Lack of MEF2A Δ7aa mutation in Irish families with early onset ischaemic heart disease, a family based study

Horan, Paul; Allen, Adrian; Hughes, Anne E.; Patterson, Chris; Spence, Mark S.; McGlinchey, Paul G.; Belton, Christine; Jardine, Tracy; McKeown, Pascal

doi:10.1186/1471-2350-7-65

Cited by 14 publications

(22 citation statements)

References 9 publications

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“…15 However, this variant was not associated with MI in our much lager sample of patients with nonfamilial MI and displayed no association with MI in the abovementioned Spanish MI population. 14 Our findings are in line with the results obtained by Weng et al 12 and Horan et al 24 Weng and colleagues found no causative MI mutation in 300 CAD cases, and Horan and associates failed to detect the 21-bp deletion described by Wang et al 10 in 1481 individuals with a positive family history for ischemic heart disease. Similarly, we found no disease-causing mutation in our 23 extended MI families, suggesting that MEF2A mutations are responsible for only a relatively small proportion of familial MI cases.…”

Section: Discussionsupporting

confidence: 80%

Lack of Association Between the MEF2A Gene and Myocardial Infarction

Lieb

Mayer²,

König³

et al. 2008

Circulation

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Background— Coronary artery disease (CAD) and myocardial infarction (MI) are caused in part by genetic factors. Recently, the MEF2A gene was linked to MI/CAD in a single pedigree with autosomal-dominant pattern of inheritance. In addition, genetic variants within the gene have been associated with MI in case-control settings, producing inconsistent results. Methods and Results— The MEF2A gene was sequenced in MI patients from 23 MI families (≥5 affected members per family), but no mutation was identified in any of these extended families. Moreover, the Pro279Leu variant in exon 7 was analyzed in 1181 unrelated MI patients with a positive family history for MI/CAD, in 533 patients with sporadic MI, and in 2 control populations (n=1021 and n=1055), showing no evidence for association with MI/CAD. In addition, a (CAG)n repeat in exon 11 was genotyped in 543 sporadic MI patients and in 1190 controls without evidence for association with MI. Finally, analyzing 11 single-nucleotide polymorphisms from the GeneChip Mapping 500K Array, genotyped in 1644 controls and 753 cases, failed to provide evidence for association (region-wide P =0.23). Conclusions— Studying independent samples of >1700 MI patients, 2 large control populations, and multiple families with apparently mendelian inheritance of the disease, we found no evidence for any linkage or association signal in the MEF2A gene.

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Section: Discussionsupporting

confidence: 80%

Lack of Association Between the MEF2A Gene and Myocardial Infarction

Lieb

Mayer²,

König³

et al. 2008

Circulation

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“…However, the association of MEF2A with CAD/MI has been challenged by subsequent investigations, because the originally described mutations in MEF2A were observed in unaffected individuals and did not segregate with the disease. 12, 15 The advent of Figure 4. Effect of 7 missense mutations on MEF2A transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

Section: Clinical Perspective See P 172mentioning

confidence: 99%

“…Nonetheless, the role of MEF2A in the pathogenesis of cardiovascular diseases still remains uncertain; in fact, several case-control studies have been undertaken, but controversial results were found. [12][13][14][15][16][17] Moreover, a recent study by Lieb et al 18 performed on more than 1700 patients with MI, 2 large control populations, and extended families with apparently Mendelian inheritance of the disease showed no evidence of association between MEF2A and MI.In this study, we analyzed the role of MEF2A in the pathogenesis of CAD/MI in 2 Italian populations by a combined approach based on mutational screening, association analysis, and functional characterization of identified MEF2A variants. Our analyses substantially do not support the role of MEF2A as a susceptibility gene for CAD/MI.…”

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confidence: 99%

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

Guella

Rimoldi

Asselta

et al. 2009

Circ Cardiovasc Genet

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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. Key Words: coronary artery disease Ⅲ myocardial infarction Ⅲ MEF2A Ⅲ association analysis Ⅲ expression experiments Ⅲ genetics C oronary artery disease (CAD) is the most common cause of death and disability in the Western world, and its prevalence is dramatically increasing in developing countries. Myocardial infarction (MI) is the prevalent and often fatal manifestation of CAD. 1 MI is a complex disease characterized by the inheritance of multiple genetic variants acting in concert with environmental factors to promote the disease state. Many risk factors have been identified for CAD/MI, including family history, hypertension, hypercholesterolemia, obesity, smoking, and diabetes mellitus. Among these, a positive family history is one of the most significant independent predictors for CAD/MI, especially in the young. 2,3 Conclusions-All Clinical Perspective see p 172Recently, the development of high-density genotyping arrays opened the possibility to perform large-scale genomewide association studies. The first promising results of this approach, among several additional loci, pointed the attention to a region on chromosome 9p21.3, which was initially found to be associated with CAD/MI in the Icelandic, 4 Canadian, 5 English, and German 6,7 populations and represents the most highly replicated locus for CAD/MI identified to date.The study of the genetic basis of complex diseases may also take advantage from the rare occurrence of autosomal dominant forms of the disease in single families. This approach identified the MEF2A gene, a member of the myocyte enhancer factor 2 (MEF2) family of MADS-box transcription factors, as the gene responsible for an autosomal dominant form of CAD in a single larg...

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“…Kajimoto et al (2005) reported that the CAG repeat sequence was not correlated with MI susceptibility in Japanese patients. Horan et al (2006) also found that the CAG repeat sequence was not associated with the susceptibility to early-onset familial CAD in an Irish population. Hsu et al (2010) identified no correlation between the CAG repeat sequence and CAD susceptibility in the Taiwanese population.…”

Section: Discussionmentioning

confidence: 89%