| Authors |
Balakrishnan P, Vaidya D, Voruganti VS, Haack K, Kent JW, North KE, Laston S,
Howard BV, Umans JG, Lee ET, Best LG, MacCluer JW, Cole SA, Navas-Acien A,
Franceschini N
|
| Submitted By |
Nora Franceschini on 11/5/2018 |
| Status |
Published |
| Journal |
Frontiers in genetics |
| Year |
2018 |
| Date Published |
|
| Volume : Pages |
9 : 466 |
| PubMed Reference |
30369944 |
| 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.
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