Abstract
Background: Genetic research may inform underlying mechanisms for disparities in the burden of type 2 diabetes mellitus among American Indians. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS).Methods and Results: We examined the association of variants, previously associated with cardiometabolic traits (∼200,000 from Illumina Cardio MetaboChip), using mixed models of HOMA-B residuals corrected for HOMA-IR (cHOMA-B), log transformed HOMA-IR, and incident diabetes, adjusted for age, sex, population stratification, and familial relatedness. Center-specific estimates were combined using fixed effect meta-analyses. We used Bonferroni correction to account for multiple testing (P < 4.13 × 10−7). We also assessed the association between variants in candidate diabetes genes with these metabolic traits. We explored the top SNPs in an independent, replication sample from Southwestern Arizona. We identified significant associations with cHOMA-B for common variants at 26 loci of which 8 were novel (PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, FLJ16686). The most significant variant association with cHOMA-B was observed on chromosome 5 for an intergenic variant near PARP8 (rs2961831, P = 6.39 × 10−9). In the replication study, we found a signal at rs4607517 near GCK/YKT6 (P = 0.01). Variants near candidate diabetes genes (especially GCK and KCNQ1) were also nominally associated with HOMA-IR and cHOMA-B.Conclusion: We identified variants at novel loci and confirmed those at known candidate diabetes loci associations for cHOMA-B. This study also provided evidence for association of variants at KCNQ2, CTNAA2, and KCNQ1with cHOMA-B among American Indians. Further studies are needed to account for the high heritability of diabetes among the American Indian participants of the SHFS cohort.
Highlights
MATERIALS AND METHODSThe burden of type 2 diabetes mellitus among American Indians is disproportionately high with an estimated prevalence ranging between 34 and 68% compared to 9.3% in the general U.S population (Acton et al, 2002; Lee et al, 2002)
We identified several genes in the Cardio MetaboChip significantly associated with HOMA-beta cell function residuals corrected for HOMA-IR (cHOMA-B) (P < 4.13 × 10−7) (Supplementary Table 1)
The associations observed near PRSS7, FCRL5, PEL1, LRP12, IGLL1, ARHGEF10, PARVA, and FLJ16686 are novel for a biomarker of B cell dysfunction
Summary
The burden of type 2 diabetes mellitus among American Indians is disproportionately high with an estimated prevalence ranging between 34 and 68% compared to 9.3% in the general U.S population (Acton et al, 2002; Lee et al, 2002). The main goal of this study was to assess the associations between genetic variants previously associated with cardiometabolic traits and dysglycemia traits of HOMA-B, HOMA-IR, and incident diabetes in American Indians among SHFS participants who were free of diabetes at baseline and replicated significant associations in an independent sample from Southwestern Arizona. Our objective was to assess the association of genetic variants in cardiometabolic candidate genes with B cell dysfunction via HOMA-B, insulin resistance via HOMA-IR, and type 2 diabetes mellitus in the Strong Heart Family Study (SHFS)
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