Atherosclerosis 209 (2010) 152–154 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis A study of the role of the myocyte-specific enhancer factor-2A gene in coronary artery disease Samar Elhawari a , Olyan Al-Boudari a , Paul Muiya a , Hanif Khalak a , Editha Andres a , Maie Al-Shahid b , Mohammed Al-Dosari c , Brian F. Meyer a , Futwan Al-Mohanna d , Nduna Dzimiri a,∗ a Genetics Department, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia b King Faisal Heart Institute, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia c Department of Pharmacology, King Saud University, Riyadh, Saudi Arabia d Biological and Medical Research Department, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia article info Article history: Received 2 September 2009 Accepted 3 September 2009 Available online 9 September 2009 Keywords: MEF2A Gene polymorphism CAD Haplotype abstract We evaluated the role of the MEF2A as a risk factor for coronary artery disease (CAD) in 1186 subjects with angiographically documented disease compared with 885 CAD-free individuals in the Saudi population. Screening the gene revealed exon 11 as the most polymorphic of all coding regions, harbouring several substitution polymorphisms and insertion/deletions (indels) at a locus containing an 11 CAG trinucleotide chain and a CCGCCGCCA sequence, which introduced frameshifts and premature stop codons at nt146637 and nt146647, nt146780 or nt146783. While these indels were not significantly associated with CAD, a causative relationship was established for rs1059759 G>C [1.21(1.02–1.43); p = 0.029], and a borderline one for rs34851361 A>G [1.22(0.9–1.54); p = 0.088]. Importantly, a haplotype 1A-2G-3G-4A-5C-6G-7G- 8A constructed from the studied SNPs was also associated with CAD [6.39(0.93–43.75); p = 0.0052]. These results identify MEF2A gene as a susceptibility gene for CAD. © 2009 Elsevier Ireland Ltd. All rights reserved. 1. Introduction The myocyte-specific enhancer factor subtype 2A (MEF2A) is highly expressed in the endothelium of coronary arteries. In muscle cells, MEF2A inhibits myogenesis by interacting with the members of the myogenic regulatory factor family of transcriptional activa- tors and other transcription factors such as TWIST [1,2] through negative regulation by MEF2-interacting transcription repressors in association with histone deacetylases [3,4]. Because of its role in morphogenesis, alterations in its sequence are likely to adversely influence the regulation of these processes, possibly leading to vas- cular disorders. Indeed, the MEF2A gene has been implicated in coronary artery disease (CAD) [5–8]. However, some other stud- ies have also refuted such a functional role in vessel disease [9–15]. To verify this issue further, we determined the MEF2A gene vari- ants and their association with CAD in a cohort of patients with angiographically established disease in the Saudi population. ∗ Corresponding author at: MBC-03-05, Genetics Department, King Faisal Spe- cialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. Tel.: +966 1 442 7870; fax: +966 1 442 4585. E-mail address: dzimiri@kfshrc.edu.sa (N. Dzimiri). 2. Methods 2.1. Study subjects The study was performed in two stages: first to determine the MEF2A gene variants prevalent in the Saudi population, followed by investigating their impact on CAD manifestation. One hundred individuals were initially selected randomly from blood donors visiting our Blood Donor Clinic to detect the gene variants, and a further 450 individuals sequenced to estimate their prevalence in the population and facilitate selection of SNPs of potential interest. Association of the discovered SNPs with disease was then evaluated in 1156 CAD cases (851 male and 305 female; 61.7 ± 0.3 years), with angiographically confirmed narrowing of the coronary ves- sels by ≥50%. Another group of 859 angiographed individuals (419 male and 440 female; 49.9 ± 0.5 years) randomly and sequentially selected among candidates visiting our Institutional Catheteri- zation Clinic for diagnostic or follow-up procedures related to rheumatic heart disease or idiopathic dilated cardiomyopathy, and those who reported with chest pain, but were established to have no significant coronary stenosis served as controls (CON). Detailed inclusion/exclusion criteria and complete description of the methodology are provided in Supplementary data. This study was performed in accordance with the regulations of the Hospital Ethics Committee. 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.09.005