De-coding genetic risk variants in type 1 diabetes.

Shapiro, Melanie R; Thirawatananond, Puchong; Peters, Leeana; Sharp, Robert C; Ogundare, Similoluwa; Posgai, Amanda; Perry, Daniel J; Brusko, Todd M

The conceptual basis for a genetic predisposition underlying risk for type 1 diabetes (T1D) development predates modern human molecular genetics. Over half of genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and the insulin (INS) gene locus - both thought to confer direction of autoreactivity and tissue specificity. Notwithstanding, questions still remain regarding the functional contributions of a vast array of minor polygenic risk variants scattered throughout the genome that likely influence disease heterogeneity and clinical outcomes. Herein, we summarize the available literature related to the T1D-associated coding variants defined at the time of this review, for the genes PTPN22,IFIH1,SH2B3,CD226,TYK2,FUT2,SIRPG,CTLA4,CTSH, and UBASH3A. Data from genotype-selected human cohorts are summarized, and studies from the non-obese diabetic (NOD) mouse are presented to describe the functional impact of these variants in relation to innate and adaptive immunity as well as β-cell fragility, with expression profiles in tissues and peripheral blood highlighted. Each variant's contribution to progression through T1D staging, including environmental interactions, are discussed with consideration of how their respective protein products may serve as attractive targets for precision-medicine based therapeutics to prevent or suspend T1D development.