Background and Objective. Glutathione-S-transferase (GST) is the superfamily of genes that provides protection to the cells against reactive oxygen species and plays a vital role in phase II of biotransformation of many substances. Overexpression of GST (EC 2.5.1.18) has been documented in the erythrocytes of patients with chronic renal failure, which may be of clinical relevance. Keeping this background in mind, we have investigated the relationship between human GST gene polymorphism in end stage renal disease (ESRD) patients. Design and Methods. We have assessed 184 patients with ESRD and 569 age-and sex-matched controls from North India. The GSTT1 and GSTM1 null genotypes were identified by polymerase chain reaction (PCR). GSTP1–313 A/G mutation was determined by PCR followed by restriction enzyme digestion. Results. The gene frequency of GSTM1, GSTT1, and GSTP1 polymorphism were evaluated. We observed that GSTM1 null genotype was present in 46.74% of the ESRD patients while GSTT1 null genotype was present in 58.7% of the ESRD subjects. The genotypic distribution of GSTP1 was Ile₁₀₅/Ile₁₀₅ in 47.3%, Ile₁₀₅/Val₁₀₅ in 30.97% and Val₁₀₅/Val₁₀₅ in 21.74% of ESRD patients. There was a significant association of null alleles of the GSTM1 (p = 0.0386; OR = 1.445, 95% CI = 1.033–2.021) and GSTT1 (p ≤ 0.0001; OR = 4.568, 95% CI = 3.215–6.492) and in the -313 G alleles (Val) of the GSTP1 gene (p = 0.0032; OR = 1.956, 95% CI = 1.265–3.024) with end stage renal disease. The combined analysis of the three genotypes showed a further increased risk to ESRD (p ≤ 0.0001; OR = 9.01, 95% CI = 5.55–14.626). Interpretations and Conclusions. The null / low polymorphism of the detoxifying enzymes GSTT1, GSTM1, and GSTP1 are associated with the risk of developing ESRD in North Indian patients.

Allogeneic hematopoietic cell transplantation (HCT) can be curative for many hematologic diseases. However, complications such as graft-versus-host disease (GVHD) and relapse of primary malignancy remain significant and are the leading causes of morbidity and mortality. Effects of killer Ig-like receptors (KIR)-influenced NK cells on HCT outcomes have been extensively pursued over the last decade. However, the relevance of the reported algorithms on HLA matched myeloablative HCT with rabbit antithymocyte globulin (ATG) is used for GVHD prophylaxis remains elusive. Here we examined the role of KIR and KIR-ligands of donor-recipient pairs in modifying the outcomes of ATG conditioned HLA matched sibling and unrelated donor HCT The study cohort consisted of 281 HLA matched sibling and unrelated donor-recipient pairs of first allogeneic marrow or blood stem cell transplantation allocated into ‘discovery’ (135 pairs) and ‘validation’ (146 pairs) cohorts. High resolution HLA typing was obtained from the medical charts and KIR gene repertoires were obtained by a Luminex^® based SSO method. All surviving patients were followed-up for a minimum of two years. KIR and HLA class I distributions of HCT pairs were stratified as per applicable definitions and were tested for their association with cause specific outcomes [acute GVHD grade II-IV (aGVHD), chronic GVHD needing systemic therapy (cGVHD) and relapse] using a multivariate competing risks regression model as well as with survival outcomes [relapse-free survival (RFS), cGVHD & relapse free survival (cGRFS) and overall survival (OS)] by multivariate Cox proportional hazards regression model. A significant association between KIR genotype mismatching (KIR-B/x donor into KIR-AA recipient or vice versa) and cGVHD was found in both discovery (p = 0.001; SHR = 2.78; 95%CI: 1.50–5.17) and validation cohorts (p = 0.005; SHR = 2.61; 95%CI: 1.33–5.11). High incidence of cGVHD associated with KIR genotype mismatching was applicable to both sibling and unrelated donors and was specific to recipients who had one or two C1 bearing HLA-C epitopes (HLA-C1/x, p = 0.001; SHR = 2.40; 95%CI: 1.42–4.06). When compared with KIR genotype mismatched transplants, HLA-C1/x patients receiving grafts from KIR genotype matched donors had a significantly improved cGRFS (p = 0.013; HR = 1.62; 95%CI: 1.11–2.39). Although there was no effect of KIR genotype matching on survival outcomes, a significantly reduced incidence of relapse (p = 0.001; SHR = 0.22; 95%CI: 0.10–0.54) and improved relapse-free survival (p = 0.038; HR = 0.40; 95%CI: 0.17–0.95) was observed with one or more missing ligands for donor inhibitory KIR among the recipients of unrelated donor transplants. The present study for the first time presents the beneficial effects of KIR genotype matching in reducing cGVHD in myeloablative transplant setting using HLA matched (sibling and unrelated) donors. The findings offer a clinically applicable donor selection strategy that can help control cGVHD without affecting the risk of relapse and/or identify patients at a high risk of developing cGVHD as potential candidates for preemptive therapy. The findings also affirm the beneficial effect of one or more missing inhibitory KIR ligands in the recipient in reducing relapse and improving a relapse free survival in unrelated donor transplants.

