectively). Furthermore, we found that the presence of the 27Gln allele in asthmatics younger than 50 years leads to a better response to therapy with long-acting beta2-agonists (LABA) in combination with prevailing low and moderate doses of inhaled corticosteroids (ICS), while carriers of the 27Glu allele over 50 years old are more likely to respond to LABA + ICS therapy.
Conclusion:
We identified that in Serbian adults the 27Gln allele and 27Gln homozygosity are risk factors for asthma, which may be of clinical interest in disease prevention. The finding that younger carriers of the 27Gln allele respond better to LABA + ICS therapy may be utilized in personalized asthma treatment.
The essential route to blood parasitaemia in malaria, erythrocyte invasion is facilitated by activation of the G-protein coupled receptor signaling pathway mediated by the β2-adrenoreceptor as one of the proteins on the surface of red blood cells. The effectiveness of bronchodilators and inhaled corticosteroids in the clinical treatment for asthma patients also depend on polymorphisms in the β2-adrenoreceptor gene (ADRB2). In a case control study, individuals affected by Plasmodium falciparum malaria, asthma and controls were tested for association of six ADRB2 single nucleotide polymorphisms (SNPs) viz. rs1042711, rs1801704, rs1042713, rs1042714, rs1042717 and rs1042718, by direct DNA sequencing. The rs1801704 locus was significantly associated with malaria when compared against controls. The rs1042713 polymorphism was associated with forced expiratory flow between 25-75% of the FVC in asthma patients, pre (p = 0.048) and post (p = 0.038) treatment measurements. Predicted haplotype of the six SNPs computed from genotype data showed T-T-A-C-G-C conferred significant risk of malaria (p = 0.02) whereas T-T-A-C-G-A was associated with risk of asthma (p = 0.02). The haplotype T-T-G-C-G-C was protective against both malaria (p = 0.02) as well as asthma (p = 0.026) and C-C-G-G-G-C was protective uniquely for asthma (p = 0.04). A significant outcome was that all variant alleles at the SNP loci were part of the haplotype conferring resistance to malaria disease and asthma, except rs1042713 and rs1042718 which showed very high frequency in asthma. The pairwise linkage disequilibrium (LD) estimates showed a distinct LD block of all SNP loci (D'=1 or > 0.8) in malaria patients. This characteristic haplotype block was disrupted in the controls due to non-significant pairwise LD of the SNP loci; and a more extensive disruption of the block was noted in asthma patients. The study provides evidence for the proposed role of β2-adrenoreceptor mediated molecular mechanisms in etiology of malaria, as well as asthma disease and drug response, for further clinical and therapeutic application studies.
Porcine adrenergic receptor beta 2 (ADRB2) gene exhibits differential allelic expression in skeletal muscle, and its genetic variation has been associated with muscle pH. Exploring the molecular-genetic background of expression variation for porcine ADRB2 will provide insight into the mechanisms driving its regulatory divergence and may also contribute to unraveling the genetic basis of muscle-related traits in pigs. In the present study, we therefore examined haplotype effects on the expression of porcine ADRB2 in four tissues: longissimus dorsi muscle, liver, subcutaneous fat, and spleen. The diversity and structure of haplotypes of the proximal gene region segregating in German commercial breeds were characterized. Seven haplotypes falling into three clades were identified. Two clades including five haplotypes most likely originated from introgression of Asian genetics during formation of modern breeds. Expression analyses revealed that the Asian-derived haplotypes increase expression of the porcine ADRB2 compared to the major, wild-type haplotype independently of tissue type. In addition, several tissue-specific differences in the expression of the Asian-derived haplotypes were found. Inspection of haplotype sequences showed that differentially expressed haplotypes exhibit polymorphisms in a polyguanine tract located in the core promoter region. These findings demonstrate that expression variation of the porcine ADRB2 has a complex genetic basis and suggest that the promoter polyguanine tract is causally involved. This study highlights the challenges of finding causal genetic variants underlying complex traits.
Many reports of genetic associations with health-related fitness phenotypes have been published over the past decade or so
but there has been limited progress in discovering and characterizing the genetic contribution to these phenotypes due to
few coordinated research efforts involving major funding initiatives/consortia and the use primarily of the candidate gene
approach. Hence, it is timely that exercise genetic research has moved into the genomics era with new approaches that involve
well-phenotyped, large cohorts, and genome-wide technologies: such approaches are now known to be required for meaningful
progress to be made with reference to clinical significance. This chapter summarizes the most recent and significant findings
from exercise genetics and explores future trends and possibilities.
KeywordsBody mass index-Coronary artery disease-Genome-wide association study-Knockout-Linkage disequilibrium-Maximal oxygen consumption (
[(V)\dot]O2max \dot{\rm V}{\rm O}_{2}\max
)-Odds ratio-Performance-associated polymorphism-Recombinant human erythropoietin-One-repetition maximum-Single nucleotide polymorphism-Triglyceride-Type 2 diabetes mellitus
There is significant evidence to suggest that psychological and stress-related factors are important predictors of the onset of chronic widespread pain (CWP) and fibromyalgia (FM). The hypothalamic-pituitary-adrenal axis, together with the efferent sympathetic/adrenomedullary system, influence all body organs (including muscles) during short- and long-term threatening stimuli. The aim of this study was to investigate the relationship between genetic variants in adrenergic candidate genes and chronic musculoskeletal complaints (MSCs) in adolescents.
Adolescents from the Western Australian Pregnancy (Raine) Cohort attending the 17-year cohort review completed a questionnaire containing a broad range of psychosocial factors and pain assessment (n = 1004). Blood samples were collected for DNA extraction and genotyping. Genotype data was obtained for 14 single nucleotide polymorphisms (SNPs) in two candidate genes - beta-2 adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT). Haplotypes were reconstructed for all individuals with genotype data.
Both female gender and poor mental health were associated with (1) an increased risk for chronic, disabling comorbid neck and low back pain (CDCP); and (2) an increase in the number of areas of pain. Of the 14 SNPs evaluated, only SNP rs2053044 (ADRB2, recessive model) displayed an association with CDCP [odds ratio (OR) = 2.49; 95% confidence interval (CI) = 1.25, 4.98; p = 0.01] and pain in three to four pain areas in the last month (OR = 1.86; 95% CI = 1.13, 3.06; p = 0.02). These data suggest that genetic variants in ADRB2 may be involved in chronic MSCs.
Risperidone non-compliance is often high due to undesirable side effects, whose development is in part genetically determined. Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results. Thus, the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment: sleepiness, weight gain, extrapyramidal symptoms and sexual adverse events. A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response. Presence of adverse events was the main variable and potential confounding factors were considered. Allele 16Gly of ADRB2 was significantly associated with a higher risk of sexual adverse events. There were other non-significant trends for DRD3 9Gly and SLC6A4 S alleles. Our results, although preliminary, provide new candidate variants of potential use in risperidone safety prediction.The Pharmacogenomics Journal advance online publication, 3 January 2012; doi:10.1038/tpj.2011.57.
