Genetic variants related to cardiometabolic traits are associated to B cell function, insulin resistance, and diabetes among American Indians: The strong heart family study

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  • Balakrishnan, P.
    • Other Affiliation: Columbia University Mailman School of Public Health
  • Vaidya, D.
    • Other Affiliation: Johns Hopkins University
  • Voruganti, V.S.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Haack, K.
    • Other Affiliation: Texas Biomedical Research Institute
  • Kent, J.W.
    • Other Affiliation: Texas Biomedical Research Institute
  • North, K.E.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
  • Laston, S.
    • Other Affiliation: University of Texas, Rio Grande Valley
  • Howard, B.V.
    • Other Affiliation: MedStar Health Research Institute
  • Umans, J.G.
    • Other Affiliation: MedStar Health Research Institute
  • Lee, E.T.
    • Other Affiliation: University of Oklahoma Health Sciences Center
  • Best, L.G.
    • Other Affiliation: Missouri Breaks Industries Research, Inc.
  • MacCluer, J.W.
    • Other Affiliation: Texas Biomedical Research Institute
  • Cole, S.A.
    • Other Affiliation: Texas Biomedical Research Institute
  • Navas-Acien, A.
    • Other Affiliation: Columbia University Mailman School of Public Health
  • Franceschini, N.
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
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 HOMAIR, 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 KCNQ1 with 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.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
Journal title
  • Frontiers in Genetics
Journal volume
  • 9
Journal issue
  • OCT
Language
  • English
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  • Publisher
Funder
  • National Heart, Lung, and Blood Institute, NHLBI: R01-HL090863, R01-HL10 553 9301, R01-HL109282, R01-HL109284, R01-HL109315, R01-HL109319, U01-HL41642, U01-HL41652, U01-HL41654, U01-HL65520
  • P30ES009089, P42ES010349, R01ES021367, R01ES025216

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