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Increased genetic risk for obesity in premature coronary artery disease

There is ongoing controversy as to whether obesity confers risk for CAD independently of associated risk factors including diabetes mellitus. We have carried out a Mendelian randomization study using a genetic risk score (GRS) for body mass index (BMI) based on 35 risk alleles to investigate this qu...

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Autores principales: Cole, Christopher B, Nikpay, Majid, Stewart, Alexandre FR, McPherson, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929880/
https://www.ncbi.nlm.nih.gov/pubmed/26220701
http://dx.doi.org/10.1038/ejhg.2015.162
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author Cole, Christopher B
Nikpay, Majid
Stewart, Alexandre FR
McPherson, Ruth
author_facet Cole, Christopher B
Nikpay, Majid
Stewart, Alexandre FR
McPherson, Ruth
author_sort Cole, Christopher B
collection PubMed
description There is ongoing controversy as to whether obesity confers risk for CAD independently of associated risk factors including diabetes mellitus. We have carried out a Mendelian randomization study using a genetic risk score (GRS) for body mass index (BMI) based on 35 risk alleles to investigate this question in a population of 5831 early onset CAD cases without diabetes mellitus and 3832 elderly healthy control subjects, all of strictly European ancestry, with adjustment for traditional risk factors (TRFs). We then estimated the genetic correlation between these BMI and CAD (rg) by relating the pairwise genetic similarity matrix to a phenotypic covariance matrix between these two traits. GRS(BMI) significantly (P=2.12 × 10(−12)) associated with CAD status in a multivariate model adjusted for TRFs, with a per allele odds ratio (OR) of 1.06 (95% CI 1.042–1.076). The addition of GRS(BMI) to TRFs explained 0.75% of CAD variance and yielded a continuous net recombination index of 16.54% (95% CI=11.82–21.26%, P<0.0001). To test whether GRS(BMI) explained CAD status when adjusted for measured BMI, separate models were constructed in which the score and BMI were either included as covariates or not. The addition of BMI explained ~1.9% of CAD variance and GRS(BMI) plus BMI explained 2.65% of CAD variance. Finally, using bivariate restricted maximum likelihood analysis, we provide strong evidence of genome-wide pleiotropy between obesity and CAD. This analysis supports the hypothesis that obesity is a causal risk factor for CAD.
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spelling pubmed-49298802016-07-13 Increased genetic risk for obesity in premature coronary artery disease Cole, Christopher B Nikpay, Majid Stewart, Alexandre FR McPherson, Ruth Eur J Hum Genet Article There is ongoing controversy as to whether obesity confers risk for CAD independently of associated risk factors including diabetes mellitus. We have carried out a Mendelian randomization study using a genetic risk score (GRS) for body mass index (BMI) based on 35 risk alleles to investigate this question in a population of 5831 early onset CAD cases without diabetes mellitus and 3832 elderly healthy control subjects, all of strictly European ancestry, with adjustment for traditional risk factors (TRFs). We then estimated the genetic correlation between these BMI and CAD (rg) by relating the pairwise genetic similarity matrix to a phenotypic covariance matrix between these two traits. GRS(BMI) significantly (P=2.12 × 10(−12)) associated with CAD status in a multivariate model adjusted for TRFs, with a per allele odds ratio (OR) of 1.06 (95% CI 1.042–1.076). The addition of GRS(BMI) to TRFs explained 0.75% of CAD variance and yielded a continuous net recombination index of 16.54% (95% CI=11.82–21.26%, P<0.0001). To test whether GRS(BMI) explained CAD status when adjusted for measured BMI, separate models were constructed in which the score and BMI were either included as covariates or not. The addition of BMI explained ~1.9% of CAD variance and GRS(BMI) plus BMI explained 2.65% of CAD variance. Finally, using bivariate restricted maximum likelihood analysis, we provide strong evidence of genome-wide pleiotropy between obesity and CAD. This analysis supports the hypothesis that obesity is a causal risk factor for CAD. Nature Publishing Group 2016-04 2015-07-29 /pmc/articles/PMC4929880/ /pubmed/26220701 http://dx.doi.org/10.1038/ejhg.2015.162 Text en Copyright © 2016 Macmillan Publishers Limited http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
spellingShingle Article
Cole, Christopher B
Nikpay, Majid
Stewart, Alexandre FR
McPherson, Ruth
Increased genetic risk for obesity in premature coronary artery disease
title Increased genetic risk for obesity in premature coronary artery disease
title_full Increased genetic risk for obesity in premature coronary artery disease
title_fullStr Increased genetic risk for obesity in premature coronary artery disease
title_full_unstemmed Increased genetic risk for obesity in premature coronary artery disease
title_short Increased genetic risk for obesity in premature coronary artery disease
title_sort increased genetic risk for obesity in premature coronary artery disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929880/
https://www.ncbi.nlm.nih.gov/pubmed/26220701
http://dx.doi.org/10.1038/ejhg.2015.162
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