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Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans (vol 40, pg 189, 2008)

Authors:
Sekar Kathiresan
Sekar Kathiresan
Sekar Kathiresan
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Olle Melander at Lund University
Olle Melander
Candace Guiducci
Candace Guiducci
Candace Guiducci
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Aarti Surti
Aarti Surti
Aarti Surti
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Abstract

Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 × 10-8 for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.
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Corrigendum: Six new loci associated with blood low-density lipoprotein
cholesterol, high-density lipoprotein cholesterol or triglycerides in humans
Sekar Kathiresan, Olle Melander, Candace Guiducci, Aarti Surti, Noël P Burtt, Mark J Rieder, Gregory M Cooper, Charlotta Roos,
Benjamin F Voight, Aki S Havulinna, Björn Wahlstrand, Thomas Hedner, Dolores Corella, E Shyong Tai, Jose M Ordovas, Göran Berglund,
Erkki Vartiainen, Pekka Jousilahti, Bo Hedblad, Marja-Riitta Taskinen, Christopher Newton-Cheh, Veikko Salomaa, Leena Peltonen,
Leif Groop, David M Altshuler & Marju Orho-Melander
Nat. Genet. 40, 189–197 (2008); published online 13 January 2008; corrected after print 29 October 2008
In the version of this article initially published, the institutional affiliation for Dolores Corella was not complete. Her affiliation is with the
Department of Preventive Medicine, School of Medicine, University of Valencia and CIBER Fisiopatología de la Obesidad y Nutrition, ISCIII,
Valencia, 46010, Spain. The error has been corrected in the HTML and PDF versions of the article.
Corrigenda
1384 volume 40 | number 11 | november 2008 | nature genetics
Corrigendum: Mutations of CASK cause an X-linked brain malformation
phenotype with microcephaly and hypoplasia of the brainstem and cerebellum
Juliane Najm, Denise Horn, Isabella Wimplinger, Jeffrey A Golden, Victor V Chizhikov, Jyotsna Sudi, Susan L Christian, Reinhard Ullmann,
Alma Kuechler, Carola A Haas, Armin Flubacher, Lawrence R Charnas, Gökhan Uyanik, Ulrich Frank, Eva Klopocki, William B Dobyns &
Kerstin Kutsche
Nat. Genet. 40, 1065–1067 (2008); published online 10 August 2008; corrected after print 29 October 2008
In the version of this article initially published, there was an error in the text on page 1066. The protein interacting with CASK is the CASK inter-
acting nucleosome assembly protein (CINAP/TSPYL2) and not the TATA-binding protein associated factor TAF9. This error has been corrected
in the HTML and PDF versions of the article.
©2008 Nature Publishing Group http://www.nature.com/naturegenetics
... Herman et al. (2012) demonstrated that ChREBP can be transcribed from an alternative promoter and alternative exon 1 that skips the canonical exon 1a and can be translated from a start codon in exon 4. Kooner et al. (2008) found association of a G771C nonsynonymous mutation (rs3812316, Gln241His) in ChREBP gene with plasma triglyceride levels in Indian Asians. Kathiresan et al. (2008) andWiller et al. (2008) indicated that the T/C (rs17145738) mutation at 7q11 near TBL2 and MLXIPL had the strongest effect on blood triglyceride concentrations. Gao et al. (2016) found 2 SNPs (rs1051921, rs17145750) had not identified any significant association between individual SNP or haplotype and levels of ChREBP DNA methylation, and ChREBP DNA methylation was associated with TC, TG and LDL-C. ...
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... Therefore, among these genes, only rs708272 of CETP, rs4775041 and rs1077843 of the LIPC gene and rs2144300 of the GALNT2 gene were taken into consideration in the calculation of the weighted genetic risk score, resulting in a wGRS composed of 13 SNPs. Effect size estimates for these thirteen SNPs are described in Table 2 [29e34, 39,40]. The wGRS data were normally distributed in both the Roma and General populations. ...
