Functional polymorphisms in matrix metalloproteinases-1, -3, -9 are associated with arteriovenous fistula patency in hemodialysis patients

Background and objectives: Matrix metalloproteinases (MMPs) are risk factors for cardiovascular diseases. This study evaluated the association of genotype polymorphisms of MMPs and tissue inhibitors of metalloproteinases (TIMPs) in hemodialysis (HD) patients with arteriovenous fistula (AVF) failure. Design, setting, participants, & measurements: Genotype polymorphism of MMP-1, MMP-2, MMP-3, and MMP-9 and TIMP-1 and TIMP-2 and clinical and laboratory parameters were compared between Chinese HD patients with (n = 170) and without (n = 426) AVF failure. Results: Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.007 per month), lower pump flow (0.991 per ml/min), higher dynamic venous pressure (1.016 per mmHg), location of AVF on right side (1.630 versus left side) and upper arm (2.385 versus forearm), history of cardiovascular disease (1.656 versus absence of history), 1G/1G genotype of MMP-1 -1607 1G >2G SNP (2.315 versus 1G/2G + 2G/2G genotypes), 6A/6A genotype of MMP-3 -1612 5A >6A SNP (1.712 versus 5A/6A + 5A/5A), and C/C genotype of MMP-9 -1562 C>T SNP (1.650 versus C/T+T/T). The positive predictive rates for AVF failure were 63.0% and 6.7% for patients with the highest-risk (1G1G/6A6A/ CC) and lowest-risk (2G2G or 2G1G/5A5A or 6A6A/TT or TC) composite MMP-1/MMP-3/MMP-9 genotype, respectively. The unassisted patency of AVF at 5 years decreased significantly from 93.3% to 38.4% for the composite MMP-1/MMP-3/MMP-9 genotypes (lowest versus highest risk, P < 0.001). Conclusions: Specific genotypes of MMP-1, MMP-3 and MMP-9 with lower transcriptional activity are associated with higher frequencies of AVF failure, which may result from more accumulation of extracellular matrix, leading to AVF stenosis.