Candidate gene and genome-wide association studies have led to the discovery of nine loci involved in Mendelian forms of obesity and 58 loci contributing to polygenic obesity. These loci explain a small fraction of the heritability for obesity and many genes remain to be discovered. However, efforts in obesity gene identification greatly modified our understanding of this disorder. In this review, we propose an overlook of major lessons learned from 15 years of research in the field of genetics and obesity. We comment on the existence of the genetic continuum between monogenic and polygenic forms of obesity that pinpoints the role of genes involved in the central regulation of food intake and genetic predisposition to obesity. We explain how the identification of novel obesity predisposing genes has clarified unsuspected biological pathways involved in the control of energy balance that have helped to understand past human history and to explore causality in epidemiology. We provide evidence that obesity predisposing genes interact with the environment and influence the response to treatment relevant to disease prediction.
Hepatic β-adrenergic receptors (β-ARs) play a pivotal role in mobilization of reserves via gluconeogenesis and glycogenolysis to supply the animal with its energy needs during decreased nutrient availability. Using a unique nutrient-deprived baboon model, we have demonstrated for the first time that immunoreactive hepatic β(1)- and β(2)-AR subtypes are regionally distributed and localized on cells around the central lobular vein in 0.5 and 0.9 gestation (G) fetuses of ad libitum fed control (CTR) and maternal nutrient restricted (MNR) mothers. Furthermore, MNR decreased fetal liver immunoreactive β(1)-AR and increased immunoreactive β(2)-AR at 0.5G. However, at 0.9G, immunohistochemistry and Western blot analysis revealed a decrease in β(1)-AR and no change in β(2)-AR levels. Thus, MNR in a nonhuman primate species has effects on hepatic β(1)- and β(2)-ARs that are receptor- and gestation stage-specific and may represent compensatory systems whose effects would increase glucose availability in the presence of nutrient deprivation.
Background: the association of single nucleotide polymorphisms (SNPs) of the adrenergic system with essential hypertension (EH) and with the blood pressure (BP) response to beta-blockers is debated. Aims: to analyse the association of haplotypes of the adrenergic system with EH and with the BP response to atenolol. Materials and Methods: in 1112 never treated EH patients and 203 normotensives, tightly linked single nucleotide polymorphisms (SNPs) of beta-adrenergic receptors (ADRB1--Ser49Gly and Arg389Gly--; ADRB2--Cys19Arg, Gly16Arg and Gln27Glu--) and G-protein beta3-subunit (GNB3-- A3882C, G5249A and C825T--) were genotyped (either PCR followed by RFLP or Realtime Taq-Man PCR). Association of haplotypes with EH and with the BP response to atenolol 50 mg b.i.d. in a subgroup of EH patients (n= 340) was evaluated (Haploview 3.2, Stata 9.2). Results: no SNPs or haplotypes were associated with EH. In females only, GNB3 SNPs and haplotypes were associated with the BP response (p<0.05). Conclusions: our study confirmed the sex-specific association of GNB3 with the BP response to atenolol with no substantial advantage of the analysis of haplotypes over SNPs.
To analyze the association of haplotypes of the adrenergic system with essential hypertension and with the blood pressure response to beta-blockers.
In 1112 never-treated essential hypertension patients and 203 normotensive controls, tightly linked SNPs of beta-adrenergic receptors (ADRB1 - Ser49Gly and Arg389Gly; ADRB2 - Cys19Arg, Gly16Arg and Gln27Glu) and the G-protein beta3-subunit (GNB3 - A3882C, G5249A and C825T) were genotyped. Association of haplotypes with essential hypertension and with the blood pressure response to atenolol 50 mg twice daily in a subgroup of essential hypertension patients (n = 340) was evaluated (Haploview 3.2).
No SNPs or haplotypes were associated with essential hypertension. In females only, GNB3 SNPs and haplotypes were associated with the blood pressure response (p < 0.05).
Our study confirmed the sex-specific association of GNB3 with the blood pressure response to atenolol with no substantial advantage of the analysis of haplotypes over SNPs.
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More than 1 in 10 adults in the general population experience chronic widespread body pain (CWP), which lies at one end of a continuous spectrum of pain ranging in both severity and duration. Neuroendocrine factors can modify the effect of known psychological and psychosocial risk factors for progression along the spectrum of pain and development of CWP, and genetic variants that affect neuroendocrine and neural processing potentially affect susceptibility to chronic pain development. We have examined variants across genes encoding the beta2-adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT) - key neuroendocrine signalling factors - in a large population-based sample to determine whether these may be involved in pain progression and CWP development. A nested association study was conducted using individuals from the 1958 British Birth Cohort Study who had been assessed for pain status. Genotypes were available for nine single nucleotide polymorphisms (SNPs) across ADRB2 and 11 SNPs across COMT. ADRB2 SNPs rs12654778 and rs1042713 were associated either with CWP alone (p=0.02 for both) or with position along pain spectrum (pain status; p=0.04). Common functional ADRB2 haplotype combinations were also associated with pain status (p(model)=0.002) and, further, with both extent and duration of pain (p(model)=0.003 and p(model)=0.002, respectively). There were no associations of either CWP or pain status with COMT genotypes or haplotypes. These results are the first to suggest that functional ADRB2 variants are involved in regulating pain status at a population level. A role for COMT in chronic pain development was not identified, though could not be excluded.
Because visceral obesity predicts insulin resistance, we studied whether alterations in the gene encoding for the beta 3-adrenergic receptor in visceral fat are associated with insulin resistance.
We studied the frequency of a cytosine-to-thymidine mutation that results in the replacement of tryptophan by arginine at position 64 (Trp64Arg) of the beta 3-adrenergic receptor by restriction-enzyme digestion with BstOl in 335 subjects from western Finland, 207 of whom were nondiabetic and 128 of whom had non-insulin-dependent diabetes mellitus (NIDDM). We also determined the frequency of the mutation in 156 subjects from southern Finland. Sensitivity to insulin was measured by the hyperinsulinemic-euglycemic clamp technique in 66 randomly selected nondiabetic subjects.
In the subjects from western Finland, the frequency of the mutated allele was similar in the nondiabetic subjects and the subjects with NIDDM (12 vs. 11 percent). The mean age of the subjects at the onset of diabetes was lower among those with the mutation than those without it (56 vs. 61 years, P = 0.04). Among the nondiabetic subjects, those with the mutation had a higher ratio of waist to hip circumference (P = 0.02), a greater increase in the serum insulin response after the oral administration of glucose (P = 0.05), a higher diastolic blood pressure (82 vs. 78 mm Hg, P = 0.01), and a lower rate of glucose disposal during the clamp study (5.3 vs. 6.5 mg [29 vs. 36 mumol] per kilogram of body weight per minute; P = 0.04) than the subjects without the mutated allele. In an analysis of sibling pairs, the siblings with the mutation generally had higher waist:hip ratios (P = 0.05) and higher responses of blood glucose and serum insulin after the oral administration of glucose than their siblings without the mutation (P = 0.02 and P = 0.005, respectively).
