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

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.