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We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated locus on 15q22.2 to identify a likely causal variant, determine its direction-of-effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of sixteen strongly associated (p0.8) with the GWAS index SNP rs7172432. These variants reside in an evolutionarily and functionally conserved islet/beta cell stretch/super enhancer (SE) the most strongly associated variant (rs7163757, p=3x10-19) overlaps a conserved islet open chromatin site. DNA sequence containing the rs7163757 risk allele displayed two-fold higher enhancer activity than the non-risk allele in reporter assays (p<0.01) and was differentially bound by beta cell nuclear extract proteins. Moreover, eQTL analysis linked the rs7163757 risk allele to significant increases in human islet C2CD4B expression, implicating it as a target gene. The NFAT transcription factor specifically potentiated risk allele enhancer activity and altered patterns of nuclear protein binding to the risk allele in vitro, suggesting it may be a factor mediating risk allele effects. Together, our data suggest that the rs7163757 risk allele contributes to genetic risk of islet dysfunction and T2D by increasing NFAT-mediated islet enhancer activity and modulating C2CD4B, and possibly C2CD4A, expression.ENAfalseMouse, RatA common type 2 diabetes risk variant potentiates activity of an evolutionarily conserved islet stretch enhancer and increases C2CD4A/B expression2023-05-192018-04-06PRJNA398550