The Trp64Arg allele of the beta 3-adrenergic receptor is associated with abdominal obesity and resistance to insulin and may contribute to the early onset of NIDDM:
Inherited mutations in the gene BRCA2 predispose carriers to early onset breast cancer, but such mutations account for fewer than 2% of all cases in East Anglia. It is likely that low penetrance alleles explain the greater part of inherited susceptibility to breast cancer; polymorphic variants in strongly predisposing genes, such as BRCA2, are candidates for this role. BRCA2 is thought to be involved in DNA double strand break-repair1,
2. Few mice in which Brca2 is truncated survive to birth; of those that do, most are male, smaller than their normal littermates and have high cancer incidence3,
4. Here we show that a common human polymorphism (N372H) in exon 10 of BRCA2 confers an increased risk of breast cancer: the HH homozygotes have a 1.31-fold (95% CI, 1.07−1.61) greater risk than the NN group. Moreover, in normal female controls of all ages there is a significant deficiency of homozygotes compared with that expected from Hardy-Weinberg equilibrium, whereas in males there is an excess of homozygotes: the HH group has an estimated fitness of 0.82 in females and 1.38 in males. Therefore, this variant of BRCA2 appears also to affect fetal survival in a sex-dependent manner.
Surveys of protein-coding sequences for evidence of positive selection in humans and chimpanzees have flagged surprisingly few genes known to be involved in neural or nutritional processes, despite the pronounced differences between humans and chimpanzees in behavior, cognition, and diet. It may be that most such differences are due to changes in gene regulation rather than protein structure. Here, we present the first survey of promoter (5'-flanking) regions, which are rich in _cis_-regulatory sequences, for signatures of positive selection in humans. Our results indicate that positive selection has targeted the regulation of many genes known to be involved in neural development and function, both in the brain and elsewhere in the nervous system, and in nutrition, particularly glucose metabolism.
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant
role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook
a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS
and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of
2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance.
The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 × 10−7 and 1.16 × 10−6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional
independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring
additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed,
the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest
that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been
made available online to facilitate such future endeavors.
We compare the utility of two methods for estimating the average levels of gene flow from DNA sequence data. One method is based on estimating FST from frequencies at polymorphic sites, treating each site as a separate locus. The other method is based on computing the minimum number of migration events consistent with the gene tree inferred from their sequences. We compared the performance of these two methods on data that were generated by a computer simulation program that assumed the infinite sites model of mutation and that assumed an island model of migration. We found that in general when there is no recombination, the cladistic method performed better than FST while the reverse was true for rates of recombination similar to those found in eukaryotic nuclear genes, although FST performed better for all recombination rates for very low levels of migration (Nm = 0.1).
We have recently identified several naturally occurring variants of the human β2-adrenergic receptor (β2AR). One of these polymorphisms, which is relatively uncommon, is a mutation occurring in the fourth transmembrane spanning domain, with Ile substituted for Thr at amino acid 164 within the proposed ligand binding pocket. This mutation is adjacent to Ser165 which has been predicted to interact with the β-carbon hydroxyl group of adrenergic ligands. To determine the functional significance of this variant, we constructed by site-directed techniques a mutated β2AR (Ile164) with this substitution and expressed it in CHW-1102 cells. In the presence of guanine nucleotide, Ile164 displayed a lower binding affinity for epinephrine as compared with the wild-type β2AR (Ki = 1450 ± 79 versus 368 ±39 nM; p < 0.001). A similarly decreased affinity was found with the catecholamines isoproterenol and norepinephrine, but not with dobutamine or dopamine which lack hydroxyl groups on their β-carbons. In addition, antagonists without aromatic ring polar substituents displayed a decreased affinity for the mutated receptor. In agonist competition experiments conducted in the absence of guanine nucleotide, Ile164 failed to exhibit detectable high affinity binding, suggesting an impairment in the formation of the agonist-receptor-Gs complex. Consistent with this finding, functional coupling to Gs as determined in adenylyl cyclase assays was significantly (∼50%) depressed with Ile164 under both basal and agonist-stimulated conditions. β2AR sequestration, which is also triggered by agonist binding, was also found to be ∼65% reduced in the Ile164 polymorphism. This study represents the first characterization of a naturally occurring mutation of a human adrenergic receptor. Our findings generally support the hypothesized role of this region of the receptor for ligand binding and receptor activation, as well as for establishing critical interactions for overall receptor conformation.
DNA sequence variation in a 1410-bp region including the Cu,Zn Sod locus was examined in 41 homozygous lines of Drosophila melanogaster. Fourteen lines were from Barcelona, Spain, 25 were from California populations and the other two were from laboratory stocks. Two common electromorphs, SODS and SODF, are segregating in the populations. Our sample of 41 lines included 19 SodS and 22 SodF alleles (henceforward referred to as Slow and Fast alleles). All 19 Slow alleles were identical in sequence. Of the 22 Fast alleles sequenced, nine were identical in sequence and are referred to as the Fast A haplotypes. The Slow allele sequence differed from the Fast A haplotype at a single nucleotide site, the site that accounts for the amino acid difference between SODS and SODF. There were nine other haplotypes among the remaining 13 Fast alleles sequenced. The overall level of nucleotide diversity (pi) in this sample is not greatly different than that found at other loci in D. melanogaster. It is concluded that the Slow/Fast polymorphism is a recently arisen polymorphism, not an old balanced polymorphism. The large group of nearly identical haplotypes suggests that a recent mutation, at the Sod locus or tightly linked to it, has increased rapidly in frequency to around 50%, both in California and Spain. The application of a new statistical test demonstrates that the occurrence of such large numbers of haplotypes with so little variation among them is very unlikely under the usual equilibrium neutral model. We suggest that the high frequency of some haplotypes is due to natural selection at the Sod locus or at a tightly linked locus.
A possible pathogenic mutation in the beta 3-adrenergic-receptor gene (Trp64Arg) has been reported to be associated with an earlier age of onset of non-insulin-dependent diabetes mellitus (NIDDM) and clinical features of the insulin resistance syndrome in Pima Indian, Finnish and French subjects. Since marked heterogeneity has been reported in the association of mutations of candidate genes with NIDDM between Japanese and other ethnic groups, we investigated the association of Trp64Arg with NIDDM in Japanese subjects. The allele frequency of the mutation (Arg) was slightly, but not significantly, higher in NIDDM than in control subjects (70 out of 342 alleles [20.5%] vs 40 out of 248 [16.1%], respectively, p > 0.2). When our data were combined with those of Pima Indian and Finnish subjects, however, the Arg/Arg genotype was significantly associated with NIDDM as compared with the other two genotypes (p < 0.005, relative risk [RR] 2.13, 95% confidence interval [CI] 1.28-3.55). The Arg allele was also associated with NIDDM (p < 0.05, RR 1.27, 95% CI 1.06-1.52). Japanese subjects homozygous for the mutation had a significantly higher body mass index (mean +/- SD: 25.5 +/- 3.9 kg/m2) than heterozygotes (22.6 +/- 4.1, p < 0.05) and normal homozygotes (22.8 +/- 3.8, p < 0.05). NIDDM patients homozygous for the mutation tended to have an earlier age of onset of NIDDM than those with other genotypes. These data suggest that the Trp64Arg mutation not only contributes to weight gain and age-at-onset of NIDDM but is also associated with susceptibility to NIDDM.
