P1613INFLUENCE OF GENETIC POLYMORPHISM IN MMPS AND TIMPS ON ALLOGRAFT OUTCOME IN RENAL TRANSPLANT RECIPIENTS

Abstract

Abstract Background and Aims Renal transplantation (RT) is currently the most effective replacement therapy and believed as a boon for patients with end-stage renal disease (ESRD). Allograft rejection remains to be one of the crucial impediments in successful renal transplantation. Matrix metalloproteinases (MMPs) and their natural inhibitors (tissue inhibitors of matrix metalloproteinases; TIMPs) play an important role in immune-mediated tissue destruction of the allograft by allowing influx of leucocytes and mononuclear cells into the graft. The study of MMPs and TIMPs in transplant rejection may also lead to novel approaches in the therapy of rejection processes. To investigate the association of functional polymorphisms in MMP-1 (-1607 1G/2G), (-519 A/G); MMP-3(5356 A/G), (1161 A/G); MMP-9 (1721G/C), (Q279R A/G), (R668Q G/A); TIMP1(+536 C/T) and TIMP3(-1298 C/T gene with risk of allograft rejection in renal transplant recipients of North India. Method A total of two hundred live related renal transplant donors and recipients pairs blood sample was collected and were genotyped for MMP-1 (-1607 1G/2G), (-519 A/G); MMP-3(5356 A/G), (1161 A/G); MMP-9 (1721G/C), (Q279R A/G), (R668Q G/A); TIMP1(+536 C/T) and TIMP3(-1298 C/T) gene polymorphisms by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) methodology. All two hundred renal transplant recipients were categorized into 162 non-rejecters and 32 rejecters and were analyzed further. All the statistical analysis was done using SPSS software. Results The genotype frequencies of MMP1 (-1607 1G/2G) [2G/2G; odds ratio (OR) = 2.97, 95% confidence intervals (95% CI) = 1.69-5.20, P ≤ 0.05]; MMP9 (Q279R) [RQ; odds ratio (OR) = 0.47, 95% confidence intervals (95% CI) = 0.25-0.99, P = 0.02 & QQ; odds ratio (OR) = 0.49, 95% confidence intervals (95% CI) = 0.25-0.94, P = 0.03]; MMP9 (P574R) [PR; odds ratio (OR) = 2.70, 95% confidence intervals (95% CI) = 1.77-4.13, P ≤ 0.05 & RR; odds ratio (OR) = 2.70, 95% confidence intervals (95% CI) = 1.09-6.71, P = 0.03]; TIMP1(+536 C/T) [CT; odds ratio (OR) = 15.41, 95% confidence intervals (95% CI) = 9.12-26.05, P ≤ 0.05 & TT; odds ratio (OR) = 7.01, 95% confidence intervals (95% CI) = 3.39-14.49, P ≤ 0.05] and TIMP3(-1298 C/T) [CT; odds ratio (OR) = 0.31, 95% confidence intervals (95% CI) = 0.19-0.50, P ≤ 0.05] was significantly associated with allograft rejection. On comparison of genotypic frequencies for MMP-1, MMP-3, MMP-9, TIMP1 and TIMP3 gene polymorphisms between rejecters and non-rejecters no significant difference was found while comparing genotypic frequencies of non-rejecters with donors a significant association was observed in MMP1 (-1607 1G/2G) [P ≤ 0.05]; MMP9 (Q279R) [P = 0.02]; MMP9 (P574R) [P ≤ 0.05]; TIMP1 [P ≤ 0.05] and TIMP 3 [P ≤ 0.05] respectively. Therefore, MMP1 (-1607 1G/2G), MMP9 (Q279R), MMP9 (P574R), TIMP1 and TIMP3 demonstrated significantly reduced risk for allograft rejection. MMP1 (-1607 1G/2G) [P ≤ 0.02]; MMP9 (P574R) [P ≤ 0.05]; TIMP1 [P ≤ 0.05] and TIMP3 [P =0.01] was also found significantly associated on comparison between rejecters and donors. Conclusion Mutant genotypes/ alleles for MMP1 (-1607 1G/2G); MMP9 (Q279R); MMP9 (P574R); TIMP1 (+536 C/T) and TIMP3 (-1298 C/T) are associated with reduced risk for allograft rejection and improved allograft survival in North Indian transplant recipients and could serve as an ideal marker to predict pre-transplant allograft outcome.