Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.
Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.
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DOI：
10.1038/ncomms4983
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发表时间：
2014-06-02
影响因子：
16.6
通讯作者：
Pajukanta P
中科院分区：
文献类型：
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作者：
Ko A;Cantor RM;Weissglas-Volkov D;Nikkola E;Reddy PM;Sinsheimer JS;Pasaniuc B;Brown R;Alvarez M;Rodriguez A;Rodriguez-Guillen R;Bautista IC;Arellano-Campos O;Muñoz-Hernández LL;Salomaa V;Kaprio J;Jula A;Jauhiainen M;Heliövaara M;Raitakari O;Lehtimäki T;Eriksson JG;Perola M;Lohmueller KE;Matikainen N;Taskinen MR;Rodriguez-Torres M;Riba L;Tusie-Luna T;Aguilar-Salinas CA;Pajukanta P
血脂异常和肥胖在具有美洲印第安人背景的人群中尤其普遍，例如墨西哥裔美国人，这使这些人容易患心血管疾病。在这里，我们设计了一种方法，称为跨群体等位基因筛查(CPAS)，我们在对19,273名欧洲人和墨西哥人进行全基因组关联研究(GWAS)之前进行了这一方法，以识别墨西哥人中的美洲印第安人风险基因。利用CPA将GWAS输入变量限制在两个群体之间频率不同的那些，我们发现了新的美洲印第安人脂基因，受体相关孤儿受体α(RORA)和盐诱导蛋白3(SIK3)，以及三个以前与血脂异常或肥胖无关的基因座。我们还检测到脂蛋白脂酶(LPL)和载脂蛋白A5(APOA5)含有特定的美洲印第安人的风险变异和单倍型特征。值得注意的是，我们观察到SIK3和一个新的脂类基因座在墨西哥人中经历了正选择。此外，在高脂肪饮食后，SIK3风险变异携带者表现出高甘油三酯水平。这些发现表明，美洲印第安人特有的遗传结构导致现代墨西哥人血脂异常和肥胖症的发生率更高。血脂异常和肥胖在具有美洲印第安人背景的人群中有很高的流行率，例如墨西哥裔美国人。在这里，作者设计了一种方法来识别墨西哥人的美洲印第安人危险基因，并确定了五个基因组座位，其中包括可能导致美洲印第安人人群血脂异常和肥胖风险的RORA和SIK3。
Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican–Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans. Dyslipidemia and obesity have a high prevalence in populations with Amerindian backgrounds, such as Mexican–Americans. Here, the authors design an approach to identify Amerindian risk genes in Mexicans and identify five genomic loci, which include RORA and SIK3 that may contribute to the risk of dyslipidemia and obesity in Amerindian populations.