Rare mutations in MEF2A have been proposed as a cause of coronary artery disease (CAD) and myocardial infarction (MI). In this issue of the JCI, Pennacchio and colleagues report sequencing MEF2A in 300 patients with premature CAD and in controls. Only 1 CAD patient was found to carry a missense mutation not found in controls. The specific 21-bp deletion in MEF2A previously proposed as causal for CAD and/or MI was observed in unaffected individuals and did not segregate with CAD in families. These results do not support the hypothesis that mutations in MEF2A are a cause of CAD and/or MI but do illustrate general principles regarding the difficulty of connecting genetic variation to common diseases.

Known risk factors explain only a small fraction of interindividual risk of coronary artery disease (CAD). An important clue to understanding the etiology of CAD is its substantial heritability, which demonstrates that variation in DNA sequence influences risk (1). It was recently proposed that mutations in MEF2A, which encodes a member of the myocyte enhancer factor–2 (MEF2) family of transcription factors, are a cause of CAD and myocardial infarction (MI)(2), a finding that, if true, would provide an important and previously unsuspected insight into the pathogenesis of this clinically important disease. In this issue of the JCI, however, Pennacchio and colleagues report that rare missense changes in MEF2A are not observed at a substantial frequency in patients with early-onset CAD (3). More critically, they discovered that a specific 21-bp deletion in MEF2A—originally claimed to be the causal mutation in the index family—is also present in unaffected individuals, where it does not cosegregate with CAD. How can we reconcile these results; what do they tell us about the proposed role of MEF2A in CAD; and what general principles do they highlight about the challenges in reliably implicating genetic variants in human disease?