The beta3 adrenergic receptor, located on chromosome 8, is a regulator of energy expenditure and lipolysis. A missense mutation in this gene, characterized by the replacement of tryptophan by arginine at codon 64 (Trp64Arg), is associated with obesity in some studies. We examined the effect of this variant on obesity in Mexican Americans, using a paired sibling design to minimize variability due to genetic background and a previously identified major susceptibility locus for obesity. We identified 45 sib-pairs that were concordant (identical by descent) for a locus on chromosome 2 which we have shown previously to be tightly linked to obesity in this population. The Trp64Arg variant, detected by PCR-restriction fragment length polymorphism analysis, was present in one sibling within each of the 45 sib-pairs. Presence of the variant was associated with significantly higher values in body mass index (P = 0.04), fat mass (P = 0.04), and waist circumference (P = 0.05). We conclude that the Trp64Arg variant is associated with obesity in this Mexican American population. The paired sibling design probably enhanced our ability to detect the effects of this variant by allowing us to account for variation attributable to another obesity susceptibility locus and to background genes.
The β1-adrenergic receptor (β1AR) is a key cell surface signaling protein expressed in the heart and other organs that mediates the actions of catecholamines
of the sympathetic nervous system. A polymorphism in the intracellular cytoplasmic tail near the seventh transmembrane-spanning
segment of the human β1AR has been identified in a cohort of normal individuals. At amino acid position 389, Gly or Arg can be found (allele frequencies
0.26 and 0.74, respectively), the former previously considered as the human wild-type β1AR. Using site-directed mutagenesis to mimic the two variants, CHW-1102 cells were permanently transfected to express the
Gly-389 and Arg-389 receptors. In functional studies with matched expression, the Arg-389 receptors had slightly higher basal
levels of adenylyl cyclase activities (10.7 ± 1.2 versus 6.1 ± 0.4 pmol/min/mg). However, maximal isoproterenol-stimulated levels weremarkedly higher for the Arg-389 as compared to the Gly-389 receptor (63.3 ± 6.1 versus 20.9 ± 2.0 pmol/min/mg). Agonist-promoted [35S]guanosine 5′-O-(thiotriphosphate) binding was also increased with the Arg-389 receptor consistent with enhanced coupling to Gsand increased adenylyl cyclase activation. In agonist competition studies carried out in the absence of guanosine 5′-(β,γ-imido)triphosphate,
high affinity binding could not be resolved with the Gly-389 receptor, whereas Arg-389 displayed an accumulation of the agonist
high affinity receptor complex (R
H = 26%). Taken together, these data indicate that this polymorphic variation of the human β1AR results in alterations of receptor-Gs interaction with functional signal transduction consequences, consistent with its localization in a putative G-protein binding
domain. The genetic variation of β1AR at this locus may be the basis of interindividual differences in pathophysiologic characteristics or in the response to
therapeutic βAR agonists and antagonists in cardiovascular and other diseases.
Positive selection can be inferred from its effect on linked neutral variation. In the restrictive case when there is no recombination, all linked variation is removed. If recombination is present but rare, both deterministic and stochastic models of positive selection show that linked variation hitchhikes to either low or high frequencies. While the frequency distribution of variation can be influenced by a number of evolutionary processes, an excess of derived variants at high frequency is a unique pattern produced by hitchhiking (derived refers to the nonancestral state as determined from an outgroup). We adopt a statistic, H, to measure an excess of high compared to intermediate frequency variants. Only a few high-frequency variants are needed to detect hitchhiking since not many are expected under neutrality. This is of particular utility in regions of low recombination where there is not much variation and in regions of normal or high recombination, where the hitchhiking effect can be limited to a small (<1 kb) region. Application of the H test to published surveys of Drosophila variation reveals an excess of high frequency variants that are likely to have been influenced by positive selection.
The human beta(2)-adrenergic receptor gene has multiple single-nucleotide polymorphisms (SNPs), but the relevance of chromosomally phased SNPs (haplotypes) is not known. The phylogeny and the in vitro and in vivo consequences of variations in the 5' upstream and ORF were delineated in a multiethnic reference population and an asthmatic cohort. Thirteen SNPs were found organized into 12 haplotypes out of the theoretically possible 8,192 combinations. Deep divergence in the distribution of some haplotypes was noted in Caucasian, African-American, Asian, and Hispanic-Latino ethnic groups with >20-fold differences among the frequencies of the four major haplotypes. The relevance of the five most common beta(2)-adrenergic receptor haplotype pairs was determined in vivo by assessing the bronchodilator response to beta agonist in asthmatics. Mean responses by haplotype pair varied by >2-fold, and response was significantly related to the haplotype pair (P = 0.007) but not to individual SNPs. Expression vectors representing two of the haplotypes differing at eight of the SNP loci and associated with divergent in vivo responsiveness to agonist were used to transfect HEK293 cells. beta(2)-adrenergic receptor mRNA levels and receptor density in cells transfected with the haplotype associated with the greater physiologic response were approximately 50% greater than those transfected with the lower response haplotype. The results indicate that the unique interactions of multiple SNPs within a haplotype ultimately can affect biologic and therapeutic phenotype and that individual SNPs may have poor predictive power as pharmacogenetic loci.
The total and regional peripheral resistance and capacitance of the vascular system is regulated by the sympathetic nervous system, which influences the vasculature mainly through changes in the release of catecholamines from both the sympathetic nerve terminals and the adrenal medulla. The knowledge of the targets for noradrenaline and adrenaline, the main endogenous catecholamines mediating that influence, has recently been greatly expanded. From two types of adrenoceptors (α and β), we have now nine subtypes (α1A, α1B, α1D, α2A/D, α2B, α2A/D, β1, β2, and β3) and two other candidates (α1L and β4), which may be conformational states of α1A and β1-adrenoceptors, respectively. The vascular endothelium is now known to be more than a pure anatomical entity, which smoothly contacts the blood and forms a passive bartier against plasma lipids. Instead, the endothelium is an important organ possessing at least five different adrenoceptor subtypes (α2A/D, α2C, β1, β2, and β3), which either directly or through the release of nitric oxide actively participate in the regulation of the vascular tone. The availability of transgenic models has resulted in a stepwise progression toward the identification of the role of each adrenoceptor subtype in the regulation of blood pressure and fine-tuning of blood supply to the different organs: α2A/D-adrenoceptors are involved in the central control of blood pressure; α1-(primarily) and α2B-adrenoceptors (secondarily) contribute to the peripheral regulation of vascular tone; and α2A/D- and α2C-adrenoceptors modulate transmitter release. The increased knowledge on the involvement of vascular adrenoceptors in many diseases like Raynaud's, scleroderma, several neurological degenerative diseases (familial amyloidotic polyneuropathy, Parkinson disease, multiple-system atrophy), some kinds of hypertension, etc., will contribute to new and better therapeutic approaches.
