Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk.
Systematic evaluation of coding variation identifies a candidate causal variant in TM6SF2 influencing total cholesterol and myocardial infarction risk.
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DOI：
10.1038/ng.2926
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发表时间：
2014-04
期刊：
影响因子：
30.8
通讯作者：
Willer CJ
中科院分区：
文献类型：
--
作者：
Holmen OL;Zhang H;Fan Y;Hovelson DH;Schmidt EM;Zhou W;Guo Y;Zhang J;Langhammer A;Løchen ML;Ganesh SK;Vatten L;Skorpen F;Dalen H;Zhang J;Pennathur S;Chen J;Platou C;Mathiesen EB;Wilsgaard T;Njølstad I;Boehnke M;Chen YE;Abecasis GR;Hveem K;Willer CJ
血脂水平是心血管疾病的可遗传、可治疗的危险因素。我们系统地评估了全基因组编码变异，以确定新的脂质基因，精细定位已知的脂质基因座，并评估是否存在具有较大影响的低频变异。使用外显子组阵列，我们对5，643名挪威人的80，137个编码变体进行了基因分型。我们追踪了4，666名挪威人的18种变异，以确定10个与脂质性状相关的编码变异基因座（P < 5×10−8）。TM 6SF 2中的一个编码变体（p.Glu167Lys）位于GWAS基因座中，用于调节脂质水平，改变总胆固醇水平，并与心肌梗死相关。在小鼠中瞬时过表达和敲低TM 6SF 2产生与在人类中观察到的相关性一致的血清脂质谱改变，将TM 6SF 2鉴定为先前称为NCAN/CILP 2/PBX 4或19 p13的大GWAS基因座处的功能基因。这项研究表明，编码变异的系统评估可以快速指向候选致病基因。
Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify novel lipid genes, fine-map known lipid loci, and evaluate whether low frequency variants with large effect exist. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians to identify 10 loci with coding variants associated with a lipid trait (P < 5×10−8). One coding variant in TM6SF2 (p.Glu167Lys), residing in a GWAS locus for lipid levels, modifies total cholesterol levels and is associated with myocardial infarction. Transient overexpression and knockdown of TM6SF2 in mouse produces alteration in serum lipid profiles consistent with the association observed in humans, identifying TM6SF2 as the functional gene at a large GWAS locus previously known as NCAN/CILP2/PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.