[show abstract][hide abstract] ABSTRACT: Fundamental to definitively identifying neonates at risk of developing significant hyperbilirubinemia is a better understanding of the genetic factors associated with early bilirubin rise. Previous genetic studies have focused on the UGT1A1 gene, associating common variation in the coding or promoter regions with qualitative assessments of bilirubin (i.e. significantly elevated or not). These studies have had conflicting results and limited success. We chose to approach the problem by focusing on the quantitative (absolute) change in bilirubin levels early in post-natal life. We apply this approach to the UGT1A1 gene--exploring the contribution of both rare and common variants to early bilirubin changes.
We sequenced the exons, PBREM, 5'-, and 3'- regions of the UGT1A1 gene in 80 otherwise healthy term neonates who had repeat bilirubin levels measured within the first five days of life.
Three novel coding variants were observed, but there was no clear relationship between rare coding variants and bilirubin rise. Adjusted linear regression models fit to evaluate the relationship between changing bilirubin levels and common UGT1A1variants found that among 39 neonates whose bilirubin was resampled within 33 hours, individuals homozygous for the mutant allele of a 3'UTR SNP had significantly smaller changes in bilirubin (P=0.003) than individuals carrying the wild-type allele.
Collectively, rare UGT1A1 coding variants do not appear to play a prominent role in determining early bilirubin levels; however common variants in the 3' UTR of UGT1A1 may modulate the early bilirubin rise. A quantitative approach to evaluating early bilirubin kinetics provides a more robust framework in which to better understand the genetics of neonatal hyperbilirubinemia.
BMC Medical Genetics 01/2011; 12:57. · 2.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Fetal haemoglobin (HbF) is a major ameliorating factor in sickle cell disease. We investigated if a quantitative trait locus on chromosome 6q23 was significantly associated with HbF and F cell levels in individuals of African descent. Single nucleotide polymorphisms (SNPs) in a 24-kb intergenic region, 33-kb upstream of the HBS1L gene and 80-kb upstream of the MYB gene, were typed in 177 healthy Afro-Caribbean subjects (AC) of approximately 7% European admixture, 631 healthy Afro-Germans (AG, a group of African and German descendents located in rural Jamaica with about 20% European admixture), 87 West African and Afro-Caribbean individuals with sickle cell anaemia (HbSS), as well as 75 Northern Europeans, which served as a contrasting population. Association with a tag SNP for the locus was detected in all four groups (AC, P = 0.005, AG, P = 0.002, HbSS patients, P = 0.019, Europeans, P = 1.5 x 10(-7)). The association signal varied across the interval in the African-descended groups, while it is more uniform in Europeans. The 6q QTL for HbF traits is present in populations of African origin and is also acting in sickle cell anaemia patients. We have started to distinguish effects originating from European and African ancestral populations in our admixed study populations.
PLoS ONE 02/2009; 4(1):e4218. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: The pathophysiological basis of severe respiratory syncytial virus (RSV) bronchiolitis in infancy is poorly understood and has hindered vaccine development. Studies implicate the cell-mediated immune response in the pathogenesis of the disease. A recent twin study estimated a heritable contribution of 22% to RSV bronchiolitis. Genetic epidemiology provides a new approach to identifying important immune determinants of disease severity.
A comprehensive high-density gene-region association study for severe RSV bronchiolitis in infancy at 5q31 across 11 genes including the Th2-cytokine cluster was performed. A haplotype tagging approach was used to analyse genetic variation at 113 single nucleotide polymorphisms (SNPs) in 780 independent cases and 1045 controls. The study had sufficient power to detect small effects, perform extensive haplotype analysis and analyse both a principal phenotype and a refined age-limited phenotype enriched for first-exposure RSV infection.
