A genetic polymorphism in connexin 37 as a prognostic marker for atherosclerotic plaque development

Background and objectives. Atherosclerosis is a multifactorial disease, in part characterized by chronic inflammatory changes in the vessel wall and l oss of normal physical and biochemical interactions between endothelial cel ls and smooth muscle cells. Previous studies [Hu J., Cotgreave IA. I Clin I nvest; 99: 1-5] have provided molecular links between inflammation and myoe ndothelial communication via gap junctions, suggesting that these structure s may be important in the development of the atherosclerotic vessel phenoty pe. In order to strengthen this premise, the aim of the present work was to probe for structural polymorphisms in connexin 37, a gap junctional protei n uniquely expressed in endothelial cells, and to assess for potential geno typic segregation in individuals displaying atherosclerotic plaque. Methods and results. Computer-based comparisons of Expressed Sequence Tags (ESTs) predicted a polymorphism in the human gap junctional protein connexi n 37 (cx37). The C-1019-T mutation results in a proline to serine shift at codon 319 (cx37*1-cx37*2). A Restriction Fragment Length Polymorphism (RFLP ) assay, involving the insertion of a novel Drd I cleavage site in the prol ine variant revealed a statistically significant over-representation of the cx37*1 allele in association with atherosclerotic plaque-bearing individua ls (Odds-ratio for the homozygote = 2.38, X-2 = 7.693, P = 0.006), in compa rison to individuals lacking plaque, irrespective of a history of hypertens ion. Conclusions. These data suggest that the C-1019-T polymorphism in cx37 may provide 'single gene marker', which could be useful in assessing atheroscle rotic plaque development, particularly in cardiovascular risk groups such a s those with borderline hypertension.