Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.
Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.
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DOI：
10.1371/journal.pgen.1002138
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发表时间：
2011-06
期刊：
影响因子：
4.5
通讯作者：
Crawford DC
中科院分区：
文献类型：
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作者：
Dumitrescu L;Carty CL;Taylor K;Schumacher FR;Hindorff LA;Ambite JL;Anderson G;Best LG;Brown-Gentry K;Bůžková P;Carlson CS;Cochran B;Cole SA;Devereux RB;Duggan D;Eaton CB;Fornage M;Franceschini N;Haessler J;Howard BV;Johnson KC;Laston S;Kolonel LN;Lee ET;MacCluer JW;Manolio TA;Pendergrass SA;Quibrera M;Shohet RV;Wilkens LR;Haiman CA;Le Marchand L;Buyske S;Kooperberg C;North KE;Crawford DC
在过去的五年中，全基因组关联研究（GWAS）已经确定了数百种与人类疾病和特征相关的常见变异，包括高密度脂蛋白胆固醇（HDL-C），低密度脂蛋白胆固醇（LDL-C）和甘油三酯（TG）水平。大约95个与血脂水平相关的基因座主要在欧洲血统的人群中被确定。使用基因组学和流行病学（PAGE）研究的群体结构于2008年建立，以表征GWAS在各种基于人群的研究中鉴定的变体。我们在至少两项PAGE研究中对49个GWAS鉴定的SNP进行了基因分型，这些SNP与一种或多种脂质性状相关，分布在6个种族/民族中。我们进行了一项荟萃分析测试SNP与空腹HDL-C，LDL-C和ln（TG）水平的相关性，研究对象包括自我认定的欧洲裔美国人（20,000人），非洲裔美国人（209000人），美洲印第安人（206000人），墨西哥裔美国人/西班牙裔（202500人），日本人/东亚人（20690人）和太平洋岛民/夏威夷原住民（20175人）成人。无论是否使用降脂药物。我们在欧洲裔美国人中重复了60个SNP关联中的55个（92%），p<0.05。尽管有足够的把握度，但我们无法复制先前与HDL-C相关的ABCA 1 rs 4149268和rs 1883025、CETP rs 1864163和TTC 39 B rs 471364以及先前与LDL-C相关的MAFB rs6102059。基于显著性（p<0.05）和一致的效应方向，在欧洲裔美国人中，HDL-C、LDL-C和ln（TG）的大多数重复基因型-表型关联可推广至非洲裔美国人（48%、61%和57%）、美洲印第安人（45%、64%和77%）和墨西哥裔美国人/西班牙裔美国人（57%、56%和86%）。总体而言，16个协会在所有三个人群中推广。对于没有概括的关联，效应大小、等位基因频率和连锁不平衡的差异为这些性状的下一代关联研究提供了线索。低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）和甘油三酯（TG）水平是众所周知的心血管疾病的独立危险因素。在欧洲血统样本的全基因组关联研究（GWAS）中发现了与脂质相关的遗传变异，但在其他人群中存在的数据不足。因此，强烈需要表征这些GWAS鉴定的变体在更多样化的群组中的作用。在这项研究中，我们选择了40多个先前与血脂水平相关的遗传位点，并在一个大型的欧洲裔美国人队列中进行了复制测试。我们还调查了这些变异的影响是否普遍适用于非欧洲血统人群，包括非洲裔美国人，美洲印第安人和墨西哥裔美国人/西班牙裔美国人。大多数这些GWAS确定的协会复制在我们的欧洲裔美国人队列。然而，关联在其他种族/民族人群中推广的能力差异很大，表明这些GWAS鉴定的变体中的一些可能不是功能性的，并且更可能与功能性变体处于连锁不平衡。
For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS–identified variants in diverse population-based studies. We genotyped 49 GWAS–identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (∼20,000), African American (∼9,000), American Indian (∼6,000), Mexican American/Hispanic (∼2,500), Japanese/East Asian (∼690), and Pacific Islander/Native Hawaiian (∼175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits. Low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG) levels are well known independent risk factors for cardiovascular disease. Lipid-associated genetic variants are being discovered in genome-wide association studies (GWAS) in samples of European descent, but an insufficient amount of data exist in other populations. Therefore, there is a strong need to characterize the effect of these GWAS–identified variants in more diverse cohorts. In this study, we selected over forty genetic loci previously associated with lipid levels and tested for replication in a large European American cohort. We also investigated if the effect of these variants generalizes to non-European descent populations, including African Americans, American Indians, and Mexican Americans/Hispanics. A majority of these GWAS–identified associations replicated in our European American cohort. However, the ability of associations to generalize across other racial/ethnic populations varied greatly, indicating that some of these GWAS–identified variants may not be functional and are more likely to be in linkage disequilibrium with the functional variant(s).
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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影响因子：
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作者：
Göring, HHH;Terwilliger, JD;Blangero, J
通讯作者：
Blangero, J
DOI：
10.1111/j.1530-0277.2010.01156.x
发表时间：
2010-05
期刊：
Alcoholism, clinical and experimental research
影响因子：
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作者：
Edenberg HJ;Koller DL;Xuei X;Wetherill L;McClintick JN;Almasy L;Bierut LJ;Bucholz KK;Goate A;Aliev F;Dick D;Hesselbrock V;Hinrichs A;Kramer J;Kuperman S;Nurnberger JI Jr;Rice JP;Schuckit MA;Taylor R;Todd Webb B;Tischfield JA;Porjesz B;Foroud T
通讯作者：
Foroud T