Cited by 216Genetic Associations and EpidemiologyDiabetes, Cardiovascular Risks, and LipoproteinsNutrition, Genetics, and Disease

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Causal Effects of Body Mass Index on Cardiometabolic Traits and Events: A Mendelian Randomization Analysis

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Holmes, Michael V., Lange, Leslie A., Palmer, Tom, Lanktree, Matthew B., North, Kari E., Almoguera, Berta, Buxbaum, Sarah, Chandrupatla, Hareesh R., Elbers, Clara C., Guo, Yiran, Hoogeveen, Ron C., Li, Jin, Li, Yun R., Swerdlow, Daniel I., Cushman, Mary, Price, Tom S., Curtis, Sean P., Fornage, Myriam, Hakonarson, Hakon, Patel, Sanjay R., Redline, Susan, Siscovick, David S., Tsai, Michael Y., Wilson, James G., van der Schouw, Yvonne T., FitzGerald, Garret A., Hingorani, Aroon D., Casas, Juan P., de Bakker, Paul I.W., Rich, Stephen S., Schadt, Eric E., Asselbergs, Folkert W., Reiner, Alex P., Keating, Brendan J.·2014·The American Journal of Human Genetics

DOI 10.1016/j.ajhg.2013.12.014PMC PMC3928659

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Abstract

Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m(2) genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m(2) genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m(2) increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.

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Authors: Holmes, M. V., Lange, L. A., Palmer, T., Lanktree, M. B., North, K. E., Almoguera, B., Buxbaum, S., Chandrupatla, H. R., Elbers, C. C., Guo, Y., Hoogeveen, R. C., Li, J., Li, Y. R., Swerdlow, D. I., Cushman, M., Price, T. S., Curtis, S. P., Fornage, M., Hakonarson, H., Patel, S. R., Redline, S., Siscovick, D. S., Tsai, M. Y., Wilson, J. G., van der Schouw, Y. T., FitzGerald, G. A., Hingorani, A. D., Casas, J. P., de Bakker, P. I. W., Rich, S. S., Schadt, E. E., Asselbergs, F. W., Reiner, A. P., & Keating, B. J.
Affiliations: University College London (GB)
University of North Carolina at Chapel Hill (US)
University of Warwick (GB)
McMaster University (CA)
Children's Hospital of Philadelphia (US)
Jackson State University (US)
University Medical Center Utrecht (NL)
Baylor College of Medicine (US)
University of Vermont (US)
University of Pennsylvania (US)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
The University of Texas Health Science Center at Houston (US)
Brigham and Women's Hospital (US)
University of Washington (US)
University of Minnesota (US)
University of Mississippi Medical Center (US)
London School of Hygiene & Tropical Medicine (GB)
University of Virginia (US)
Icahn School of Medicine at Mount Sinai (US)
Fred Hutch Cancer Center (US)
Corresponding author: Holmes, Michael V.
Keating, Brendan J.
ORCID: Holmes, Michael V.
Lange, Leslie A.
Palmer, Tom
Lanktree, Matthew B.
North, Kari E.
Almoguera, Berta
Buxbaum, Sarah
Chandrupatla, Hareesh R.
Elbers, Clara C.
Guo, Yiran
Hoogeveen, Ron C.
Swerdlow, Daniel I.
Cushman, Mary
Fornage, Myriam
Hakonarson, Hakon
Patel, Sanjay R.
Redline, Susan
Siscovick, David S.
Tsai, Michael Y.
Wilson, James G.
FitzGerald, Garret A.
Hingorani, Aroon D.
Casas, Juan P.
Rich, Stephen S.
Schadt, Eric E.
Asselbergs, Folkert W.
Reiner, Alex P.
Keating, Brendan J.
Venue: The American Journal of Human Genetics
Publisher: Elsevier BV
Published: 2014-02
Volume: 94
Issue: 2
Pages: 198-208
ISSN: 0002-9297 (ISSN-L)
DOI: 10.1016/j.ajhg.2013.12.014
PMC: PMC3928659
OpenAlex: W2005648153
Cited by: 216
References: 57
Citations by year: 2026: 5 · 2025: 9 · 2024: 10 · 2023: 11 · 2022: 14 · 2021: 15 · 2020: 16 · 2019: 21 · 2018: 30 · 2017: 23 · 2016: 26 · 2015: 24 · 2014: 11
FWCI: 18.34
Type: journal article
Language: en
Update notices: erratum (2014-02-06)
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 186 d)
Locations: The American Journal of Human Genetics (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Lancaster EPrints (Lancaster University) (submittedVersion)
UCL Discovery (University College London) (submittedVersion)
Explore Bristol Research (submittedVersion, other-oa)
Bristol Research (University of Bristol) (submittedVersion, other-oa)
Funders: British Heart Foundation (PG/09/022/26739)
Medical Research Council (MR/K006584/1)
National Institute on Minority Health and Health Disparities (P20MD006899)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
Keywords: body mass index, obesity, cardiometabolic traits, type 2 diabetes, coronary artery disease, stroke, fasting blood glucose, fasting insulin, interleukin-6, systolic blood pressure, HDL cholesterol, LDL cholesterol, genetic score, causal effects, genetic epidemiology, cardiovascular risk factors, dyslipidemia, inflammation, insulin resistance
MeSH terms: Adolescent, Adult, Aged, Aged, 80 and over, Blood Glucose, Blood Pressure, Coronary Disease, Diabetes Mellitus, Type 2, Fasting, Female, Humans, Insulin, Cholesterol, HDL, Cholesterol, LDL, Longitudinal Studies, Male, Middle Aged, Phenotype, Prospective Studies, Risk Factors, Selection, Genetic, Sensitivity and Specificity, Meta-Analysis as Topic, Interleukin-6, Body Mass Index, Odds Ratio, Stroke, Polymorphism, Single Nucleotide, White People, Young Adult, Genetic Association Studies, Mendelian Randomization Analysis

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Causal Effects of Body Mass Index on Cardiometabolic Traits and Events: A Mendelian Randomization Analysis

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