BACK GROUND AND OBJECTIVES: Vitamin D receptor (VDR) gene polymorphism is reported to be associated with end-stage renal disease (ESRD). We have investigated the potential role of VDR gene polymorphisms among ESRD. The influence of VDR gene polymorphism in 258 ESRD patients comprising of 226 (87.5%) male and 32 (12.5%) females was investigated in this study. We compared ESRD patients with 569 healthy controls. The distribution of male and female among controls was 485 (85.3%) males and 84 (14.7%) females. This polymorphism was studied by using polymerase chain reaction (PCR). The product was digested by using restriction enzymes Apa1, Taq1, Fok1, and Bsm1. We observed a significant difference in the genotype frequencies of the Apa1-aa (p = 0.0001, OR = 2.1, 95% CI = 1.45-3.08), Fok1-ff (p = 0.001, OR = 3.44, 95% CI = 1.76-6.76), and Bsm1-BB (p = 0.0004, OR = 6.8, 95% CI = 2.2-21.58). At allelic level B allele of Bsm1 was significantly different among ESRD patients as compared to controls (p = 0.0001). The combined analysis revealed that ESRD patients with Fok1 and Bsm1 polymorphism were at increased risk of 4.33-fold. The haplotype analysis revealed individuals with a/t/F/b haplotype were at greater risk of 11.0-fold (95% CI = 1.38-87.69). The serum calcium levels were significantly higher (p = 0.001) in Bsm1 "BB" genotype. Bsm1 and Fok1 gene polymorphism of VDR gene were associated with ESRD among north Indians.

Immunological responses may be possibly involved in the pathogenesis of idiopathic nephrotic syndrome (INS). Cytokines act as a potent immunomodulator. Pathogenesis of INS is associated with Th1 and Th2 cytokines imbalance. AIMS, SETTINGS AND DESIGN: We have investigated the association of IL-4, IL-6, and TNF-alpha gene polymorphisms and analyzed the data to evaluate the effect of these polymorphisms on the pathogenesis and clinical course of INS. One hundred fifty children with INS were selected. Children were analyzed for IL-4, IL-6, and TNF-alpha gene polymorphisms by using polymerase chain reaction and restriction fragment length polymorphism. Chi-square test was used for different comparisons. The synergistic effects of IL-4, IL-6, and TNF-alpha gene polymorphisms were evaluated by using logistic regression analysis. We compared the steroid-resistant (SR) and steroid-responsive (SS) groups. Our results showed strong association of IL-6 -G174C, and IL-4 -C590T at genotypic level (P = 0.0121, OR = 14.71, 95% CI = 1.59-136.46; and P = 0.0386, OR = 7.29, 95% CI = 1.26-41.69). TNF-alpha revealed a strong association at genotypic level (P = 0.0121, OR = 14.71, 95% CI = 1.59-136.46), as well as at allelic level (P = 0.0433, OR = 2.251, 95% CI = 1.09-4.66), demonstrating that it may be considered one of the genetic risk factors affecting the steroid response in INS patients. The GG genotype of IL-6 -G174C, TT genotype of IL-4 -C590T, and AA genotype of TNF-alpha -G308A cytokine gene polymorphisms may be causative factors for nonresponsiveness towards steroid therapy among INS children.