Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with mortality in haemodialysis patients

Abstract

Vascular calcification and accelerated atherosclerosis are major causes of death in haemodialysis (HD) patients. Matrix metalloproteinases (MMPs) are a family of enzymes, involved in the biology of extracellular matrix and in atherogenesis. MMP1 and MMP3 contribute to the enlargement and instability of atherosclerotic plaque, respectively. The common polymorphisms on MMP1 (2G/2G) and MMP3 (6A/6A) gene promoters have been related to increased coronary artery calcification and to carotid artery stenosis. The aim of this study was to evaluate the association of MMP1 and MMP3 polymorphisms with end-stage renal failure (ESRD) and all-cause mortality risk in HD. Ninety-nine HD patients, followed-up for 36 months, and 133 matched controls were genotyped for the two polymorphisms. HD patients' characteristics were age 64 +/- 13 years, males 64%, diabetic 24%, hypertensive 62%, smokers 38%, dyslipidaemic 28%, all undergoing standard HD thrice weekly. ESRD was strongly associated with the combination of 2G/2G and 6A/6A homozygosity: OR 2.57 (0.95-7.4), P = 0.037, but not with isolated 2G/2G and 6A/6A homozygosity (P = 0.09 and P = 0.11, respectively). Isolated 2G/2G was associated with all-cause mortality risk independently from age, gender, diabetes, hypertension, smoking, dyslipidaemia, C-reactive protein, albumin, dialysis vintage and history of cardio-vascular disease: HR 2.96 (1.29-6.80), P = 0.01. A trend for the association of mortality and isolated 6A/6A homozygosity was also observed: HR 3.01 (0.88-10.26), P = 0.078. Combination of 2G/2G and 6A/6A homozygosity significantly increased the mortality risk in the same Cox regression model: HR 4.69 (1.72-12.81), P = 0.003. In this study, we demonstrated for the first time that MMP-1 and MMP-3 gene polymorphisms are negative prognostic risk factors for all-cause mortality in HD patients, independently from traditional risk factors. These data may have important implications for better understanding the pathogenesis of the increased mortality in HD patients.