SNP associations were found at IL4 and a highly significant risk haplotype was identified across IL13 CNS-1 and IL4 (odds ratio 1.69, p<0.0001), present in both case-control and family-based analyses. All associations were strongest for a phenotype limited to <6 months of age, implicating this locus in primary RSV disease. The same risk haplotype has previously been shown to be associated with increased IL13 expression.
A haplotype at IL13-1L4, which is associated with increased IL13 production, confers an increased risk of severe primary RSV bronchiolitis in early infancy. This study, together with previous studies implicating the same locus in atopic sensitisation, suggests that primary RSV bronchiolitis and atopy share a genetic contribution at the IL13-IL4 locus.
[show abstract][hide abstract] ABSTRACT: High levels of fetal haemoglobin (HbF) are protective in beta-haemoglobinopathies. The proportion of erythrocytes containing HbF (F-cells, FC) was measured in healthy adults of African and Caucasian ancestry to assess the feasibility of localizing genes for the FC trait using admixture mapping. Participants were Afro-Caribbean (AC) blood donors and residents of a rural enclave with a history of recent German admixture (Afro-German, AG) recruited in Jamaica, and Caucasian Europeans recruited in Jamaica and the UK. FC levels were significantly different between groups (P < 0.001); the geometric mean FC level in the AC sample (n = 176) was 3.75% [95% confidence interval (CI) 3.36-4.18], AG sample (n = 631) was 2.77% (95% CI 2.63-2.92), and among Caucasians (n = 1099) was 3.26% (95% CI 3.13-3.39). After adjustment for age, sex, haemoglobin electrophoresis pattern, and HBG2 genotype, FC levels in the AC group remained significantly different (P < 0.001) from those in the Caucasian and the AG group but the difference between the Caucasian and AG groups became non-significant (P = 0.46) despite substantial differences in average ancestry. The data confirm ethnic differences in FC levels and indicate the potential usefulness of these populations for admixture mapping of genes for FC levels.
British Journal of Haematology 12/2008; 144(6):954-60. · 4.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Plasma levels of tumor necrosis factor-alpha (TNF-alpha) are significantly raised in malaria infection and TNF-alpha is thought to inhibit intestinal iron absorption and macrophage iron release. This study investigated putative functional single nucleotide polymorphisms (SNPs) and haplotypes across the major histocompatibility complex (MHC) class III region, including TNF and its immediate neighbors nuclear factor of kappa light polypeptide gene enhancer in B cells (lkappaBL), inhibitor-like 1 and lymphotoxin alpha (LTA), in relation to nutritional iron status and anemia, in a cohort of 780 children across a malaria season. The prevalence of iron deficiency anemia (IDA) increased over the malaria season (P < .001). The TNF(-308) AA genotype was associated with an increased risk of iron deficiency (adjusted OR 8.1; P = .001) and IDA (adjusted OR 5.1; P = .01) at the end of the malaria season. No genotypes were associated with IDA before the malaria season. Thus, TNF appears to be a risk factor for iron deficiency and IDA in children in a malaria-endemic environment and this is likely to be due to a TNF-alpha-induced block in iron absorption.
[show abstract][hide abstract] ABSTRACT: Childhood malnutrition is known to be associated with visible lightening of hair colour (hypochromotrichia). Nevertheless, no systematic investigations have been carried out to determine the biochemical basis of this change. We used an HPLC method to measure melanins in the scalp hair of thirteen Jamaican children, diagnosed as having primary malnutrition, during various stages of their treatment and after recovery. During treatment for malnutrition, a progressive decrease in total melanin content along the hair shaft from tip to root (root:tip ratio: 0.62 (sd 0.31)) was observed. This ratio was significantly different (P = 0.003) from the ratio observed among children sampled several months after discharge from hospital (0.93 (sd 0.23)) and among normal control children (0.97 (sd 0.12)). Thus, it appears that a decrease in melanin content is associated with periods of malnutrition. The low root:tip ratio during malnutrition presumably arises because the tips reflect prior hair growth during 'normal' nutrition and the roots reflect hair growth during malnutrition; a return of the root:tip ratio to that seen among controls reflects 'recovery' from malnutrition. It is possible that reduced intake or availability of tyrosine, a key substrate in melanin synthesis, may play a role in the reduction of hair melanin content during periods of malnutrition. The precise mechanisms by which melanin content is reduced, and the role of aromatic amino acid availability in hair colour change and other features of childhood malnutrition remain to be explored.