Genetic factors exist behind the high prevalence of reduced high-density lipoprotein cholesterol levels in the Roma population
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Background and aims: Previous findings showed that reduced plasma high-density lipoprotein cholesterol (HDL-C) levels are more frequent in all age groups of the Hungarian Roma compared to the general population. It suggests that genetic factors may exist behind this phenomenon. Our present study was designed to test this hypothesis, i.e., to define whether genetic factors contribute to the higher prevalence of reduced HDL-C among Roma. Single nucleotide polymorphisms (N = 21) contributing to the variation in plasma HDL-C concentrations were analysed in the Hungarian Roma (N = 646) and general (N = 1542) populations. Methods: Genetic risk scores, unweighted (GRS) and weighted (wGRS), were computed and compared. Associations between the GRSs and the prevalence of reduced HDL-C levels were analysed. Results: The GRS and wGRS were significantly higher in the Roma compared to the general population (GRS: 22.2 ± 3.2 vs. 21.5 ± 3.3; wGRS: 0.57 ± 0.1 vs. 0.53 ± 0.1; p<0.001). One half per cent of Roma subjects were in the bottom fifth of the wGRS (wGRS≤ 0.3) compared with 1.8% of those in the general population (p=0.025), while 5% of the Roma subjects were in the top fifth of the wGRS (wGRS≥ 0.75) compared with 2.6% of those in the general population (p=0.004). The GRS showed similar correlation with reduced plasma HDL-C levels in the two populations, whilst the wGRS showed stronger correlation with the trait among Roma after controlling for confounders. Conclusions: These results strongly suggest that genetic factors contribute to the higher prevalence of reduced HDL-C levels among Roma, so interventions aiming to improve Roma health status need to consider their increased genetic susceptibility.
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... Research into the physiological role of sortilin outside the nervous system has found sortilin to be involved in trafficking of glucose transporter type 4 vesicles [19] and expressed in several types of cancer cells202122. Furthermore, GWAS studies have found an allele of the sortilin gene locus that increases hepatic sortilin expression and confers a protective effect against cardiovascular disease [23, 24]. Subsequent studies of this have produced results suggesting that increased expression of hepatic sortilin reduces levels of low density lipoprotein (LDL)-cholesterol in blood, and thereby atherosclerosis [25]. ...
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Background Sortilin and SorCS2 are part of the Vps10p receptor family. They have both been studied in nervous tissue with several important functions revealed, while their expression and possible functions in developing peripheral tissue remain poorly understood. Here we deliver a thorough characterization of the prenatal localization of sortilin and SorCS2 in mouse peripheral tissue. Results Sortilin is highly expressed in epithelial tissues of the developing lung, nasal cavity, kidney, pancreas, salivary gland and developing intrahepatic bile ducts. Furthermore tissues such as the thyroid gland, developing cartilage and ossifying bone also show high expression of sortilin together with cell types such as megakaryocytes in the liver. SorCS2 is primarily expressed in mesodermally derived tissues such as striated muscle, adipose tissue, ossifying bone and general connective tissue throughout the body, as well as in lung epithelia. Furthermore, the adrenal gland and liver show high expression of SorCS2 in embryos 13.5 days old. Conclusions The possible functions relating to the expression patterns of Sortilin and SorCS2 in development are numerous and hopefully this paper will help to generate new hypotheses to further our understanding of the Vps10p receptor family.
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Sugar-sweetened Beverage Consumption May Modify Associations between Genetic Variants in the CHREBP Locus and HDL-C and TG Concentrations
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  • Jul 2021
Background - Carbohydrate responsive element binding protein (ChREBP) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the CHREBP locus have separately been linked to high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) concentrations. We hypothesized SSB consumption would modify the association between genetic variants in the CHREBP locus and dyslipidemia. Methods - Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium (N=63,599) and the UK Biobank (UKB) (N=59,220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and TG concentrations using linear regression models. A total of 1,606 single-nucleotide polymorphisms (SNPs) within or near CHREBP were considered. SSB consumption was estimated from validated questionnaires and participants were grouped by their estimated intake. Results - In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers [β (95% CI) = 2.12 (1.16, 3.07) mg/dl; p <0.0002], but not significantly among the lowest SSB consumers ( p =0.81; p Diff <0.0001). Similar results were observed for two additional variants (rs35709627 and rs71556736). For TG, rs55673514 was positively associated with TG concentrations only among the highest SSB consumers [β (95% CI): 0.06 (0.02, 0.09) per allele count for log(mg/dl), p =0.001], but not the lowest SSB consumers ( p =0.84; p Diff =0.0005). Conclusions - Our results identified genetic variants in the CHREBP locus that may protect against SSB-associated reductions in HDL-C and other variants that may exacerbate SSB-associated increases in TG concentrations.
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Identifying the Lipidomic Effects of a Rare Loss-of-Function Deletion in ANGPTL3
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Role of cell polarity and planar cell polarity (PCP) proteins in spermatogenesis
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  • Mar 2020
Studies on cell polarity proteins and planar cell polarity (PCP) proteins date back to almost 40 years ago in Drosophila and C. elegans when these proteins were shown to be crucial to support apico-basal polarity and also directional alignment of polarity cells across the plane of an epithelium during morphogenesis. In adult mammals, cell polarity and PCP are most notable in cochlear hair cells. However, the role of these two groups of proteins to support spermatogenesis was not explored until a decade earlier when several proteins that confer cell polarity and PCP proteins were identified in the rat testis. Since then, there are several reports appearing in the literature to examine the role of both cell polarity and PCP in supporting spermatogenesis. Herein, we provide an overview regarding the role of cell polarity and PCP proteins in the testis, evaluating these findings in light of studies in other mammalian epithelial cells/tissues. Our goal is to provide a timely evaluation of these findings, and provide some thought provoking remarks to guide future studies based on an evolving concept in the field.