Positive selection can be inferred from its effect on linked neutral variation. In the restrictive case when there is no recombination, all linked variation is removed. If recombination is present but rare, both deterministic and stochastic models of positive selection show that linked variation hitchhikes to either low or high frequencies. While the frequency distribution of variation can be influenced by a number of evolutionary processes, an excess of derived variants at high frequency is a unique pattern produced by hitchhiking (derived refers to the nonancestral state as determined from an outgroup). We adopt a statistic, H, to measure an excess of high compared to intermediate frequency variants. Only a few high-frequency variants are needed to detect hitchhiking since not many are expected under neutrality. This is of particular utility in regions of low recombination where there is not much variation and in regions of normal or high recombination, where the hitchhiking effect can be limited to a small (<1 kb) region. Application of the H test to published surveys of Drosophila variation reveals an excess of high frequency variants that are likely to have been influenced by positive selection.
We compare the utility of two methods for estimating the average levels of gene flow from DNA sequence data. One method is based on estimating FST from frequencies at polymorphic sites, treating each site as a separate locus. The other method is based on computing the minimum number of migration events consistent with the gene tree inferred from their sequences. We compared the performance of these two methods on data that were generated by a computer simulation program that assumed the infinite sites model of mutation and that assumed an island model of migration. We found that in general when there is no recombination, the cladistic method performed better than FST while the reverse was true for rates of recombination similar to those found in eukaryotic nuclear genes, although FST performed better for all recombination rates for very low levels of migration (Nm = 0.1).
Motoo Kimura, as founder of the neutral theory, is uniquely placed to write this book. He first proposed the theory in 1968 to explain the unexpectedly high rate of evolutionary change and very large amount of intraspecific variability at the molecular level that had been uncovered by new techniques in molecular biology. The theory - which asserts that the great majority of evolutionary changes at the molecular level are caused not by Darwinian selection but by random drift of selectively neutral mutants - has caused controversy ever since. This book is the first comprehensive treatment of this subject and the author synthesises a wealth of material - ranging from a historical perspective, through recent molecular discoveries, to sophisticated mathematical arguments - all presented in a most lucid manner.
β(2)-Adrenoceptors (AR) play an important role in regulation of vascular and bronchial smooth muscle tone; functional β(2)-AR, however, also exist in human heart where they can mediate positive inotropic and chronotropic effects. Recent studies have discovered that β(2)-AR are polymorphic. The most common single nucleotide polymorphisms (SNPs) are: Arg16Gly, Gln27Glu, Thr164IIe in the coding region, and Arg-16Gly in the 5&PRIME; upstream peptide. These SNPs affect receptor function in vitro; however, conflicting data exist on their functional relevance in vivo. This might be due to the fact that the four SNPs in the 5&PRIME; upstream peptide and in the coding region, respectively, are linked and form certain haplotypes. This review gives an overview on the contribution Of β(2)-AR polymorphisms to cardiovascular diseases or altered drug responses. In addition, the relevance of SNPs vs. haplotypes for β(2)-AR functional responsiveness is discussed. © 2005 Lippincott Williams & Wilkins.
We have recently delineated three naturally occurring polymorphisms of the human beta 2-adrenergic receptor caused by missense mutations encoding for amino acids 16 and 27 of the extracellular N-terminus of the receptor. We have studied the functional consequences of these polymorphisms by site-directed mutagenesis and the recombinant expression of these receptors in Chinese hamster fibroblasts. The polymorphisms consist of substitutions of Gly for Arg at amino acid 16 (Arg16-->Gly), Glu for Gln at amino acid 27 (Gln27-->Glu), and a combination of both substitutions. All three mutated receptors displayed normal agonist binding and functional coupling to Gs, resulting in the stimulation of adenylyl cyclase activity. However, these mutations markedly altered the degree of agonist-promoted downregulation of receptor expression. After 24-h exposure to 10 microM isoproterenol, wild-type beta 2AR underwent a 26 +/- 3% reduction in receptor density. In contrast, Arg16-->Gly underwent a 41 +/- 3% reduction. Gln27-->Glu, on the other hand, was found to be completely resistant to downregulation. Arg16-->Gly+Gln27-->Glu also underwent an increased downregulation compared to wild-type beta 2AR (39 +/- 4%). The rates of new receptor synthesis after irreversible alkylation were not different between these receptors, nor were the rates of agonist-promoted receptor internalization to the intracellular pool. Gln27-->Glu cellular mRNA minimally increased during agonist exposure, and wild-type beta 2AR and the other mutated receptor mRNAs did not change, which infer that the aberrant downregulation patterns of these polymorphisms may be due to the altered degradation of receptor protein.(ABSTRACT TRUNCATED AT 250 WORDS)
Our purpose was to determine whether the functional genetic polymorphisms of the beta(2)-adrenergic receptor (beta(2)AR) that result in changes in amino acid residues 16 and 27 are associated with preterm delivery.
A case-control study comparing the distribution of beta(2)AR genotype between 251 Hispanic women delivered at term and 28 Hispanic women delivered preterm. Preterm delivery was defined as spontaneous onset of labor resulting in delivery before 37 weeks of gestation, in a singleton pregnancy, with no apparent etiology for preterm labor and delivery. Genomic DNA was isolated from peripheral blood, and beta( 2)AR alleles were identified by established techniques.
Only one woman (4%) with preterm labor was homozygous for Arg16 versus 79 (31%) in the control group (P =.01, odds ratio 0.08). There was no association of preterm labor with genotype at position 27.
Our data demonstrate that homozygosity for Arg16, which in vitro is associated with decreased down-regulation of the beta(2)AR, protects from preterm delivery.
Interference with delivery of oxygen to the fetus or infant and other environmental risk factors have been associated with the development of cerebral palsy (CP). Several lines of evidence suggest that genetic risk factors are also involved; genes associated with vascular disease or inflammation, the fetal inflammatory response, and the apolipoprotein E genotype are all associated with increased susceptibility to CP. In addition, increased risk of CP has been demonstrated among groups with high rates of consanguinity and in certain families. This population-based study evaluated the association of selected genetic polymorphisms with later-diagnosed CP among 413 South Australian children born to Caucasian mothers between 1986 and 1999. Blood samples obtained from newborn screening blood spots were tested for 28 single-nucleotide polymorphisms (SNPs) using TaqMan assays. The genotype frequencies were evaluated in all cases of cerebral palsy, and in subgroups based on gestational age (<37 or ≥37 weeks), the type of cerebral palsy (diplegia, hemiplegia, or quadriplegia), and gender. Logistic regression models were used to assess associations between genotypic distributions and CP.