British Journal Of Nutrition 08/2007; 98(1):159-64. · 3.30 Impact Factor
[show abstract][hide abstract] ABSTRACT: Tumor necrosis factor (TNF) is thought to be a key mediator of the inflammatory and fibrotic response to Chlamydia trachomatis (Ct) infection. A large matched-pair case-control study investigated putative functional single nucleotide polymorphisms (SNPs) across the major histocompatibility complex (MHC) class III region, including TNF and its immediate neighbors nuclear factor of kappa light polypeptide gene enhancer in B cells (IkappaBL), inhibitor like 1 and lymphotoxin alpha (LTA) in relation to the risk of scarring sequelae of ocular Ct infection. Haplotype and linkage disequilibrium analysis demonstrated two haplotypes, differing at position TNF-308, conferring an increased risk of trichiasis. The TNF-308A allele, and its bearing haplotype, correlated with increased TNF production in lymphocyte cultures stimulated with chlamydial elementary body antigen. Thus TNF-308A may determine directly, or be a marker of a high TNF producer phenotype associated with increased risk of sequelae of chlamydial infection. Multivariate analysis provided evidence for the presence of additional risk-associated variants near the TNF locus.
Genes and Immunity 07/2007; 8(4):288-95. · 3.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: The sickle (betas) mutation in the beta-globin gene (HBB) occurs on five "classical" betas haplotype backgrounds in ethnic groups of African ancestry. Strong selection in favour of the betas allele - a consequence of protection from severe malarial infection afforded by heterozygotes - has been associated with a high degree of extended haplotype similarity. The relationship between classical betas haplotypes and long-range haplotype similarity may have both anthropological and clinical implications, but to date has not been explored. Here we evaluate the haplotype similarity of classical betas haplotypes over 400 kb in population samples from Jamaica, The Gambia, and among the Yoruba of Nigeria (Hapmap YRI).
The most common betas sub-haplotype among Jamaicans and the Yoruba was the Benin haplotype, while in The Gambia the Senegal haplotype was observed most commonly. Both subtypes exhibited a high degree of long-range haplotype similarity extending across approximately 400 kb in all three populations. This long-range similarity was significantly greater than that seen for other haplotypes sampled in these populations (P < 0.001), and was independent of marker choice and marker density. Among the Yoruba, Benin haplotypes were highly conserved, with very strong linkage disequilibrium (LD) extending a megabase across the betas mutation.
Two different classical betas haplotypes, sampled from different populations, exhibit comparable and extensive long-range haplotype similarity and strong LD. This LD extends across the adjacent recombination hotspot, and is discernable at distances in excess of 400 kb. Although the multi-centric geographic distribution of betas haplotypes indicates strong subdivision among early Holocene sub-Saharan populations, we find no evidence that selective pressures imposed by falciparum malaria varied in intensity or timing between these subpopulations. Our observations also suggest that cis-acting loci, which may influence outcomes in sickle cell disease, could lie considerable distances away from beta-globin.
