Interaction of Insulin Resistance and Related Genetic Variants With Triglyceride-Associated Genetic Variants

Q Medicine

Circulation-Cardiovascular Genetics Pub Date : 2016-04-01 DOI:10.1161/CIRCGENETICS.115.001246

Y. Klimentidis, Amit Arora

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引用次数: 9

Abstract

Background—Several studies suggest that some triglyceride-associated single-nucleotide polymorphisms (SNPs) have pleiotropic and opposite effects on glycemic traits. This potentially implicates them in pathways such as de novo lipogenesis, which is presumably upregulated in the context of insulin resistance. We therefore tested whether the association of triglyceride-associated SNPs with triglyceride levels differs according to one’s level of insulin resistance. Methods and Results—In 3 cohort studies (combined n=12 487), we tested the interaction of established triglyceride-associated SNPs (individually and collectively) with several traits related to insulin resistance, on triglyceride levels. We also tested the interaction of triglyceride SNPs with fasting insulin–associated SNPs, individually and collectively, on triglyceride levels. We find significant interactions of a weighted genetic risk score for triglycerides with insulin resistance on triglyceride levels (Pinteraction=2.73×10−11 and Pinteraction=2.48×10–11 for fasting insulin and homeostasis model assessment of insulin resistance, respectively). The association of the triglyceride genetic risk score with triglyceride levels is >60% stronger among those in the highest tertile of homeostasis model assessment of insulin resistance compared with those in the lowest tertile. Individual SNPs contributing to this trend include those in/near GCKR, CILP2, and IRS1, whereas PIGV-NROB2 and LRPAP1 display an opposite trend of interaction. In the pooled data set, we also identify a SNP–by–SNP interaction involving a triglyceride-associated SNP, rs4722551 near MIR148A, with a fasting insulin–associated SNP, rs4865796 in ARL15 (Pinteraction=4.1×10−5). Conclusions—Our findings may thus provide genetic evidence for the upregulation of triglyceride levels in insulin-resistant individuals, in addition to identifying specific genetic loci and a SNP–by–SNP interaction implicated in this process.

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胰岛素抵抗和相关遗传变异与甘油三酯相关遗传变异的相互作用

一些研究表明，一些甘油三酯相关的单核苷酸多态性(SNPs)对血糖性状具有多效性和相反的作用。这可能暗示它们参与了新生脂肪生成等途径，这可能在胰岛素抵抗的背景下被上调。因此，我们测试了甘油三酯相关snp与甘油三酯水平的关系是否因胰岛素抵抗水平而异。方法和结果:在3项队列研究中(合计n= 12487)，我们测试了已建立的甘油三酯相关snp(单独和集体)与胰岛素抵抗相关的几个性状对甘油三酯水平的相互作用。我们还测试了甘油三酯snp与空腹胰岛素相关snp的相互作用，单独和集体，甘油三酯水平。我们发现甘油三酯加权遗传风险评分与甘油三酯水平的胰岛素抵抗之间存在显著的相互作用(空腹胰岛素和胰岛素抵抗稳态模型评估的Pinteraction=2.73×10 - 11和Pinteraction= 2.48×10-11)。甘油三酯遗传风险评分与甘油三酯水平的相关性在胰岛素抵抗稳态模型评估中处于最高分位数的人群中比处于最低分位数的人群强60%。导致这一趋势的单个snp包括GCKR、CILP2和IRS1中/附近的snp，而PIGV-NROB2和LRPAP1则表现出相反的相互作用趋势。在汇总的数据集中，我们还发现了一个SNP - SNP相互作用，涉及甘油三酯相关SNP, MIR148A附近的rs4722551，以及ARL15中空腹胰岛素相关SNP, rs4865796 (p相互作用=4.1×10−5)。结论:我们的研究结果可能因此为胰岛素抵抗个体甘油三酯水平上调提供了遗传学证据，此外还确定了与此过程相关的特定遗传位点和snp - snp相互作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation-Cardiovascular Genetics CARDIAC & CARDIOVASCULAR SYSTEMS-GENETICS & HEREDITY

CiteScore

3.95

自引率

0.00%

发文量

期刊介绍： Circulation: Genomic and Precision Medicine considers all types of original research articles, including studies conducted in human subjects, laboratory animals, in vitro, and in silico. Articles may include investigations of: clinical genetics as applied to the diagnosis and management of monogenic or oligogenic cardiovascular disorders; the molecular basis of complex cardiovascular disorders, including genome-wide association studies, exome and genome sequencing-based association studies, coding variant association studies, genetic linkage studies, epigenomics, transcriptomics, proteomics, metabolomics, and metagenomics; integration of electronic health record data or patient-generated data with any of the aforementioned approaches, including phenome-wide association studies, or with environmental or lifestyle factors; pharmacogenomics; regulation of gene expression; gene therapy and therapeutic genomic editing; systems biology approaches to the diagnosis and management of cardiovascular disorders; novel methods to perform any of the aforementioned studies; and novel applications of precision medicine. Above all, we seek studies with relevance to human cardiovascular biology and disease. Manuscripts are examined by the editorial staff and usually evaluated by expert reviewers assigned by the editors. Both clinical and basic articles will also be subject to statistical review, when appropriate. Provisional or final acceptance is based on originality, scientific content, and topical balance of the journal. Decisions are communicated by email, generally within six weeks. The editors will not discuss a decision about a manuscript over the phone. All rebuttals must be submitted in writing to the editorial office.