From 2005 to now, some data do not support a role for MEF2A in CAD patients from different country, included Iran, Japan, Italy, and Germany.[sup],,,,, In Beijing of China, Dai et al.
For example, the linkage study in a family with 13 members over three generations with coronary disease, nine of whom had suffered MI, narrowed a linkage signal to chromosome 15q26.[sup] Of 93 genes in the locus, the MEF2A gene was subjected to deep resequencing in family members as a plausible candidate gene, given its expression in embryonic coronary vasculature.
However, a large follow-up study attempting to identify additional deleterious mutations in MEF2A in sporadic cases of premature MI did not find any definitive mutations, but did succeed in finding the 21-bp mutation in three individuals who had not suffered MI.[sup] By genotyping family members of these individuals, researchers confirmed that the mutation exists at very low frequency in the general population (rather than being exclusive to one family); it did not segregate with MI or coronary disease outside of the family in which the mutation had originally been described.
Another group reported that the mutations of MEF2A exon 12 are implicated in premature CAD, suggesting a strong genetic component in the pathogenesis of premature CAD in the Chinese population.[sup] Gonzalez et al .[sup] has reported that subjects with a Pro279Leu variant of MEF2A in exon 7 has an odds ratio of 3.1 for MI.
How can we reconcile these results, in these controversial studies,[sup],,,,,,,,,,, the 21-bp deletion was absent in unrelated individuals with normal angiograms, and was found to alter the ability of the MEF2A protein to activate transcription in vitro .
If the available evidence is not adequate to conclude that mutations in MEF2A play a causal role in CAD and/or MI, what general principles can we take away?
The genomic sequence of MEF2A gene is highly polymorphic.
Finally, it remains to be determined whether disruption of MEF2A function is unique to this particular pedigree or will prove to be more widely associated with CAD.
The significance of identification of MEF2A as the first disease-causing gene for CAD and MI is two-fold.
A immunostaining study with an antibody for MEF2A revealed that the MEF2A protein is highly expressed in the endothelium.[sup] The endothelium plays a protective role for coronary arteries and prevents the arteries from damage by blood elements such as platelets and monocytes.
It is important to point out, the recent discovery of MEF2A as a disease-causing gene for CAD and MI and its high expression in the endothelium lead us to hypothesize that an early trigger for the pathogenesis of CAD and MI may be dysfunction or abnormal development of the endothelium, which increases susceptibility of the coronary arteries to inflammation, leading to the development of CAD and MI.
In conclusion, MEF2A may play an important role in cardiovascular biology, and rare variants inMEF2A may influence its activity as a transcription factor in vitro , but the genetic evidence available to date does not demonstrate that these mutations play a causal role in CAD and/or MI in humans.