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Proteomics reveals changes in hepatic proteins during chicken embryonic development: An alternative model to study human obesity
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Background: Chicken embryos are widely used as a model for studies of obesity; however, no detailed information is available about the dynamic changes of proteins during the regulation of adipose biology and metabolism. Thus, the present study used an isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic approach to identify the changes in protein abundance at different stages of chicken embryonic development. Results: In this study, the abundances of 293 hepatic proteins in 19-day old of chicken embryos compared with 14-day old and 160 hepatic proteins at hatching compared with 19-day old embryos were significantly changed. Pathway analysis showed that fatty acid degradation (upregulated ACAA2, CPT1A, and ACOX1), protein folding (upregulated PDIs, CALR3, LMAN1, and UBQLN1) and gluconeogenesis (upregulated ACSS1, AKR1A1, ALDH3A2, ALDH7A1, and FBP2) were enhanced from embryonic day 14 (E14) to E19 of chicken embryo development. Analysis of the differentially abundant proteins indicated that glycolysis was not the main way to produce energy from E19 to hatching day during chicken embryo development. In addition, purine metabolism was enhanced, as deduced from increased IMPDH2, NT5C, PGM2, and XDH abundances, and the decrease of growth rate could be overcome by increasing the abundance of ribosomal proteins from E19 to the hatching day. Conclusion: The levels of certain proteins were coordinated with each other to regulate the changes in metabolic pathways to satisfy the requirement for growth and development at different stages of chicken embryo development. Importantly, ACAA2, CPT1A, and ACOX1 might be key factors to control fat deposition during chicken embryonic development. These results provided information showing that chicken is a useful model to further investigate the mechanism of obesity and insulin resistance in humans.
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Regulatory RNAs and Cardiovascular Disease – With a Special Focus on Circulating MicroRNAs
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MicroRNAs (miRNAs) are a class of short non-coding regulatory RNA molecules which play an important role in intracellular communication and cell signaling and which influence cellular processes such as proliferation, differentiation, and cellular death. Over the past two decades, the crucial role of microRNAs in controlling tissue homeostasis and disease in cardiovascular systems has become widely recognized. By controlling the expression levels of their targets, several miRNAs have been shown to modulate the function of endothelial cells (miR-221/222 and -126), vascular smooth muscle cells (miR-143/145) and macrophages (miR-33, -758, and -26), thereby regulating the development and progression of atherosclerosis. The stability of miRNAs within the blood suggests that circulating miRNAs may function as important biomarkers of disease development and progression. Numerous circulating miRNAs have been found to be dysregulated in a wide variety of different disease states, including diabetes, cancer, and cardiovascular disease.
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Additional file 1
Data
Full-text available
  • Sep 2011
Additional tables and references. Additional Tables S1-S4 and references cited in these tables. Table S1 gives a descriptive statistics for males and females in the two genotyped cohorts. Table S2 gives the phenotypic correlations between each pair of age-corrected traits separately for males and females in combined sample. Table S3 compares the multivariate and univariates results from our study with published results. Table S4 gives a summary of borderline significant associations from multivariate analysis.
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Hunting the genes in male pattern alopecia: How important are they, how close are we, and what will they tell us?
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Androgenetic alopecia (AGA) is a highly heritable condition, and the most common form of hair loss in men. The phenotype is characterized by an androgen-dependent, progressive loss of hair from the scalp, which may commence during puberty. Up to 80% of European men experience some degree of androgen-dependent hair loss during their lifetime. Current treatment options for AGA have limited efficacy, and improved understanding of the underlying biological causes is required to facilitate novel therapeutic approaches. To date, molecular genetic studies have implicated 12 genomic regions in AGA, and identified a number of candidate genes. The latter include those encoding the androgen receptor (AR); the histone-deacetylases (HDAC) 4 and 9; and the WNT-molecule WNT10A. However, the majority of contributing genetic risk factors still await identification. This review describes the current status of AGA genetic research. We discuss the strength of the genetic approach and anticipated developments in the field, and how these will facilitate the systematic unravelling of AGA pathobiology, a process which may lead to the identification of new therapeutic targets. This article is protected by copyright. All rights reserved.
