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Classification of Type 2 Diabetes Genetic Variants and a Novel Genetic Risk Score Association with Insulin Clearance

Goodarzi, Mark1; Palmer, Nicholette D2; Cui, Jinrui1; Guo, Xiuqing3; Chen, Yii-Der I3; Taylor, Kent D3; Raffel, Leslie J4; Wagenknecht, Lynne E2; Buchanan, Thomas A5; Hsueh, Willa A6; Rotter, Jerome I3

Published Nov 12, 2019; Updated Nov 25, 2019 on Dryad. https://doi.org/10.5061/dryad.s1rn8pk3t

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Nov 25, 2019 version files 220.67 KB

Abstract

Abstract Context Genome-wide association studies have identified >450 single nucleotide polymorphisms (SNPs) for type 2 diabetes (T2D). Objective To facilitate use of these SNPs in future genetic risk score (GRS)-based analyses, we aimed to classify the SNPs based on physiology. We also sought to validate GRS associations with insulin-related traits in deeply-phenotyped Mexican Americans. Design, Setting, and Participants 457 T2D SNPs from the literature were assigned physiologic function based on association studies and cluster analyses. All SNPs (All-GRS), beta-cell (BC-GRS), insulin resistance (IR-GRS), lipodystrophy (Lipo-GRS), and body mass index plus lipids (B+L-GRS) were evaluated for association with diabetes and indexes of insulin secretion (from oral glucose tolerance test), insulin sensitivity and insulin clearance (from euglycemic clamp), and adiposity and lipid markers in 1,587 Mexican Americans. Results Of the 457 SNPs, 52 were classified as BC, 30 as IR, 12 as Lipo, 12 as B+L, while physiologic function of 351 was undefined. All-GRS was strongly associated with T2D. Among the non-diabetic Mexican-Americans, BC-GRS was associated with reduced insulinogenic index, IR-GRS was associated with reduced insulin sensitivity, and Lipo-GRS was associated with reduced adiposity. B+L-GRS was associated with increased insulin clearance. The latter did not replicate in an independent cohort wherein insulin clearance was assessed by a different method. Conclusions Supporting their utility, BC-GRS, IR-GRS, and Lipo-GRS, based on SNPs discovered largely in Europeans, exhibited expected associations in Mexican Americans. The novel association of B+L-GRS with insulin clearance suggests that impaired ability to reduce insulin clearance in compensation for insulin resistance may play a role in the pathogenesis of T2D. Whether this applies to other ethnic groups remains to be determined.