Diabetes genetic clusters and clinical outcomes in American Indians

<p dir="ltr">Diabetes has a large medical and public health impact in American Indians. Studies have used genetic data to distinguish type 1 (T1D) and type 2 diabetes (T2D) and uncover biologic mechanisms underlying T2D clinical heterogeneity. We applied a T1D polygenic score (PS) to 3,084 American Indians (mean age 56 years, 58% female, 39% diabetes). We also calculated partitioned PS for eight clusters of T2D-associated variants and evaluated their association with twenty cardiometabolic traits and five clinical outcomes. The profile of T1D PS for individuals with diabetes was consistent with T2D. A total T2D PS was significantly associated with early age of onset of T2D (p-value = 3.5x10<sup>-11</sup>). Partitioned PS for T2D clusters were significantly associated with cardiometabolic traits for the obesity cluster (increased measures of body fat and total triglycerides but lower HDL cholesterol), while the lipodystrophy cluster was associated with increased fasting insulin, waist/hip ratio, triglycerides, and blood pressure and lower body fat % and HDL cholesterol. T2D clusters were not associated with cardiovascular and kidney outcomes. Our findings support a relationship of cluster-specific T2D partitioned PS with cardiometabolic traits described in other populations but there are opportunities for developing improved clustering methods using genetic variation from American Indians.</p>