Introduction & Objective. The heterogeneity of type 2 diabetes (T2D) risk has a genetic basis that can be reflected in genetic risk scores (GRS). It is currently unknown if the nature of genetic risk for T2D varies with ancestral backgrounds. The aim of this study was to determine if patterns of genetic risk for T2D exist, and if they differ by ancestry in a sample of 342 Non-Hispanic White (NHW), Non-Hispanic Black (NHB), and Hispanic (HIS) adults with obesity and T2D.
Methods: Participants were genotyped using the Infinium Global array with imputation. Six GRS representing distinct T2D pathophysiological pathways (beta-cell, proinsulin, obesity, lipodystrophy, liver/lipid, and insulin resistance (IR)) were calculated. Principal components analysis was performed on the GRS and genetic admixture values to identify ancestry-specific patterns for risk. Spearman correlations quantified strength and direction of associations of variables to each component. Participant self-reported ethnicity was used as a supplementary categorical variable.
Results: Two principal components (PC) were retained. PC1 was associated with greater African ancestry (r=0.92, p <0.001) and the beta-cell and proinsulin GRS (r=0.442, p <0.001 and r=0.453, p<0.001, respectively). PC2 was associated with higher Native American ancestry (r=0.4691, p<0.001) and the IR and lipodystrophy GRS (r=0.52, p <0.001 and r=0.66, p<0.001, respectively). NHB were distinctly different from NHW for all variables. NHB had the highest scores for PC1, suggesting that genetic susceptibility to T2D in this group arises from impaired insulin secretion and processing abilities. HIS had the highest scores for PC2, which suggests T2D risk in this group is characterized by lipodystrophy-driven IR.
Conclusion: Our results demonstrate that genetic risk for T2D manifests in patterns that are ancestry-specific. This may be useful in future research to help refine criteria for identifying at-risk individuals based on ancestral background.
L.A. Fowler: None. B. Gower: Advisory Panel; Cook Keto, Simply Good Foods, Abbott. J.R. Fernandez: None. P.M. O'Neil: Other Relationship; Novo Nordisk.
National Institutes of Health (T32HL105349); National Institutes of Health (T32DK062710)Clinical trial from which data were collected was sponsored by Weight Watchers International to the Medical University of South Carolina (NCT01601574)
