The search for novel polymorphisms that increase the likelihood of IHD has recently led to the discovery of a potentially important role of the myocyte enhancing factor 2A gene (MEF2A). In 2003, Wang and colleagues 1 reported that they had identified a 21 base pair (bp) deletion (Δ7aa) of the MEF2A gene in a family with IHD, where the disease appeared to have an autosomal dominant pattern of inheritance. Subsequent investigation by the same research group revealed 3 further mutations in a separate part of the MEF2A gene. These authors suggest that mutations in the MEF2A gene may play a substantial role in the development of IHD.

Attempts to confirm this association to date have not been successful in case-control studies in both a Canadian 3 and, more recently, a Japanese population 4. We sought to investigate the role of the Δ7aa mutation in a large family based study of patients with early-onset IHD in Ireland.

The risk factors for both probands and siblings are shown below in Table 1. Of note, there are more male probands, and more female siblings, this reflects the earlier onset of IHD in men compared with women. Smoking and diabetes are more common in the probands. However, hypertension and elevated levels of lipoproteins were less common in the probands probably reflecting the use of vasoactive drugs to reduce blood pressure and the widespread use of lipid lowering agents in this population.

A total of 1494 individuals from 580 families were included (803 discordant sib-pairs and 64 parent-child trios). Due to incomplete genotyping 13 individuals from 7 families were removed, leaving 1481 individuals from 573 families. Analysis was based on amplicon size of the Δ7aa region of the MEF2A gene.

The Δ7aa mutation was not found in any individual in the study sample. Differences in amplicon size were identified and were due to variation in the numbers of triplet repeats in a nearby region coding for glutamate or proline residues, as previously reported 3. Using the TDT/sib-TDT and PDT (352 informative families), the number of triplet repeats was not found to be associated with disease in our study group (Table 2).

Although the majority of researchers working in the field of complex traits propose a common-variant, small-effect model, the possibility also exists of a rare- variant, large-effect model. Wang and colleagues 1 reported the Δ7aa mutation in a family of 13 patients who exhibited an autosomal dominant inheritance pattern of IHD. Subsequent work by the same group 2 was undertaken in 207 unrelated patients, with a diagnosis of IHD based on angiography or development of MI, and 191 control subjects. Three novel mutations in exon 7 were found in four patients and in none of their control subjects. However, other groups have not confirmed this work. Weng and co-workers 3 did identify the Δ7aa mutation in 3 individuals without evidence of IHD and further work within their families did not show any evidence for cosegregation of the mutation with early onset IHD. Similarly, Kajimoto and colleagues, in a Japanese population, screened the MEF2A gene in 379 patients with MI and 589 control individuals. They identified one nonsense mutation (R447X) but were uncertain regarding the significance of this finding, as the patient was elderly and had other conventional risk factors for ischaemic heart disease. Research performed by other groups have also identified similar variations in the number of glutamate residues, they to have not found this to be associated with IHD; however, other mutations may be 10.

Our research suggests that the Δ7aa mutation of the MEF2A gene is unlikely to play a significant role in the development of IHD in the Irish population. In addition, statistical analysis using family-based methods suggests that the triplet repeat polymorphism in this gene is not associated with IHD in our study group.

Ischaemic heart disease: IHD

Myocardial infarction: MI

Transmission disequilibrium test: TDT

Pedigree disequilibrium test: PDT

Polymerase chain reaction: PDT

The author(s) declare that they have no competing interests.

Paul G Horan: Recruited subjects and processed samples, laboratory analysis and wrote the paper.

Adrian R Allen: designed laboratory processes and results collection.

Anne E Hughes: Supervised all laboratory procedures.

Chris C Patterson: Provided statistical analysis.

Mark S Spence: Recruited subjects and processed samples form 1999–2001.

Paul G McGlinchey: Recruited subjects and processed samples from 2000–2002.

Christine Belton: Performed the majority of laboratory work.

Tracy CL Jardine: Recruited subjects 2002–2004.

Pascal P McKeown: Supervising consultant 1999–2004.