[show abstract][hide abstract] ABSTRACT: The high frequency of the sickle allele in some parts of Africa is understood to be a consequence of high malarial endemicity. One corollary of this is that the sickle allele frequency should be declining in populations of African ancestry that are no longer exposed to malaria. We have previously shown that there has been no change in sickle allele frequency in malaria-free Jamaica between two large-scale neonatal screening exercises conducted in 1973-1981 and 1995-2003. To evaluate the determinants of, and derive expected values for, sickle allele frequency in Jamaica, local empirical data were used to estimate the parameters of deterministic models of allele frequency decline. We found that although model predictions were broadly consistent with observed values in the 1973-1981 cohort, the predicted change in allele frequency between the two cohorts was larger than the observed, nonsignificant, reduction. Close agreement between predicted and observed values was only achieved by simulating a recent, marked increase in HbSS fitness. Thus, the "unexpected" persistence of the sickle allele in Jamaica may reflect the fact that the actual fitness among SS individuals is higher than that previously realized. If true, our models suggest that without substantial changes in current screening and counseling practice, there will be little "natural" reduction in sickle allele frequency for several hundred years. Better estimates of relative fitness will be helpful in refining these predictions and may aid in assigning health care priorities in Jamaica and the African Diaspora.
American Journal of Hematology 12/2006; 81(11):817-23. · 4.00 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is presently much interest in utilizing patterns of linkage disequilibrium (LD) to further genetic association studies. This is particularly pertinent in the class III region of the human major histocompatibility complex (MHC), which has been extensively studied as a disease susceptibility locus in a number of ethnic groups. To date, however, few studies of LD in the MHC have considered non-Caucasian populations. With the advent of large-scale haplotyping of the human genome, the question of utilizing LD patterns across populations has come to the fore. We have previously used LD mapping to direct an MHC class III association study in a UK Caucasian population. As an extension of this, we sought to determine to what extent the pattern of LD observed in that study could be used to conduct a similar study in a West African Gambian population. We found that broad patterns of LD were similar in the two populations, resulting in similar candidate region delineations, but at a higher resolution, marker-specific patterns of LD and population-dependent allele frequencies confounded the choice of regional tagging SNPs. Our results have implications for the applicability of large-scale haplotype maps such as the HapMap to complex regions like the MHC.
[show abstract][hide abstract] ABSTRACT: Transmission ratio distortion (TRD) describes a significant departure from expected Mendelian inheritance ratios that is fundamental to both the biology of reproduction and statistical genetics. The relatively high fetal wastage in humans, with consequent selection of alleles in utero, makes it likely that TRD is prevalent in the human genome. The central region of the human major histocompatibility complex (MHC) is a strong TRD candidate, as it houses a number of immune and regulatory genes that may be important in pregnancy outcome. We used a nonhaplotype-based method to select 13 tagging SNPs from three central MHC candidate regions, and analysed their transmission in 380 newborns and their parents (1138 individuals). A TRD of 54:46 was noted in favour of the common allele of a promoter SNP in the CLIC1 gene (P = 0.025), with a similar distortion using haplotypes across the same gene region (P = 0.016). We also found evidence that markers in the CLIC1 gene region may have been subject to recent selection (P < 0.001). The study illustrates the potential benefits of screening for TRD and highlights the difficulties encountered therein.
Genes and Immunity 02/2006; 7(1):51-8. · 3.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is growing interest in the use of haplotype-based methods for detecting recent selection. Here, we describe a method that uses a sliding window to estimate similarity among the haplotypes associated with any given single-nucleotide polymorphism (SNP) allele. We used simulations of natural selection to provide estimates of the empirical power of the method to detect recently selected alleles and found it to be comparable in power to the popular long-range haplotype test and more powerful than methods based on nucleotide diversity. We then applied the method to a recently selected allele--the sickle mutation at the HBB locus--and found it to have a signal of selection that was significantly stronger than that of simulated models both with and without strong selection. Using this method, we also evaluated >4,000 SNPs on chromosome 20, indicating the applicability of the method to regional data sets.
The American Journal of Human Genetics 01/2006; 78(1):153-9. · 11.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Linkage disequilibrium across the human genome is generally lower in West Africans than Europeans. However in the 5q31 region, which is rich in immune genes, we find significantly more examples of apparent nonrecombination between distant marker pairs in West Africans. Much of this effect is due to SNPs that are absent in Europeans, possibly reflecting recent positive selection in the West African population.
