Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci.
Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci.
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DOI：
10.1136/jmedgenet-2012-101461
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发表时间：
2013-05
影响因子：
4
通讯作者：
Pajukanta P
中科院分区：
文献类型：
--
作者：
Weissglas-Volkov D;Aguilar-Salinas CA;Nikkola E;Deere KA;Cruz-Bautista I;Arellano-Campos O;Muñoz-Hernandez LL;Gomez-Munguia L;Ordoñez-Sánchez ML;Reddy PM;Lusis AJ;Matikainen N;Taskinen MR;Riba L;Cantor RM;Sinsheimer JS;Tusie-Luna T;Pajukanta P
墨西哥人口和其他美洲印第安人的遗产表现出很大的易患血脂异常和冠心病。然而，这些人群仍然没有得到基因组研究的充分调查，到目前为止，还没有关于这些迅速扩大的人群中脂质的全基因组关联（GWA）研究报告。我们在墨西哥人（n= 4，361）中进行了一项关于高甘油三酯血症和低高密度脂蛋白胆固醇（HDL-C）的两阶段GWA研究，并在Niemann-Pick C1型蛋白（NPC 1）基因附近发现了一个新的墨西哥特异性血清甘油三酯（TG）全基因组显著位点（P=2.43×10−08）。此外，TG的三个欧洲位点（APOA 5，GCKR和LPL）和HDL-C的四个位点（ABCA 1，CETP，LIPC和LOC 55908）在墨西哥人中达到全基因组意义。我们利用跨种族作图来缩小三个欧洲TG GWA基因座，APOA 5，MLXIPL和CILP 2，这些基因座在欧洲扫描中很宽并且包含多个候选变体。在APOA 5位点，这将最可能的易感性变体减少到rs 964184。重要的是，我们的功能分析表明rs 964184和餐后血清apoAV蛋白水平之间存在直接联系，支持rs 964184作为欧洲和墨西哥GWA信号的致病变体。总体而言，欧洲脂质GWA荟萃分析报告的100个关联中有52个概括为墨西哥人。然而，在100个欧洲GWA位点中的82个中，除了欧洲领先/最佳代理变体之外的不同变体在墨西哥人中具有最强的区域关联证据。这项墨西哥的第一项脂质GWA研究确定了一个新的高TG水平GWA基因座;利用群体间异质性来显着限制三个先前已知的欧洲GWA信号;并调查了欧洲脂质GWA SNP是否延伸到墨西哥人群。
The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations. We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4,361) and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann-Pick type C1 protein (NPC1) gene (P=2.43×10−08). Furthermore, three European loci for TGs (APOA5, GCKR, and LPL) and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We utilized cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalized to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans. This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; utilized the inter-population heterogeneity to significantly restrict three previously known European GWA signals; and surveyed whether the European lipid GWA SNPs extend to the Mexican population.
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影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
影响因子：
5.8
作者：
Johnson, Andrew D.;Handsaker, Robert E.;de Bakker, Paul I. W.
通讯作者：
de Bakker, Paul I. W.
影响因子：
9.8
作者：
Li, Bingshan;Leal, Suzanne M.
通讯作者：
Leal, Suzanne M.
影响因子：
7.7
作者：
Barquera, S;Tovar-Guzmán, V;Rivera-Dommarco, J
通讯作者：
Rivera-Dommarco, J
影响因子：
30.8
作者：
Kathiresan S;Willer CJ;Peloso GM;Demissie S;Musunuru K;Schadt EE;Kaplan L;Bennett D;Li Y;Tanaka T;Voight BF;Bonnycastle LL;Jackson AU;Crawford G;Surti A;Guiducci C;Burtt NP;Parish S;Clarke R;Zelenika D;Kubalanza KA;Morken MA;Scott LJ;Stringham HM;Galan P;Swift AJ;Kuusisto J;Bergman RN;Sundvall J;Laakso M;Ferrucci L;Scheet P;Sanna S;Uda M;Yang Q;Lunetta KL;Dupuis J;de Bakker PI;O'Donnell CJ;Chambers JC;Kooner JS;Hercberg S;Meneton P;Lakatta EG;Scuteri A;Schlessinger D;Tuomilehto J;Collins FS;Groop L;Altshuler D;Collins R;Lathrop GM;Melander O;Salomaa V;Peltonen L;Orho-Melander M;Ordovas JM;Boehnke M;Abecasis GR;Mohlke KL;Cupples LA
通讯作者：
Cupples LA