Mendelian Randomization – Nature’s Clinical Trial – is Providing New Insights About the Causes and Potential Treatments for Cardiometabolic Diseases
By Kevin C. Maki, PhD
In a recent issue of JAMA Cardiology, Lyall and colleagues1 report that a score based on 97 genetic variants related to body mass index (BMI) was associated with increased risks for hypertension [odds ratio (OR) per 1-SD higher genetically-driven BMI of 1.64, 95% confidence interval (CI) 1.48-1.83], type 2 diabetes mellitus (OR 2.53; 95% CI 2.04-3.13) and coronary heart disease (CHD; OR 1.35; 95% CI 1.09-1.69). Notably, the genetic BMI score was not associated with stroke risk.
Because the genetic score provides a measure of exposure over a lifetime to genetic variants that increase BMI, it is a relatively unconfounded marker that is less likely to be influenced by reverse causality than BMI itself. Genotypes are assigned randomly when passed from parents to offspring during meiosis.2 The population genotype distribution should therefore be unrelated to the distribution of confounding variables.2 Accordingly, Mendelian randomization can be thought of as experiments of nature, similar to what is accomplished through randomization in a clinical trial. The new results from Lyall et al.1 add evidence to support a causal relationship between increased BMI and cardiometabolic diseases.
Results reported in another recent paper by Dale and colleagues3 using Mendelian randomization also suggest causal roles for abdominal (waist-hip ratio adjusted for BMI; WHRadjBMI) and total adiposity (BMI) regarding risks for CHD and type 2 diabetes mellitus. Each 1-SD higher WHRadjBMI (about 0.08 U) was associated with an excess risk of CHD (OR 1.48; 95% CI 1.28-1.71), similar to findings for BMI (SD about 4.6 kg/m2; OR 1.36; 95% CI, 1.22-1.52). WHRadjBMI, but not BMI, was associated with higher risk of ischemic stroke (OR 1.32; 95% CI, 1.03-1.70). For type 2 diabetes mellitus, both variables had significant associations: OR 1.82 (95% CI 1.38-2.42) per 1-SD higher WHRadjBMI and OR 1.98 (95% CI 1.41-2.78) per 1-SD higher BMI. These results are consistent with those reported by Lyall et al.1
Prior studies using Mendelian randomization have provided evidence for and against causality for several potentially modifiable risk factors for cardiometabolic diseases. Evidence for causality has been provided for various lipoprotein-related variables and risks for atherosclerotic cardiovascular disease, including:4
- Low-density lipoprotein cholesterol;
- Triglycerides and triglyceride-rich lipoprotein cholesterol;
- Lipoprotein (a).
Evidence against direct causality has been produced through Mendelian randomization for:4
- High-density lipoprotein cholesterol;
- C-reactive protein.
However, it should be noted that for high-density lipoprotein cholesterol and C-reactive protein, lack of association should not be interpreted to mean that these are not important risk indicators, only that the levels of these variables likely reflect other processes that are more directly involved in causal pathways.
The real promise of Mendelian randomization is to identify novel, modifiable targets for which new therapies can be developed. This process was nicely illustrated by the identification of proprotein convertase subtilisin kexin type 9 (PCSK9) variants as predictors of CHD risk5, which ultimately led to the development of a new class of pharmaceuticals, the PCSK9 inhibitors.6
- Lyall DM, Celis-Morales C, Ward J, et al. Association of body mass index with cardiometabolic disease in the UK Biobank: a Mendelian randomization study. JAMA Cardiol. July 5, 2017 [Epub ahead of print].
- Thanassoulis G, O’Donnell CJ. Mendelian randomization: nature’s randomized trial in the post-genome era. JAMA. 2009;301:2386-2387.
- Dale CE, Fatemifar G, Palmer TM, et al. Causal associations of adiposity and body fat distribution with coronary heart disease, stroke subtypes, and type 2 diabetes mellitus: a Mendelian randomization study. Circulation. 2017;135:2373-2388.
- Lacey B, Herrington WH, Preiss D, Lewington S, Armitage J. The role of emerging risk factors in cardiovascular outcomes. Curr Atheroscler Rep. 2017;19:28.
- Cohen JC, Boerwinkle E, Mosley TH, Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264-1272.
- Durairaj A, Sabates A, Nieves J, et al. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and its inhibitors: a review of physiology, biology, and clinical data. Curr Treat Options Cardio Med. 2017;19:58.