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Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels.
Circulation: Genomic and Precision Medicine ( IF 7.4 ) Pub Date : 2020-06-08 , DOI: 10.1161/circgen.119.002772
Zhe Wang 1 , Han Chen 1 , Traci M Bartz 2 , Lawrence F Bielak 3 , Daniel I Chasman 4 , Mary F Feitosa 5 , Nora Franceschini 6 , Xiuqing Guo 7 , Elise Lim 8 , Raymond Noordam 9 , Melissa A Richard 10 , Heming Wang 11, 12 , Brian Cade 11, 12 , L Adrienne Cupples 8, 13 , Paul S de Vries 1 , Franco Giulanini 4 , Jiwon Lee 11, 12 , Rozenn N Lemaitre 14 , Lisa W Martin 15 , Alex P Reiner 16 , Stephen S Rich 17 , Pamela J Schreiner 18 , Stephen Sidney 19 , Colleen M Sitlani 14 , Jennifer A Smith 3, 20 , Ko Willems van Dijk 21, 22 , Jie Yao 7 , Wei Zhao 3 , Myriam Fornage 1, 10 , Sharon L R Kardia 3 , Charles Kooperberg 1 , Ching-Ti Liu 1 , Dennis O Mook-Kanamori 23, 24 , Michael A Province 5 , Bruce M Psaty 25, 26 , Susan Redline 11, 12 , Paul M Ridker 11, 12 , Jerome I Rotter 7 , Eric Boerwinkle 1, 27 , Alanna C Morrison 1 , 1
Affiliation  

Background:Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.Methods:In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.Results:We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3, and CD300LG) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (P=6.65×10−6 for the interaction test) and replicated at nominal significance level (P=0.013) in SMC5.Conclusions:In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

中文翻译:

稀有和低频变异在基因-酒精相互作用中对血浆脂质水平的作用。

背景:酒精摄入会影响血脂水平,这种影响可能会受到遗传变异的影响。我们旨在通过与空腹血脂水平相关的饮酒相互作用来表征聚集的罕见和低频蛋白质编码变异在基因中的作用。方法:在基因组流行病学联盟的心脏和衰老研究队列中,空腹血浆甘油三酯和高- 和低密度脂蛋白胆固醇在来自 5 项发现研究的 34 153 名欧洲血统个体和来自 6 项复制研究的 32 277 名个体中进行了测量。罕见和低频功能性蛋白质编码变体(次要等位基因频率、≤5%) 由外显子阵列测量的基因聚合,并通过基因 - 环境相互作用测试和遗传主要和基因 - 环境相互作用效应的联合测试进行评估。考虑了两个二分的自我报告酒精消费变量,当前饮酒者,定义为任何反复饮酒行为,以及经常饮酒者,定义为每周至少饮酒 2 次的当前饮酒者的子集。 结果:我们发现并复制了 21 个基因-通过联合测试在 13 个已知脂质位点的脂质关联。八个位点(我们通过联合试验在 13 个已知脂质位点发现并复制了 21 个基因-脂质关联。八个位点(我们通过联合试验在 13 个已知脂质位点发现并复制了 21 个基因-脂质关联。八个位点(PCSK9LPALPLLIPGANGPTL4APOBAPOC3CD300LG)在以先前全基因组关联研究确定的共同指数单核苷酸多态性为条件后仍然显着,表明罕见和低频变异在这些位点。显着发现了一个新基因座中甘油三酯的显着基因-醇相互作用(相互作用测试P =6.65×10 -6)并在SMC5 中以名义显着性水平(P =0.013)复制.结论:总而言之,本研究应用了新的基于基因的统计方法,并表明稀有和低频遗传变异与饮酒的血脂水平相互作用。
更新日期:2020-06-08
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