Association between heme oxygenase-1 promoter polymorphisms and the development of diabetic nephropathy in type 2 diabetes

Abstract

Heme oxygenase (HO)-1 is a key enzyme in cytoprotective mechanisms against oxidative stress in the cardiovascular-renal system. The T(-413)A single nucleotide polymorphism (SNP) and (GT)n microsatellite polymorphism in the HO-1 gene promoter modulate the HO-1 gene transcriptional activity and theses polymorphisms are associated with various human diseases. We investigated the association between HO-1 promoter polymorphisms and nephropathy in type 2 diabetes. We sequenced the T(-413)A SNP and (GT)n repeat segments of the HO-1 gene promoter in 536 patients with type 2 diabetes. (GT)n alleles were divided into 2 groups: short (S, ≤25 GT repeats) and long (L, >25 GT repeats) alleles. Random urine albumin to creatinine ratio or 24-hour urine analysis was performed and clinical and biochemical parameters were measured. Patients with the TT genotype in the T(-413)A SNP were significantly more susceptible to diabetic nephropathy than those carrying the A allele, with an odds ratio of 1.577 (95% confidence interval, 1.088 - 2.285; P = 0.016). Subgroup analysis showed that patients carrying the TT genotype with long duration of diabetes (≥20 years), poor glycemic control, male gender and without hypertension had higher odds ratios for the development of diabetic nephropathy. Regarding to the (GT)n repeats, the LL genotype showed a higher odds ratio for the development of diabetic nephropathy only in patients with hypertension when compared to the S allele. The haplotype analysis of HO-1 promoter polymorphisms did not show association with diabetic nephropathy.In conclusion, the T(-413)A SNP in the HO-1 promoter is significantly associated with diabetic nephropathy development in type 2 diabetes patients, overall. On the other hand, the (GT)n microsatellite polymorphism is associated with the development of diabetic nephropathy only in patients with hypertension.