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Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study

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 vi...

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Autores principales: Balakrishnan, Poojitha, Vaidya, Dhananjay, Voruganti, V. Saroja, Haack, Karin, Kent, Jack W., North, Kari E., Laston, Sandra, Howard, Barbara V., Umans, Jason G., Lee, Elisa T., Best, Lyle G., MacCluer, Jean W., Cole, Shelley A., Navas-Acien, Ana, Franceschini, Nora
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194194/
https://www.ncbi.nlm.nih.gov/pubmed/30369944
http://dx.doi.org/10.3389/fgene.2018.00466
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author Balakrishnan, Poojitha
Vaidya, Dhananjay
Voruganti, V. Saroja
Haack, Karin
Kent, Jack W.
North, Kari E.
Laston, Sandra
Howard, Barbara V.
Umans, Jason G.
Lee, Elisa T.
Best, Lyle G.
MacCluer, Jean W.
Cole, Shelley A.
Navas-Acien, Ana
Franceschini, Nora
author_facet Balakrishnan, Poojitha
Vaidya, Dhananjay
Voruganti, V. Saroja
Haack, Karin
Kent, Jack W.
North, Kari E.
Laston, Sandra
Howard, Barbara V.
Umans, Jason G.
Lee, Elisa T.
Best, Lyle G.
MacCluer, Jean W.
Cole, Shelley A.
Navas-Acien, Ana
Franceschini, Nora
author_sort Balakrishnan, Poojitha
collection PubMed
description 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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spelling pubmed-61941942018-10-26 Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study Balakrishnan, Poojitha Vaidya, Dhananjay Voruganti, V. Saroja Haack, Karin Kent, Jack W. North, Kari E. Laston, Sandra Howard, Barbara V. Umans, Jason G. Lee, Elisa T. Best, Lyle G. MacCluer, Jean W. Cole, Shelley A. Navas-Acien, Ana Franceschini, Nora Front Genet Genetics 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. Frontiers Media S.A. 2018-10-12 /pmc/articles/PMC6194194/ /pubmed/30369944 http://dx.doi.org/10.3389/fgene.2018.00466 Text en Copyright © 2018 Balakrishnan, Vaidya, Voruganti, Haack, Kent, North, Laston, Howard, Umans, Lee, Best, MacCluer, Cole, Navas-Acien and Franceschini. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Balakrishnan, Poojitha
Vaidya, Dhananjay
Voruganti, V. Saroja
Haack, Karin
Kent, Jack W.
North, Kari E.
Laston, Sandra
Howard, Barbara V.
Umans, Jason G.
Lee, Elisa T.
Best, Lyle G.
MacCluer, Jean W.
Cole, Shelley A.
Navas-Acien, Ana
Franceschini, Nora
Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study
title Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study
title_full Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study
title_fullStr Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study
title_full_unstemmed Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study
title_short Genetic Variants Related to Cardiometabolic Traits Are Associated to B Cell Function, Insulin Resistance, and Diabetes Among AmeriCan Indians: The Strong Heart Family Study
title_sort genetic variants related to cardiometabolic traits are associated to b cell function, insulin resistance, and diabetes among american indians: the strong heart family study
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6194194/
https://www.ncbi.nlm.nih.gov/pubmed/30369944
http://dx.doi.org/10.3389/fgene.2018.00466
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