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Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease
Open accessAbstract
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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“With increasing availability of large-scale phenotyping (and genotyping), MR is being widely applied to quantitative traits (e.g. markers or adiposity, such as body mass index 13-16 ; blood lipids such as HDL-cholesterol 17-19 ; inflammation-related proteins such as interleukin-6 receptor 20,21 12 ) with the aim of discovering modifiable risk factors for disease that are causal and amenable to the”
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Metadata
- 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
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2017-02-14
- Volume
- 317
- Issue
- 6
- Pages
- 626
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- 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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