Assessing variation across 8 established East Asian loci for type 2 diabetes mellitus in American Indians: Suggestive evidence for new sex-specific diabetes signals in GLIS3 and ZFAND3

BackgroundEight new loci for type 2 diabetes mellitus (T2DM) were identified in an East Asian genome-wide association study meta-analysis. We assess tag SNPs across these loci for associations with T2DM in American Indians. MethodsA total of 435 SNPs that tag (R-2.85) common variation across the 8 loci were analyzed for association with T2DM (n=7710), early onset T2DM (n=1060), body mass index (n=6839), insulin sensitivity (n=555), and insulin secretion (n=298). ResultsTag SNPs within FITM2-R3HDML-HNF4A, GLIS3, KCNK16, and ZFAND3 associated with T2DM after accounting for locus-wide multiple testing. The T2DM association in FITM2-R3HDML-HNF4A (rs3212183; P=.0002; OR=1.19 [1.09-1.30]) was independent from the East Asian lead SNP (rs6017317), which did not associate with T2DM in American Indians. The top signals in GLIS3 (rs7875253; P=.0004; OR=1.23 [1.10-1.38]) and KCNK16 (rs1544050; P=.002; OR=1.16 [1.06-1.27]) were attenuated after adjustment for the East Asian lead SNPs (rs7041847 in GLIS3; rs1535500 in KCNK16), both of which also associated with T2DM in American Indians (P=.02; OR=1.11 [1.01-1.21]; P=.007; OR=1.19 [1.05-1.36] respectively). The top SNP in ZFAND3 (rs9470794; P=.002; OR=1.43 [1.14-1.80]) was the identical East Asian lead SNP. Additional SNPs in GLIS3 (rs180867004) and ZFAND3 (rs4714120 and rs9470701) had significant genotypexsex interactions (P.008). The GLIS3 SNP (rs180867004) associated with T2DM only in men (P=.00006, OR=1.94 [1.40-2.68]). The ZFAND3 SNPs (rs4714120 and rs9470701) associated with T2DM only in women (P=.0002, OR=1.35 [1.16-1.59]; P=.0003, OR=1.37 [1.16-1.63] respectively). ConclusionsReplication of lead T2DM SNPs in GLIS3, KCNK16, and ZFAND3 was observed in American Indians. Sex-specific T2DM signals in GLIS3 and ZFAND3, which are distinct from the East Asian GWAS signals, were also identified.