De‐coding genetic risk variants in type 1 diabetes

Abstract

The conceptual basis for a genetic predisposition underlying the risk for developing type 1 diabetes (T1D) predates modern human molecular genetics. Over half of the genetic risk has been attributed to the human leukocyte antigen (HLA) class II gene region and to 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 to β‐cell fragility, with expression profiles in tissues and peripheral blood highlighted. The contribution of each variant 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 the development of T1D.

Functional Impact of Risk Gene Variants on the Autoimmune Responses in Type 1 Diabetes

“…For many risk genes variants, there is still insufficient understanding of whether and how they functionally impact the initiation and progression of the autoimmune process causing T1D. The functional outcomes of the coding T1D risk variants have been reviewed recently ( 59 ), and a fine mapping of the 10 known susceptibility regions combined with functional analyses provided further insight in potentially causal missense and non-coding SNP variants ( 60 ). Many of these risk genes were differentially expressed in dendritic cells upon tolerogenic modulation ( 17 , 18 ).…”

“…The SH2B3 encodes LNK (lymphocyte adaptor protein) that takes parts in several signaling pathways controlling the hematopoiesis, cytokine and integrin signaling and cell migration ( 177 ). The functional consequences of the T1D risk variant (rs3184504) that causes a missense mutation remain speculative ( 11 , 59 , 146 ), one study using human cells that reports an augmented lymphocyte proliferation that correlates with the predisposing gene variant ( 178 ) Interestingly though, a recent study shows that the T1D risk-gene variant associates with a reduced mortality from sepsis in individuals with a European decent and suggest based on a mouse model that augmented phagocytosis and myelopoiesis may be underlying mechanisms ( 179 ). The gene IKZF1 codes for the transcription factor Ikaros ( 180 ), and the associated SNPs (rs10277986, rs62447205) are protective for T1D ( 11 ).…”

The Immunoregulatory Role of the Signal Regulatory Protein Family and CD47 Signaling Pathway in Type 1 Diabetes

“…We hypothesize that SIRPγ expression on immune cells may be correlated with specific stages of T1D development in a manner governed by genetic risk variants in SIRPG , and thus, could be used as a biomarker of disease progression in conjunction with C-peptide and AAbs ( 12 , 93 , 94 ). In T1D subjects, SIRPG SNP genotype was associated with T1D risk at an early age ( P-value <0.05 , unadjusted), with the greatest effect at <7 years of age, an intermediate impact from 7 to 13 years of age, and a reduced impact at >13 years of age; therefore, therapeutic approaches involving SIRPG may have the highest efficacy at delaying or reducing T1D onset in younger patients ( 12 , 93 , 94 ).…”

Human Heterogeneity and Survival of the Species: How Did It Arise and Being Sustained?—The Conundrum Facing Researchers

“…For some genes, heterogeneity can be maintained at the level of successful reproduction. For example, genes in the major histocompatibility complex (MHC) are quite complex (MHC Class I, II and III, plus many minor loci) and may be the source for risk for a number of diseases (discussed in [7][8][9]). Based on studies from the 1970s and 1980s [10][11][12], human breeding pairs with very similar MHC antigens often have trouble carrying a fetus to term.…”