Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.
Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia.
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作者：
全基因组关联研究（GWAS）已经可重复地确定了与基于人群的血脂浓度相关的多个基因座。这些基因座上的常见遗传变异共同解释了每个脂质性状总变异的<10%。个体效应较大的罕见变异体可能会导致脂质性状的“缺失遗传力”，但罕见变异体对脂质表型的影响程度仍有待证实。在这里，我们证明了一个显着的积累罕见的变异GWAS确定的基因在患者的极端表型异常血浆甘油三酯（TG）代谢。高脂血症（HTG）患者的GWAS显示，APOA 5、GCKR、LPL和APOB基因的常见变异与HTG表型在全基因组意义上相关。我们随后对这些基因的蛋白质编码区进行了重新测序，发现438名HTG患者中存在154种罕见的错义或无义变体，而327名对照中存在53种变体（P=6.2X10-8）;这相当于HTG患者的携带频率为28.1%，对照为15.3%（P=2.6X10-5）。许多罕见的变体被计算机预测为具有受损的功能;另外一些先前在体外证明了功能障碍。这4个基因中的罕见变异解释了HTG诊断中总变异的1.1%。我们的研究表明，一个显着的突变偏斜，可能有助于HTG患者的疾病病理生理。
Genome-wide association studies (GWAS) have replicably identified multiple loci associated with population-based plasma lipid concentrations. Common genetic variants at these loci together explain <10% of the total variation of each lipid trait. Rare variants of individually large effect may contribute additionally to the “missing heritability” of lipid traits, however it remains to be shown to what extent rare variants will affect lipid phenotypes. Here, we demonstrate a significant accumulation of rare variants in GWAS-identified genes in patients with an extreme phenotype of abnormal plasma triglyceride (TG) metabolism. A GWAS of hypertriglyceridemia (HTG) patients revealed that common variants in APOA5, GCKR, LPL and APOB genes were associated with the HTG phenotype at genome-wide significance. We subsequently resequenced protein coding regions of these genes and found a significant burden of 154 rare missense or nonsense variants in 438 HTG patients, in contrast to 53 variants in 327 controls (P=6.2X10-8); this corresponds to a carrier frequency of 28.1% of HTG patients and 15.3% of controls (P=2.6X10-5). Many rare variants were predicted in silico to have compromised function; additionally some had previously demonstrated dysfunctionality in vitro. Rare variants in these 4 genes explained 1.1% of total variation in HTG diagnoses. Our study demonstrates a marked mutation skew that likely contributes to disease pathophysiology in patients with HTG.
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与人类血液低密度脂蛋白胆固醇、高密度脂蛋白胆固醇或甘油三酯相关的六个新位点。
影响因子：
30.8
作者：
Kathiresan, Sekar;Melander, Olle;Guiducci, Candace;Surti, Aarti;Burtt, Noel P.;Rieder, Mark J.;Cooper, Gregory M.;Roos, Charlotta;Voight, Benjamin F.;Havulinna, Aki S.;Wahlstrand, Bjorn;Hedner, Thomas;Corella, Dolores;Tai, E. Shyong;Ordovas, Jose M.;Berglund, Goran;Vartiainen, Erkki;Jousilahti, Pekka;Hedblad, Bo;Taskinen, Marja-Riitta;Newton-Cheh, Christopher;Salomaa, Veikko;Peltonen, Leena;Groop, Leif;Altshuler, David M.;Orho-Melander, Marju
通讯作者：
Orho-Melander, Marju
影响因子：
30.8
作者：
Willer, Cristen J.;Sanna, Serena;Abecasis, Goncalo R.
通讯作者：
Abecasis, Goncalo R.
DOI：
10.1016/s0169-2607(98)00061-3
发表时间：
1999-01-01
影响因子：
6.1
作者：
Mittlböck, M;Schemper, M
通讯作者：
Schemper, M
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
DOI：
10.1161/atvbaha.109.186577
发表时间：
2009-06
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Beigneux AP;Franssen R;Bensadoun A;Gin P;Melford K;Peter J;Walzem RL;Weinstein MM;Davies BS;Kuivenhoven JA;Kastelein JJ;Fong LG;Dallinga-Thie GM;Young SG
通讯作者：
Young SG