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- Title
Genetic Support for a Causal Role of Insulin Resistance on Circulating Branched-Chain Amino Acids and Inflammation.
- Authors
Qin Wang; Holmes, Michael V.; Smith, George Davey; Ala-Korpela, Mika; Wang, Qin; Davey Smith, George
- Abstract
<bold>Objective: </bold>Insulin resistance has deleterious effects on cardiometabolic disease. We used Mendelian randomization analyses to clarify the causal relationships of insulin resistance (IR) on circulating blood-based metabolites to shed light on potential mediators of the IR to cardiometabolic disease relationship.<bold>Research Design and Methods: </bold>We used 53 single nucleotide polymorphisms associated with IR from a recent genome-wide association study (GWAS) to explore their effects on circulating lipids and metabolites. We used published summary-level data from two GWASs of European individuals; data on the exposure (IR) were obtained from meta-GWASs of 188,577 individuals, and data on the outcomes (58 metabolic measures assessed by nuclear magnetic resonance) were taken from a GWAS of 24,925 individuals.<bold>Results: </bold>One-SD genetically elevated IR (equivalent to 55% higher geometric mean of fasting insulin, 0.89 mmol/L higher triglycerides, and 0.46 mmol/L lower HDL cholesterol) was associated with higher concentrations of all branched-chain amino acids (BCAAs)-isoleucine (0.56 SD; 95% CI 0.43, 0.70), leucine (0.42 SD; 95% CI 0.28, 0.55), and valine (0.26 SD; 95% CI 0.12, 0.39)-as well as with higher glycoprotein acetyls (an inflammation marker) (0.47 SD; 95% CI 0.32, 0.62) (P < 0.0003 for each). Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy.<bold>Conclusions: </bold>We provide robust evidence that IR causally affects each individual BCAA and inflammation. Taken together with existing studies, this implies that BCAA metabolism lies on a causal pathway from adiposity and IR to type 2 diabetes.
- Subjects
INSULIN resistance; AMINO acids; SINGLE nucleotide polymorphisms; GENETIC polymorphisms; GENETIC pleiotropy; GLYCOPROTEINS; ADIPOSE tissues; HUMAN body composition; BRANCHED chain amino acids; INFLAMMATION; INSULIN; TYPE 2 diabetes; RESEARCH funding; WHITE people; SEQUENCE analysis
- Publication
Diabetes Care, 2017, Vol 40, Issue 12, p1779
- ISSN
0149-5992
- Publication type
Academic Journal
- DOI
10.2337/dc17-1642