The risk for CP in both gestational age groups was significantly associated with polymorphisms of 2 SNPs: inducible nitric oxide synthase (iNOS) and lymphotoxin α (also called LTA or tumor necrosis factor β (TNF-β). For iNOS, presence of the T allele was more common in all children with CP and among heterozygotes born at term. Homozygous variant status for LTA was associated with risk for CP and with spastic hemiplegic or quadriplegic CP. In addition to iNOS, heterozygosity for the endothelial protein C receptor SNP was more frequent among children with CP. Among infants born preterm, the variant A allele of interleukin 8 and heterozygosity for the β-2 adrenergic receptor were associated with CP. Interleukin 8 heterozygosity was associated with spastic diplegia. Some gene variants were found in girls with CP but not in boys.
These findings, together with previous studies, suggest that certain genes are associated with increased susceptibility to CP.
The β3-adrenergic receptor (β3AR) is expressed in visceral fat and is a regulator of resting metabolic rate, thermogenesis,
and lipolysis. We genotyped 61 unrelated Mexican Americans for a variant in the β3AR gene (codon 64 TGGTrp→CGGArg; TRP64ARG). The allele frequency was 0.13. The TRP64ARG variant was significantly associated with an earlier age of onset
of non-insulin-dependent diabetes mellitus (41.3 ± 4.6 years vs 55.6 ± 2.6 years; P < 0.02) and in non-diabetics, with elevated 2-h insulin levels during an oral glucose tolerance test (810 ± 120 pmol/l vs
384 ± 6 pmol/l; P < 0.005). Non-diabetic subjects with the variant allele tended to have higher body mass indices (BMI), waist-to-hip ratios,
and diastolic blood pressures. The study group was expanded to include 421 related subjects from 31 families in the San Antonio
Family Diabetes Study. Using a measured genotype analysis approach to estimate genotype-specific means for each trait, those
who were homozygous for the TRP64ARG variant had significantly higher 2-h insulin levels (P = 0.036) and trends towards higher BMI compared to the other two genotypes. We detected no associations of these traits in
the TRP64ARG heterozygotes in the larger group. We conclude that the TRP64ARG β3AR variant is a susceptibility gene for several
features of the insulin resistance syndrome in Mexican Americans. Since its effects are modest, study design (e.g., subject
selection, genetic background, and statistical analyses) may influence which traits are associated with this variant and whether
or not the effect is detectable in heterozygotes.
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10–7 and 1.16 x 10–6], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.
The objective of this study was to examine whether selected genetic polymorphisms in the infant are associated with later-diagnosed cerebral palsy.
A population-based case-control study was conducted of 28 single-nucleotide polymorphisms measured in newborn screening blood spots. A total of 413 children with later-diagnosed cerebral palsy were born to white women in South Australia in 1986-1999, and there were 856 control children. Distributions of genotypic frequencies were examined in total cerebral palsy, in gestational age groups, and by types of cerebral palsy and gender. Genotyping was performed by using a TaqMan assay.
For inducible nitric-oxide synthase, possession of the T allele was more common in all children with cerebral palsy and for heterozygotes who were born at term. For lymphotoxin alpha, homozygous variant status was associated with risk for cerebral palsy and with spastic hemiplegic or quadriplegic cerebral palsy. Among term infants, heterozygosity for the endothelial protein C receptor single-nucleotide polymorphism was more frequent in children with cerebral palsy. In preterm infants, the variant A allele of interleukin 8 and heterozygosity for the beta-2 adrenergic receptor were associated with cerebral palsy risk. Interleukin 8 heterozygote status was associated with spastic diplegia. Variants of several genes were associated with cerebral palsy in girls but not in boys.
Two of the 28 single-nucleotide polymorphisms examined were associated with all types of spastic cerebral palsy in both gestational age groups and others with cerebral palsy in gestational age or cerebral palsy subgroups. Some of these associations support previous findings. There may be a genetic contribution to cerebral palsy risk, and additional investigation is warranted of genes and gene-environment interactions in cerebral palsy.
A mathematical model for the evolutionary change of restriction sites in mitochondrial DNA is developed. Formulas based on this model are presented for estimating the number of nucleotide substitutions between two populations or species. To express the degree of polymorphism in a population at the nucleotide level, a measure called "nucleotide diversity" is proposed.
The distribution is obtained for the number of segregating sites observed in a sample from a population which is subject to recurring, new, mutations but not subject to recombination. After allowance is made for the different effective population sizes, the results apply approximately to three population models, due to Wright, Burrows and Cockerham, and Moran. Included as extreme special cases are the distributions of the number of segregating sites in the whole population and of the number of heterozygous sites in a diploid individual. Some results of Fisher, Haldane, Kimura, and Ewens concerning the means of the distributions for different models are confirmed, but the variances, and the distributions themselves, are new.
The relationship between the two estimates of genetic variation at the DNA level, namely the number of segregating sites and the average number of nucleotide differences estimated from pairwise comparison, is investigated. It is found that the correlation between these two estimates is large when the sample size is small, and decreases slowly as the sample size increases. Using the relationship obtained, a statistical method for testing the neutral mutation hypothesis is developed. This method needs only the data of DNA polymorphism, namely the genetic variation within population at the DNA level. A simple method of computer simulation, that was used in order to obtain the distribution of a new statistic developed, is also presented. Applying this statistical method to the five regions of DNA sequences in Drosophila melanogaster, it is found that large insertion/deletion (greater than 100 bp) is deleterious. It is suggested that the natural selection against large insertion/deletion is so weak that a large amount of variation is maintained in a population.
This paper considers the distribution of the genealogical tree of a sample of genes in the infinitely-many-site model where the relative age ordering of the mutations (nodes in the tree) is known. A computer implementation of a recursion for the probability of such trees is discussed when the nodes are age-labeled, or not.
Examples of stable cycling are discussed for two-locus, two-allele, deterministic, discrete-time models with constant fitnesses. The cases that cycle were found by using numerical techniques to search for stable Hopf bifurcations. One consequence of the results is that apparent cases of directional selection may be due to stable cycling.
The beta 3-adrenergic receptor is expressed in visceral adipose tissue and is thought to contribute to the regulation of the resting metabolic rate and lipolysis.
To investigate whether mutations in the gene for the beta 3-adrenergic receptor predispose patients to obesity and non-insulin-dependent diabetes mellitus (NIDDM), we studied this gene in 10 Pima Indians by analysis of single-stranded conformational polymorphisms and dideoxy sequence analysis. Association studies were performed in 642 Pima subjects (390 with NIDDM and 252 without NIDDM).
