Mendelian randomisation shows causal relation adiposity with CHD and T2DM

18-5-2017 • Dale C, et al, Circulation, 2017

​Causal Associations of Adiposity and Body Fat Distribution with Coronary Heart Disease, Stroke Subtypes and Type 2 Diabetes: A Mendelian Randomization Analysis

Dale C, Fatemifar G, Palmer P, et al; on behalf of UCLEB consortium and METASTROKE consortium
Circulation. 2017; published online ahead of print


Many observational studies evaluating the associations between adiposity and the risk of coronary heart disease (CHD), stroke and type 2 diabetes mellitus (T2DM), report consistent results with different measures of adiposity [1,2]. Some studies found a stronger association between the waist-hip-ratio (WHR) and myocardial infraction (MI) or stroke compared with BMI, whereas others found that the waist circumference (WC) is independently associated with CHD [3-5]. Based on observational studies it is difficult to understand the implications of different adiposity measures on cardiovascular disease (CVD) risk estimation because [6]:
  • There is a high degree of correlation between adiposity measures
  • Adiposity measures may differ in their reproducibility
  • All measures of adiposity suffer from confounding due to underlying ill-health at low or sub-clinical levels
Mendelian randomization (MR) studies minimise the bias resulting from confounding, regression dilution bias and reverse causation, but they are susceptible to bias from pleiotropy, e.g. the association of genetic variants with more than one variable.
In this study, MR analyses of BMI and WHR are performed with recently developed methods that are robust to pleiotropy, to quantify and contrast causal associations of central and general adiposity with cardiometabolic disease, using data from 14 studies and 4 consortia; this included 66 842 CHD cases, 12 389 ischemic stroke (IS) cases and 34 840 T2DM cases.

Main results

  • Both genetically instrumented adiposity measures (single nucleotide polymorphisms for BMI and for WHR adjusted for BMI) were causally associated with increased insulin and triglyceride levels, decreased levels of HDL-C and higher IL-6, as well as with some of the left ventricular hypertrophy ECG measures.
  • WHR was associated with increased LDL-C, systolic blood pressure (SBP) and weakly with lung function, while BMI was inversely associated with albumin.
  • The OR for CHD per 1 SD increment in BMI was 1.36 (95% CI: 1.22-1.52).  
  • There was an association between WHR and CHD using conventional MR (OR per SD 1.48; 95% CI: 1.28-1.71).  
  • The causal OR for the association between BMI and IS was 1.09 per SD (95% CI: 0.93-1.28), however, estimates for the association between BMI and stroke subtypes were imprecise and all 95% CIs included the null.
  • There was some evidence for a causal association of WHR with IS (OR per SD 1.32; 95% CI: 1.03-1.70), with limited evidence for a causal association with stroke subtypes.
  • There was a causal OR for T2DM of 1.98 (95% CI: 1.41-2.78) per SD increase in BMI.
  • There was a causal relationship between WHR and T2DM (OR per SD increase 1.82; 95% CI: 1.38-2.42).
  • The multivariate MR, adjusted for smoking, for the causal association of WHR with IS was 1.27 (95% CI: 0.84-1.93).


In a Mendelian randomization analysis of 14 studies and 4 consortia, there was a causal relationship of both central and general adiposity with the risk of CHD and T2DM. Central adiposity was associated with the risk of IS and may represent a higher risk for stroke and CHD. These results suggest that different types of adiposity may have different effects on CVD risk.
Find this article online at  Circulation 


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5. O'Donnell MJ, Chin SL, Rangarajan S, et al. Global and regional effects of potentially modifiable risk factors associated with acute stroke in 32 countries (INTERSTROKE): a case-control study. Lancet. 2016;388:761-775.
6. Dale C, Nuesch E, Prieto-Merino D, et al. Why do thin people have elevated all-cause mortality? Evidence on confounding and reverse causality in the association of adiposity and COPD from the British Women's Heart and Health Study. PLoS One. 2015;10:e0115446. 


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