School of Medicine Publications and Presentations
Document Type
Article
Publication Date
10-2018
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.
Recommended Citation
Balakrishnan P, Vaidya D, Voruganti VS, Haack K, Kent JW Jr, North KE, Laston S, Howard BV, Umans JG, Lee ET, Best LG, MacCluer JW, Cole SA, Navas-Acien A and Franceschini N (2018) Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study. Front. Genet. 9:466. doi: 10.3389/fgene.2018.00466
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Publication Title
Frontiers in Genetics
DOI
10.3389/fgene.2018.00466
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics
Comments
© 2018 Balakrishnan, Vaidya, Voruganti, Haack, Kent, North, Laston, Howard, Umans, Lee, Best, MacCluer, Cole, Navas-Acien and Franceschini.