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Multiple Rare Alleles Contribute to Low Plasma Levels of HDL Cholesterol
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  • Aug 2004
  • SCIENCE
Heritable variation in complex traits is generally considered to be conferred by common DNA sequence polymorphisms. We tested whether rare DNA sequence variants collectively contribute to variation in plasma levels of highdensity lipoprotein cholesterol (HDL-C). We sequenced three candidate genes (ABCA1, APOA1, and LCAT) that cause Mendelian forms of low HDL-C levels in individuals from a population-based study. Nonsynonymous sequence variants were significantly more common (16% versus 2%) in individuals with low HDL-C (<fifth percentile) than in those with high HDL-C (>95th percentile). Similar findings were obtained in an independent population, and biochemical studies indicated that most sequence variants in the low HDL-C group were functionally important. Thus, rare alleles with major phenotypic effects contribute significantly to low plasma HDL-C levels in the general population.
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Genetic variation in ABC transporter A1 contributes to HDL cholesterol in the general population
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  • Dec 2004
Homozygosity for mutations in ABC transporter A1 (ABCA1) causes Tangier disease, a rare HDL-deficiency syndrome. Whether heterozygosity for genetic variation in ABCA1 also contributes to HDL cholesterol (HDL-C) levels in the general population is presently unclear. We determined whether mutations or single-nucleotide polymorphisms (SNPs) in ABCA1 were overrepresented in individuals with the lowest 1% (n=95) or highest 1% (n=95) HDL-C levels in the general population by screening the core promoter and coding region of ABCA1. For all nonsynonymous SNPs identified, we determined the effect of genotype on lipid traits in 9,259 individuals from the general population. Heterozygosity for ABCA1 mutations was identified in 10% of individuals with low HDL-C only. Three of 6 nonsynonymous SNPs (V771M, V825I, and R1587K) were associated with increases or decreases in HDL-C in women in the general population and some with consistent trends in men, determined as isolated single-site effects varying only at the relevant SNP. Finally, these results were consistent over time. In conclusion, we show that at least 10% of individuals with low HDL-C in the general population are heterozygous for mutations in ABCA1 and that both mutations and SNPs in ABCA1 contribute to HDL-C levels in the general population.
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Genomewide Association Analysis of Coronary Artery Disease
Article
Full-text available
  • Aug 2007
  • NEW ENGL J MED
Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.
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Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans
Article
Full-text available
  • Feb 2008
  • Nat Genet
Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 x 10(-8) for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.
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Polymorphism in APOB Associated with Increased Low-Density Lipoprotein Levels in Both Genders in the General Population
Article
  • Oct 2005
Rare mutations in APOB cause hypercholesterolemia. Whether common polymorphisms in APOB have similar effects remains controversial. We tested the hypothesis that the APOB 7673C>T polymorphism (T2488T) is associated with variation in low-density lipoprotein (LDL) levels and with risk of ischemic heart disease (IHD), ischemic cerebrovascular disease (ICVD), and total mortality in the general population. The design was a cohort study with 22-yr follow-up (166,232 person years) and two case-control studies, The Copenhagen City Heart Study. The study was performed within the Danish general population and at a university hospital. The study was comprised of 9185 individuals from the general population, 2157 patients with IHD, and 378 patients with ICVD. The main outcome measures were lipids, lipoproteins, apolipoproteins (apo), IHD, ICVD, and total mortality. Genotype was associated with increases in total cholesterol (women/men), LDL cholesterol, and apoB of 0.20/0.26 mmol/liter (3.3%/4.4%), 0.22/0.28 mmol/liter (5.9%/7.8%), and 5.0/5.6 mg/dl (5.9%/6.7%) in TT vs. CC homozygotes, respectively. These results were consistent over time. Despite this, the 7673C>T polymorphism was not associated with risk of IHD, ICVD, or total mortality prospectively or in case-control studies. The APOB 7673C>T polymorphism is associated with moderate increases in total cholesterol, LDL cholesterol, and apoB in both genders in the general population, but not with risk of IHD, ICVD, or total mortality.
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Lipoprotein Lipase S447X A Naturally Occurring Gain-of-Function Mutation
Article
  • Jul 2006
  • ARTERIOSCL THROM VAS
Lipoprotein lipase (LPL) hydrolyzes triglycerides in the circulation and promotes the hepatic uptake of remnant lipoproteins. Since the gene was cloned in 1989, more than 100 LPL gene mutations have been identified, the majority of which cause loss of enzymatic function. In contrast to this, the naturally occurring LPL(S447X) variant is associated with increased lipolytic function and an anti-atherogenic lipid profile and can therefore be regarded as a gain-of-function mutation. This notion combined with the facts that 20% of the general population carries this prematurely truncated LPL and that it may protect against cardiovascular disease has led to extensive clinical and basic research into this frequent LPL mutant. It is only until recently that we begin to understand the molecular mechanisms that underlie the beneficial effects associated with LPL(S447X). This review summarizes the current literature on this interesting LPL variant.
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