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Invited Commentary
October 2016

Using Discordance in Monozygotic Twins to Understand Causality of Cardiovascular Disease Risk Factors

Author Affiliations
  • 1Preventive Cardiology, NorthShore University HealthSystem, Chicago, Illinois
  • 2Lipid Clinic, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois
JAMA Intern Med. 2016;176(10):1530. doi:10.1001/jamainternmed.2016.4115

The risk of developing coronary heart disease (CHD) is determined by both lifestyle and genetics. Previous twin studies1 have indicated that heritable factors may account for as much as 30% to 60% of the variation in risk. Monozygotic twins have identical DNA, but by evaluating discordance in lifestyle-induced changes, such as body weight, this natural experiment can potentially determine whether the long-term impact of obesity is causal for CHD. Just as genome-wide association studies2 have demonstrated causality for low-density lipoprotein cholesterol by demonstrating that lifelong exposure of the surrogate (ie, low-density lipoprotein cholesterol) is associated with greater-than-expected cardiovascular events, a similar understanding regarding lifestyle-stimulated risk factors such as obesity can also be evaluated through capitalizing on differences in body weight between monozygotic twins. The use of this natural experiment implicated cigarette smoking as a major causal factor for increased CHD and mortality. In the Swedish Twins Registry,3 death from CHD was increased 2.8-fold in monozygotic twins who were cigarette smokers compared with the nonsmokers.

In the study reported in this issue of JAMA Internal Medicine, Nordström et al4 used data on weight discordance in monozygotic twins from the Swedish Twins Registry to evaluate the effect of obesity on the risk of developing CHD and diabetes. In this large cohort of 4046 monozygotic twins with discordant body mass index, a higher body mass index was not associated with an increased risk of myocardial infarction or death, but it was associated with the onset of diabetes. Significant study limitations include the lack of waist circumference measures, which is a better indicator of obesity associated with metabolic disturbances such as dyslipidemia or hypertension. The Framingham Heart Study5 found that measures of central obesity were indicators of CHD events independent of body mass index. In addition, follow-up beyond the 12 years used in this evaluation may have been necessary for the higher rates of diabetes to convert to an increased prevalence of CHD.

Nevertheless, this study has important clinical implications. Foremost, the findings confirm the causal link between obesity and diabetes, which is a growing epidemic throughout the world. Therefore, weight reduction should remain the cornerstone for the prevention of diabetes. However, controversy remains regarding the causality of obesity for the development of CHD. The Framingham Heart Study6 linked obesity to increased rates of CHD; however, after adjustment for lipid levels, blood pressure, and diabetes, the risk was totally mitigated. There is a popular misconception that obesity is the primary driver for premature CHD, and lean patients are frequently under the mistaken belief that they are protected from CHD. This study clearly illustrates that, although obesity remains an important causal factor for diabetes, genetic factors that can lead to dyslipidemia and hypertension remain important modifiable causal factors for preventing CHD.

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Article Information

Corresponding Author: Michael H. Davidson, MD, The University of Chicago Medicine, Cardiology, 150 E Huron, Ste 900, Chicago, IL 60611 (mdavidso@bsd.uchicago.edu).

Published Online: August 1, 2016. doi:10.1001/jamainternmed.2016.4115.

Conflict of Interest Disclosures: None reported.

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