Genetic predisposition to higher waist-to-hip ratio predicts diabetes and coronary heart disease

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

Literature - Emdin CA, Khera AV, Natarajan P, et al. - JAMA. 2017;317(6):626


Obesity, measured by the BMI, is associated with type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). Furthermore, the waist-to-hip ratio (WHR) adjusted for BMI, is a surrogate measure of abdominal adiposity that is associated with cardiometabolic disease, although it is not known whether this association is causal [1-5].

In this study, a mendelian randomisation approach was used to determine whether a genetic predisposition to increased WHR adjusted for BMI is associated with cardiometabolic quantitative traits, T2DM and CHD. This was assessed using samples from the UK Biobank that includes 111 986 participants.

Main results

A 48-SNP polygenic risk score for WHR adjusted for BMI was a strong instrumental variable (F = 1713), statistically accounting for 1.5% of variance in WHR adjusted for BMI. 1-SD increase in WHR adjusted for BMI due to the polygenic risk score was associated with:

  • 1 point decrease in BMI (95% CI: 0.87-1.1)
  • 2 cm increase in waist circumference (95% CI: 1.5-2.4)
  • 4.1 cm decrease in hip circumference (95% CI: 3.8-4.4)
  • increase of 0.068 in WHR (95% CI: 0.066-0.070)
  • higher total cholesterol levels (5.6 mg/dL; 95% CI: 3.9-7.3 mg/dL; 0.15 mmol/L; 95% CI: 0.10-0.19 mmol/L)
  • higher LDL-C levels (5.7 mg/dL; 95% CI: 4.1-7.2 mg/dL; 0.15 mmol/L; 95% CI: 0.11-0.19 mmol/L)
  • higher triglyceride levels (27 mg/dL; 95% CI: 25-30 mg/dL; 0.31 mmol/L; 95% CI: 0.28-0.34 mmol/L)
  • lower HDL-C levels (6.0 mg/dL; 95% CI: 5.3-6.6 mg/dL; 0.16 mmol/L; 95% CI: 0.14-0.17 mmol/L)
  • higher log-transformed fasting insulin levels (0.07; 95% CI: 0.05-0.08 log[pmol/L])
  • higher 2-hour glucose levels (4.1 mg/dL; 95% CI: 1.6-6.5 mg/dL; 0.23 mmol/L; 95% CI: 0.09-0.36 mmol/L)
  • higher systolic blood pressure (2.1 mm Hg; 95% CI: 1.2-3.0 mm Hg)
  • higher risk of T2DM (OR: 1.77; 95% CI: 1.57-2.00; absolute risk increase per 1000 participant-years: 6.0; 95% CI: 4.4-7.8; P = 7.30 × 10−21; number of participants with T2DM outcome: 40 530)
  • higher risk of CHD (OR: 1.46; 95% CI: 1.32-1.62; absolute risk increase per 1000 participant-years: 1.8; 95% CI: 1.3-2.4; P = 9.90 × 10−14; number of participants with CHD outcome: 66 440)


In a mendelian randomisation study, genetic predisposition to higher WHR adjusted for BMI was associated with an increased risk of T2DM and CHD. These findings support a causal association between abdominal adiposity and these outcomes.

Editorial comment

In their editorial article [6], Smith, Paternoster and Relton discuss the mendelian randomisation methodology, its application in the Emdin et al study and its relevance to clinical practice. They conclude: ‘Mendelian randomization is slowly beginning to generate data of clear clinical and public health relevance. Attention to mendelian randomization data could have helped avoid several very expensive late-stage clinical trial failures and might improve prediction of what randomized controlled trials (RCTs) will show. Indeed, the adoption of mendelian randomization to prioritize (or deprioritize) major investment in RCTs before their inception should be actively encouraged.’ The conclusion from the first extended presentation of mendelian randomization 15 years ago is still apposite: ‘it is probably fair to say that the method offers a more robust approach to understanding the effect of some modifiable exposures on health outcomes than does much conventional observational epidemiology. Where possible RCTs remain the final arbiter of the effects of interventions intended to influence health, however.’


1. Nordestgaard BG, Palmer TM, Benn M, et al. The effect of elevated body mass index on ischemic heart disease risk: causal estimates from a Mendelian randomisation approach. PLoS Med. 2012;9(5):e1001212.

2. Whitlock G, Lewington S, Sherliker P, et al; Prospective Studies Collaboration. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. 2009;373(9669):1083-1096.

3. Després J-P. Body fat distribution and risk of cardiovascular disease: an update. Circulation. 2012;126(10):1301-1313.

4. Ashwell M, Cole TJ, Dixon AK. Obesity: new insight into the anthropometric classification of fat distribution shown by computed tomography. Br Med J (Clin Res Ed). 1985;290(6483):1692-1694.

5. Seidell JC, Björntorp P, Sjöström L, et al. Regional distribution of muscle and fat mass in men—new insight into the risk of abdominal obesity using computed tomography. Int J Obes. 1989;13(3):289-303

6. Smith GD, Paternoster L, Relton C. When Will Mendelian Randomization Become Relevant for Clinical Practice and Public Health? JAMA. 2017;317(6):589-91

Find this article online at JAMA

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