Association and Functional Analyses of MEF2A as a Susceptibility Gene for Premature Myocardial Infarction and Coronary Artery Disease

Background-Mutations in the MEF2A gene, coding for a member of the myocyte enhancer factor 2 family of transcription factors, have been reported in patients with coronary artery disease and myocardial infarction (MI). In particular, a 21-bp deletion and 3 missense mutations were demonstrated either to reduce MEF2A transcriptional activity or to impair its nuclear translocation. However, the association of MEF2A with coronary artery disease/MI was not confirmed in other studies. We analyzed the role of MEF2A in the pathogenesis of MI in 2008 Italian patients with premature MI and in 2008 controls. Methods and Results-Mutational screening of exon 8 (containing all so-far reported point mutations) disclosed 5 novel and 2 previously described missense mutations. Microsatellite genotyping and sequencing revealed the presence of the 21-bp deletion (located in exon 12) in 5 cases and in none of the controls. Functional studies on mutant proteins showed no alteration, neither in the transactivating properties (all mutants) nor in the nuclear localization (21-bp deletion). Furthermore, an association analysis performed using 3 microsatellites at the MEF2A locus showed no significant association with MI. These results were confirmed in a replication study performed on an independent Italian population with coronary artery disease. Conclusions-All together, our data do not support MEF2A as a susceptibility gene for coronary artery disease/MI in the Italian population. (Circ Cardiovasc Genet. 2009; 2: 165-172.)