A missense mutation was identified in the gene for the beta 3-adrenergic receptor that results in the replacement of tryptophan by arginine (Trp64Arg) in the first intracellular loop of the receptor. This mutation was detected with allelic frequencies of 0.31 in Pima Indians, 0.13 in 62 Mexican Americans, 0.12 in 49 blacks, and 0.08 in 48 whites in the United States. Among Pimas, the frequency of the Trp64Arg mutation was similar in nondiabetic and diabetic subjects. However, in subjects homozygous for the mutation the mean (+/- SD) age at the onset of NIDDM was significantly lower (36 +/- 10 years) than in Trp64Arg heterozygotes (40 +/- 10 years) or normal homozygotes (41 +/- 11 years; P = 0.02). Furthermore, subjects with the mutation tended to have a lower adjusted resting metabolic rate (P = 0.14 by analysis of covariance).
Pima subjects homozygous for the Trp64Arg beta 3-adrenergic-receptor mutation have an earlier onset of NIDDM and tend to have a lower resting metabolic rate. This mutation may accelerate the onset of NIDDM by altering the balance of energy metabolism in visceral adipose tissue.
The infinitely-many-sites process is often used to model the sequence variability observed in samples of DNA sequences. Despite its popularity, the sampling theory of the process is rather poorly understood. We describe the tree structure underlying the model and show how this may be used to compute the probability of a sample of sequences. We show how to produce the unrooted genealogy from a set of sites in which the ancestral labeling is unknown and from this the corresponding rooted genealogies. We derive recursions for the probability of the configuration of sequences (equivalently, of trees) in both the rooted and unrooted cases. We give a computational method based on Monte Carlo recursion that provides approximates to sampling probabilities for samples of any size. Among several applications, this algorithm may be used to find maximum likelihood estimators of the substitution rate, both when the ancestral labeling of sites is known and when it is unknown.
We develop a sampling theory for genes sampled from a population evolving with deterministically varying size. We use a coalescent approach to provide recursions for the probabilities of particular sample configurations, and describe a Monte Carlo method by which the solutions to such recursions can be approximated. We focus on infinite-alleles, infinite-sites and finite-sites models. This approach may be used to find maximum likelihood estimates of parameters of genetic interest, and to test hypotheses about the varying environment. The methods are illustrated with data from the mitochondrial control region sampled from a North American Indian tribe.
Mutations in the genealogy of the sequences in a random sample from a population can be classified as external and internal. External mutations are mutations that occurred in the external branches and internal mutations are mutations that occurred in the internal branches of the genealogy. Under the assumption of selective neutrality, the expected number of external mutations is equal to theta = 4Ne mu, where Ne is the effective population size and mu is the rate of mutation per gene per generation. Interestingly, this expectation is independent of the sample size. The number of external mutations is likely to deviate from its neutral expectation when there is selection while the number of internal mutations is less affected by the presence of selection. Statistical properties of the numbers of external mutations and of internal mutations are studied and their relationships to two commonly used estimates of theta are derived. From these properties, several new statistical tests based on a random sample of DNA sequences from the population are developed for testing the hypothesis that all mutations at a locus are neutral.
Thirty-five period locus sequences from Drosophila pseudoobscura and its siblings species, D. p. bogotana, D. persimilis, and D. miranda, were studied. A large amount of variation was found within D. pseudoobscura and D. persimilis, consistent with histories of large effective population sizes. D. p. bogotana, however, has a severe reduction in diversity. Combined analysis of per with two other loci, in both D. p. bogotana and D. pseudoobscura, strongly suggest this reduction is due to recent directional selection at or near per within D. p. bogotana. Since D. p. bogotana is highly variable and shares variation with D. pseudoobscura at other loci, the low level of variation at per within D. p. bogotana can not be explained by a small effective population size or by speciation via founder event. Both D. pseudoobscura and D. persimilis have considerable intraspecific gene flow. A large portion of one D. persimilis sequence appears to have arisen via introgression from D. pseudoobscura. The time of this event appears to be well after the initial separation of these two species. The estimated times since speciation are one mya for D. pseudoobscura and D. persimilis and 2 mya since the formation of D. miranda.
I formulate and study a series of simple one-locus two-allele models for maternal (parental) selection. I show that maternal (parental) selection can result in simultaneous stability of equilibria of different types. Thus, in the presence of maternal (parental) selection the outcome of population evolution can significantly depend on initial conditions. With maternal selection, genetic variability can be maintained in the population even if none of the offspring of heterozygous mothers survive. I demonstrate that interactions of maternal and paternal selection can result in stable oscillations of genotype frequencies. A necessary condition for cycling is strong selection.
A missense mutation of the β3-adrenergic receptor gene (Trp64Arg) has been associated with obesity and increased capacity to gain weight in nonpregnant populations. Furthermore, the mutation is a potential modifying factor in the etiology of impaired glucose tolerance and type 2 diabetes. We studied the relation of theβ 3-adrenergic receptor genotype to glucose tolerance during pregnancy, a state of physiological insulin resistance. In 179 pregnant women (mean age, 28.5 ± 0.4 yr), a 2-h oral glucose tolerance test was performed between gestational weeks 20 and 31. Theβ 3-adrenergic receptor genotype was assessed using restriction fragment length polymorphism.
The frequency of the Arg64 allele was 9.15%. In women with mild gestational diabetes (n = 70), as defined by 60 min postload glucose values, the Trp64Arg genotype was more frequent than in women with normal glucose tolerance (n = 109; 26% vs. 11%; P = 0.01). Furthermore, the Trp64Arg polymorphism was associated with increased weight gain during pregnancy (baseline to gestational weeks 20–31) and increased postload glucose, insulin, and C peptide values during the oral glucose tolerance test.
The results of the present study extend current knowledge about the association of the Trp64Arg β3-adrenergic receptor polymorphism with glucose tolerance to a pregnant population. The association with mild gestational diabetes suggests that the impact of the polymorphism may be clinically important during pregnancy, a state of physiological insulin resistance.
The diminishing incidence of parasitic infection in westernised societies has been suggested to result in an increased prevalance of asthma. Asthma is a polygenic disease and genome screens have shown that genes on chromosome 5q31-33 are strongly linked to the disease. The gene for the beta2-adrenoreceptor is located in this region and two polymorphisms have been identified that result in amino acid changes at positions 16 (ArgGly) and 27 (GlnGlu). To determine whether these polymorphisms influence asthma and parasitic infection, a genotype/phenotype study has been performed on a cohort of 126 children from Coche Island in Venezuela. There is a high incidence of asthma on the island and intestinal helminthiasis is endemic. Genotyping for both polymorphisms was carried out by using the polymerase chain reaction and allele-specific oligonucleotide hybridisation. Genotype frequencies in this cohort were consistent with other studies and both polymorphisms were in significant linkage disequilibrium. Individuals who were homozygous for Arg16 had significantly higher levels of specific IgE to Ascaris lumbricoides (P=0.002), significantly higher A. lumbricoides egg counts (P<0.001) and significantly larger wheal sizes following skin-prick testing with A. lumbricoides allergen (P=0.008). There was no association between either polymorphism and total serum IgE or asthma in this population. A combination of mast cell degranulation and the lung migratory phase of A. lumbricoides larvae may result in bronchoconstriction in infected individuals. These results suggest that the Gly 16 allele confers resistance to high levels of parasitic infection in this population. An alternative explanation for the association is that it may be the result of linkage disequilibrium with other genes in the chromosome 5q31-33 region.
