Association of protein function-altering variants with cardiometabolic traits: the strong heart study.
Association of protein function-altering variants with cardiometabolic traits: the strong heart study.
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DOI：
10.1038/s41598-022-12866-2
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发表时间：
2022-06-04
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
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蛋白质功能改变变异体携带者的临床和生物标志物表型相关性可能有助于阐明人群中的基因功能和健康效应。我们对1127名强心家族研究参与者进行了蛋白质功能改变单核苷酸变异（SNV）和插入缺失的基因分型，这些变异和插入缺失选自美洲印第安人的低覆盖率全外显子组测序。我们测试了每个SNV/indel与35个心脏代谢特征的关联。在1206个变异体中（平均次要等位基因计数= 20，范围为1至1064），约43%不存在于公开可用的储存库中。我们确定了7个SNV-性状显著相关性，包括ABCA 10（rs779392624，p = 8 × 10-9）处的错义SNV与空腹甘油三酯相关，该基因产物参与巨噬细胞脂质稳态。在非糖尿病个体中，四个基因的错义SNV与经BMI校正的空腹胰岛素相关（PHIL，chr 6：79，650，711，p = 2.1 × 10-6; TRPM 3，rs760461668，p = 5 × 10-8; SPTY 2D 1，rs756851199，p = 1.6 × 10-8; TSPO，rs 566547284，p = 2.4 × 10-6）。PHIL编码的蛋白参与胰腺β细胞的增殖和存活，TRPM 3蛋白介导胰腺β细胞中响应于葡萄糖的钙信号传导。在随访时，结合这四个基因的胰岛素风险等位基因增加的遗传风险评分与糖尿病发病几率增加53%（95%置信区间1.09，2.15）和空腹血糖受损几率增加83%（95%置信区间1.35，2.48）相关。我们的研究通过对蛋白质编码变异的研究发现了新的基因-性状关联，并证明了针对不同和高风险人群的关联筛选的优势，以研究公共资源库中不存在的变异。
Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 × 10–9) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p = 2.1 × 10–6; TRPM3, rs760461668, p = 5 × 10–8; SPTY2D1, rs756851199, p = 1.6 × 10–8; and TSPO, rs566547284, p = 2.4 × 10–6). PHIL encoded protein is involved in pancreatic β-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic β-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories.
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DOI：
10.1126/science.1215040
发表时间：
2012-02-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
MacArthur DG;Balasubramanian S;Frankish A;Huang N;Morris J;Walter K;Jostins L;Habegger L;Pickrell JK;Montgomery SB;Albers CA;Zhang ZD;Conrad DF;Lunter G;Zheng H;Ayub Q;DePristo MA;Banks E;Hu M;Handsaker RE;Rosenfeld JA;Fromer M;Jin M;Mu XJ;Khurana E;Ye K;Kay M;Saunders GI;Suner MM;Hunt T;Barnes IH;Amid C;Carvalho-Silva DR;Bignell AH;Snow C;Yngvadottir B;Bumpstead S;Cooper DN;Xue Y;Romero IG;1000 Genomes Project Consortium;Wang J;Li Y;Gibbs RA;McCarroll SA;Dermitzakis ET;Pritchard JK;Barrett JC;Harrow J;Hurles ME;Gerstein MB;Tyler-Smith C
通讯作者：
Tyler-Smith C
影响因子：
5.3
作者：
Li MX;Yeung JM;Cherny SS;Sham PC
通讯作者：
Sham PC
影响因子：
4
作者：
Liu X;White S;Peng B;Johnson AD;Brody JA;Li AH;Huang Z;Carroll A;Wei P;Gibbs R;Klein RJ;Boerwinkle E
通讯作者：
Boerwinkle E
影响因子：
3.5
作者：
Li S;Francisco AB;Han C;Pattabiraman S;Foote MR;Giesy SL;Wang C;Schimenti JC;Boisclair YR;Long Q
通讯作者：
Long Q
DOI：
10.1016/j.bbagen.2018.01.002
发表时间：
2018-04-01
影响因子：
3
作者：
Nadanaka, Satomi;Kitagawa, Hiroshi
通讯作者：
Kitagawa, Hiroshi