Genes and Immunity 01/2006; 6(8):723-7. · 3.68 Impact Factor
[show abstract][hide abstract] ABSTRACT: The 'malaria hypothesis' predicts that the frequency of the sickle allele, which is high in malaria-endemic African populations, should decline with each generation in populations of African descent living in areas where malaria is no longer endemic. In order to determine whether this has been the case in Jamaica, we compared haemoglobin electrophoresis results from two hospital-based screening programmes separated by more than 20 years (i.e. approximately one generation). The first comprised 100,000 neonates screened between 1973 and 1981, the second, 104,183 neonates screened between 1995 and 2003. The difference in frequency of the sickle allele was small (5.47% in the first cohort and 5.38% in the second screening cohort) and not significant (Z = 1.23, P = 0.22). The same was true of the sickle trait frequency (10.05% in the first cohort and 9.85% in the second, Z = 1.45, P = 0.15). These differences were smaller than predicted under simple deterministic models based on the malaria hypothesis, and suggest that these models may not capture important determinants of allele and trait frequency decline (or persistence) in contemporary populations. Refining the expectations for allele and trait frequency change for Jamaica and other similar populations is an area for future study.
British Journal of Haematology 10/2005; 130(6):939-42. · 4.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: The completion of the Human Genome Project has provided insight into human genetic variation, most commonly represented by single-nucleotide polymorphisms. There is presently a great deal of interest in linking genetic and phenotypic variation in the form of severity of, and susceptibility to, common multifactorial diseases. This article provides a background to recent advances in genetics, focusing on the application to common neonatal disorders and the practical difficulties of genetic association studies, as well as highlighting the potential impact on clinical practice.
Seminars in Fetal and Neonatal Medicine 07/2005; 10(3):283-9. · 3.51 Impact Factor
[show abstract][hide abstract] ABSTRACT: Susceptibility to viral bronchiolitis, the commonest cause of infant admissions to hospital in the industrialised world, is associated with polymorphism at the IL8 locus. Here we map the genomic boundaries of the disease association by case-control analysis and TDT in 580 affected UK infants. Markers for association mapping were chosen after determining patterns of linkage disequilibrium across the surrounding region of chromosome 4q, a 550-kb segment containing nine genes, extending from AFP to PPBP. The region has three major clusters of high linkage disequilibrium and is notable for its low haplotypic diversity. We exclude adjacent chemokine genes as the cause of the association, and identify a disease-associated haplotype that spans a 250-kb region from AFM to IL8. In between these two genes there is only one structural feature of interest, a novel gene RASSF6, which is predicted to encode a Ras effector protein.
Human Genetics 03/2004; 114(3):272-9. · 4.63 Impact Factor
[show abstract][hide abstract] ABSTRACT: It is a basic principle of genetics that each chromosome is transmitted from parent to offspring with a probability that is given by Mendel's laws. However, several known biological processes lead to skewed transmission probabilities among surviving offspring and, therefore, to excess genetic sharing among relatives. Examples include in utero selection against deleterious mutations, meiotic drive, and maternal-fetal incompatibility. Although these processes affect our basic understanding of inheritance, little is known about their overall impact in humans or other mammals. In this study, we examined genome screen data from 148 nuclear families, collected without reference to phenotype, to look for departures from Mendelian transmission proportions. Using single-point and multipoint linkage analysis, we detected a modest but significant genomewide shift towards excess genetic sharing among siblings (average sharing of 50.43% for the autosomes; P=.009). Our calculations indicate that many loci with skewed transmission are required to produce a genomewide shift of this magnitude. Since transmission distortion loci are subject to strong selection, this raises interesting questions about the evolutionary forces that keep them polymorphic. Finally, our results also have implications for mapping disease genes and for the genetics of fertility.
The American Journal of Human Genetics 02/2004; 74(1):62-72. · 11.20 Impact Factor