Reconstructing phylogenies from intraspecific data (such as human mitochondrial DNA variation) is often a challenging task because of large sample sizes and small genetic distances between individuals. The resulting multitude of plausible trees is best expressed by a network which displays alternative potential evolutionary paths in the form of cycles. We present a method ("median joining" [MJ]) for constructing networks from recombination-free population data that combines features of Kruskal's algorithm for finding minimum spanning trees by favoring short connections, and Farris's maximum-parsimony (MP) heuristic algorithm, which sequentially adds new vertices called "median vectors", except that our MJ method does not resolve ties. The MJ method is hence closely related to the earlier approach of Foulds, Hendy, and Penny for estimating MP trees but can be adjusted to the level of homoplasy by setting a parameter epsilon. Unlike our earlier reduced median (RM) network method, MJ is applicable to multistate characters (e.g., amino acid sequences). An additional feature is the speed of the implemented algorithm: a sample of 800 worldwide mtDNA hypervariable segment I sequences requires less than 3 h on a Pentium 120 PC. The MJ method is demonstrated on a Tibetan mitochondrial DNA RFLP data set.
Arner P, Hoffstedt J (Karolinska Institute, Huddinge Hospital, Stockholm, Sweden). Adrenoceptor genes in human obesity. (Minisymposium: Genes & Obesity). J Intern Med 1999; 245: 667–672.
The genes causing obesity in rodent models have been characterized, but do not seem to be important for human obesity. Recently the putative association between obesity and polymorphism in human beta-adrenergic receptor genes have been studied intensely in the light of the important role of these receptors in the regulation of energy mobilization and utilization. A polymorphism (Trp64Arg) in the beta3-adrenergic receptor gene is associated with obesity (relative risk ≈ 2) in some but not all investigations on Caucasian and Japanese populations. When expressed in artificial cell systems, the polymorphism is associated with alterations of the beta3-adrenoceptor. The genetic allele variance influences also the native receptor function when measured in isolated human fat cells. The human beta2-adrenoceptor gene shows a high degree of polymorphism. The role of beta2-receptor gene polymorphism for obesity has so far only been investigaed in women. A Gln27Glu variant is markedly associated with obesity with a relative risk for obesity of ≈ 7 and odds ratio of ≈ 10. Women who are homozygous for 27Glu have ≈ 20 kg higher fat mass than controls. Thus, polymorphism in genes coding for different beta-adrenoceptor subtypes may be important for the development of human obesity.
The beta 3 subtype of adrenaline and noradrenaline receptors has been extensively characterized at structural and functional levels. Ligand binding and adenyl cyclase activation studies have helped to define their unique beta-adrenergic profile. Humans, other larger mammals, and rodents share most of the characteristic beta 3-adrenergic receptor properties, although obvious species-specific differences have been identified. Most studies in animal models have shown a distinct beta 3-adrenergic receptor activity that results in an increase in energy expenditure, decrease of fat mass (especially of intra-abdominal fat), and increased glucose disposal efficiency. It is of interest that mild weight increase was shown to develop in female but not male mice, in whom the beta 3-adrenergic receptor gene was disrupted. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to correlate with hereditary obesity in Pima Indians and Japanese individuals. In Western obese patients, this phenotype increased the capacity to gain weight and develop type 2 diabetes mellitus. Studies of humans with the Trp64Arg variant have shown controversial results. Many studies have failed to show any effect in heterozygous male subjects, and only modest effects in homozygous male subjects. In women, several studies have shown modest-to-significant effects regarding weight gain, intra-abdominal fat, and decreased insulin sensitivity in heterozygous and homozygous women. Other studies have failed to show any effect in heterozygous females. Disruptions in the activity of the beta 3-adrenergic receptor in the homozygous male and the heterozygous or homozygous female appear to have a profound effect in animal models, but a limited consequence in human physiology. Association with obesity or diabetes in humans is still controversial. This difference between animal and human models may be explained by the different quantity and distribution of metabolically active brown adipose tissue in the two.
Current routine genotyping methods typically do not provide haplotype information, which is essential for many analyses of fine-scale molecular-genetics data. Haplotypes can be obtained, at considerable cost, experimentally or (partially) through genotyping of additional family members. Alternatively, a statistical method can be used to infer phase and to reconstruct haplotypes. We present a new statistical method, applicable to genotype data at linked loci from a population sample, that improves substantially on current algorithms; often, error rates are reduced by > 50%, relative to its nearest competitor. Furthermore, our algorithm performs well in absolute terms, suggesting that reconstructing haplotypes experimentally or by genotyping additional family members may be an inefficient use of resources.
A deviation of the maternal-neonatal joint phosphoglucomutase locus 1 (PGM1) distribution from Hardy-Weinberg expectation has been reported. It was suggested that selection on PGM1 during intrauterine life might account for these deviations and that maternal and paternal PGM1 alleles might have different associations with intrauterine survival. This study considered possible associations between the joint mother-newborn PGM1 genotype and intrauterine growth. There was a significant association between birth weight percentile class and mother-newborn PGM1 genotype in infant females. Also, the paternal PGM1*2 allele was associated negatively with macrosomia, and this effect was significant only in female infants.
An association of the phosphoglucomutase locus 1 (PGM1) genetic polymorphism with repeated spontaneous abortion (RSA), with intrauterine development in both normal and diabetic pregnancies, and with fertility has been reported in previous studies. In view of the evolutionary interest and of a possible clinical relevance of PGM1 selection during intrauterine life, this study considers healthy puerperae, consecutive newborns, and couples with RSA as well as two alleles (PGM1*1 and PGM1*2). The joint maternal-neonatal PGM1 distribution in a sample from an Italian rural population is significantly different from that expected assuming Hardy-Weinberg conditions for equilibrium. Deviation is dependent on maternal age and parity. The joint mother-newborn PGM1 genotype distribution is significantly associated with a positive history of previous spontaneous miscarriage, suggesting that the presence of the PGM1*2 allele in the father predisposes to spontaneous abortion. This hypothesis is also supported by the observation that in couples with RSA, the delivery of a live born infant within 5 years from the first episode of miscarriage is negatively associated with the presence of a PGM1*2 allele in the husband. Altogether these observations suggest the hypothesis of PGM1 maternal selection at the reproductive level involving a differential role of PGM1*1 and PGM1*2 alleles of paternal origin.