Assessing Variation across Eight Established East Asian Loci for Type 2 Diabetes in American Indians: Suggestive Evidence for New Sex-specific Diabetes Signals in GLIS3 and ZFAND3

BACKGROUND: Eight 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. METHODS: A total of 435 SNPs that tag (R2 ≥ .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). RESULTS: Tag 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 genotype × sex 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). CONCLUSIONS: Replication 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.