Cited by 378Genetic Associations and EpidemiologyDiabetes, Cardiovascular Risks, and LipoproteinsNutrition, Genetics, and Disease

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Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease

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Emdin, Connor A., Khera, Amit V., Natarajan, Pradeep, Klarin, Derek, Zekavat, Seyedeh M., Hsiao, Allan J., Kathiresan, Sekar·2017·JAMA

DOI 10.1001/jama.2016.21042PMC PMC5571980

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Abstract

Importance: In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain. Objective: To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes. Design, Setting, and Participants: A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank. Exposures: Genetic predisposition to increased WHR adjusted for BMI. Main Outcomes and Measures: Type 2 diabetes and CHD. Results: Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1-mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440). Conclusions and Relevance: A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes.

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Authors: Emdin, C. A., Khera, A. V., Natarajan, P., Klarin, D., Zekavat, S. M., Hsiao, A. J., & Kathiresan, S.
Affiliations: Broad Institute (US)
Massachusetts Institute of Technology (US)
Corresponding author: Kathiresan, Sekar
ORCID: Emdin, Connor A.
Khera, Amit V.
Natarajan, Pradeep
Klarin, Derek
Zekavat, Seyedeh M.
Kathiresan, Sekar
Venue: JAMA
Publisher: American Medical Association (AMA)
Published: 2017-02-14
Volume: 317
Issue: 6
Pages: 626
ISSN: 0002-9955 (ISSN-L)
0098-7484
DOI: 10.1001/jama.2016.21042
PMC: PMC5571980
OpenAlex: W2589093959
Cited by: 378
References: 38
Citations by year: 2026: 14 · 2025: 38 · 2024: 30 · 2023: 38 · 2022: 54 · 2021: 45 · 2020: 37 · 2019: 37 · 2018: 63 · 2017: 21
FWCI: 28.61
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: JAMA (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (5t32hl007734-30, KL2TR001100)
National Heart, Lung, and Blood Institute (R01HL127564, T-32HL007734)
National Center for Advancing Translational Sciences
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: waist-to-hip ratio, abdominal fat, type 2 diabetes, coronary artery disease, polygenic risk score, Mendelian randomization, cardiometabolic traits, triglycerides, blood pressure, glycemic traits, causal inference, single nucleotide polymorphisms, body mass index adjustment, genetic susceptibility, UK Biobank
MeSH terms: Blood Glucose, Blood Pressure, Coronary Disease, Cross-Sectional Studies, Diabetes Mellitus, Type 2, Female, Humans, Male, Middle Aged, Triglycerides, Body Mass Index, Odds Ratio, Case-Control Studies, Polymorphism, Single Nucleotide, Waist-Hip Ratio, Obesity, Abdominal, Mendelian Randomization Analysis

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Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease

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