Genetic Risk Phenotypes for Type 2 Diabetes Differ with Ancestry in US Adults with Diabetes and Overweight/Obesity.

Background: Type 2 diabetes (T2D) risk is higher among non-Hispanic black (NHB) and Hispanic individuals, for reasons that are unclear.

Aims: With this cross-sectional study, we tested the hypothesis that racial disparities in T2D prevalence can be partially traced to heterogeneity in etiology, as indicated by genetic subtypes that reflect distinct T2D phenotypes.

Methods: Using a diverse sample of 361 US adults with T2D (69.5% women; 34.1% NHB; 13.9% Hispanic), we derived genetic risk scores (GRS) representing five distinct T2D pathophysiological pathways from 94 loci: β-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. Genetic predisposition for insulin resistance (IR) was also assessed using a 52-SNP IR risk score.

Results: The β-cell and proinsulin scores (as median [IQR]) were higher among NHB participants relative to NHW and Hispanics (β-cell GRS [NHB, 0.842(0.784-0.887) vs. NHW, 0.762(0.702-0.835) and Hispanic, 0.772(0.717-0.848)]); proinsulin GRS (NHB, 1.006[0.973-1.070] vs. NHW, 0.969[0.853-1.044] and Hispanic, 0.976[0.901-1.048]), whereas the liver/lipid and 52-SNP IR scores were higher in both NHB and Hispanic participants versus NHW (liver/lipid GRS [NHB, 1.09(0.78-1.18) and Hispanic, 0.895(0.736-1.227) vs. NHW, 0.794(0.666-1.157)]); 52-SNP IR GRS (NHB, 0.0095[0.009-0.010] and Hispanic, 0.0096 [0.0092-0.0101] vs. NHW, 0.0090[0.0084-0.0095]).

Conclusions: Impaired β-cell function may underlie T2D etiology more profoundly in NHB, whereas hepatic dysfunction, lipid metabolism abnormalities, and genetic IR contribute to T2D etiology to a greater degree in both NHB and Hispanics. Further validation of these findings may form the basis for a personalized medicine approach to prevention and treatment of T2D.