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Editorial
June 10, 2009

Mendelian RandomizationNature's Randomized Trial in the Post–Genome Era

Author Affiliations

Author Affiliations: National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts (Drs Thanassoulis and O’Donnell); Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland (Dr O’Donnell); Boston University School of Medicine, Boston, Massachusetts (Dr Thanassoulis); and Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (Dr O’Donnell).

JAMA. 2009;301(22):2386-2388. doi:10.1001/jama.2009.812

Despite several observational studies showing that lipoprotein(a) is associated with myocardial infarction (MI),1,2 only circumstantial evidence exists regarding the causal nature of this association. Observational epidemiological studies, even with a sound prospective design, can provide hints to disease pathogenesis when the effect size is modest but cannot provide definitive evidence for causal relationships. Much of the current understanding of the causal factors in cardiovascular disease, such as the role of low-density lipoprotein, has been confirmed by randomized controlled trials (RCTs).3,4 However, RCTs are not always feasible. In the case of lipoprotein(a), the modest effect size and the lack of specific lipoprotein(a)-lowering therapy are major obstacles to obtaining causal evidence for its role in cardiovascular disease. In this issue of JAMA, Kamstrup and colleagues5 provide insights using a mendelian randomization approach and provide evidence for the causal role of lipoprotein(a) in MI. This study elegantly demonstrates how mendelian randomization can be used to improve the evidence for causality from observational studies and highlights the advantages and limitations of such an approach.

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