Polymorphisms in oxidative stress pathway genes and risk of diabetic nephropathy in South Indian type 2 diabetic patients.

AIM: Diabetic nephropathy (DN), a common microvascular complication of type 2 diabetes mellitus (T2DM) is polygenic, with a vast array of genes contributing to disease susceptibility. Accordingly, we explored the association between DN and six polymorphisms in oxidative stress related genes, namely eNOS, p22phox subunit of NAD(P)H oxidase, PARP-1 and XRCC1 in South Indian T2DM subjects. METHODS: The study included 155 T2DM subjects with DN and 162 T2DM patients with no evidence of DN. The selected polymorphisms were genotyped by polymerase chain reaction and Taqman allele discrimination assay. RESULTS: No significant difference was observed in the genotype and allele distribution of eNOS -786T > C, intron 4a4b, p22phox 242C > T and XRCC1 Arg399Gln polymorphisms between T2DM groups with and without DN. Contrastingly, there appeared to be a significant association of eNOS 894G > T and PARP-1 Val762Ala polymorphisms with DN wherein, the presence of 894T allele was associated with an enhanced risk for DN [P = 0.005; OR = 1.78 (1.17-2.7)], while the 762Ala allele seemed to confer significant protection against DN [P = 0.02; OR = 0.59 (0.37-0.92)]. Multiple logistic regression analysis revealed a significant and independent association of eNOS 894G > T, PARP-1 Val762Ala polymorphisms and hypertension with DN in T2DM individuals. CONCLUSIONS: eNOS 894G > T and PARP-1 Val762Ala polymorphisms appeared to associate significantly with DN, with the former contributing to an enhanced risk and the latter to a reduced susceptibility to DN in South Indian T2DM individuals.

Link between ACE I/D Gene Polymorphism and Dyslipidemia in Diabetic Nephropathy: A Case-control Study from Hyderabad, India.

INTRODUCTION: Diabetic nephropathy (DN) is the commonest single cause of end-stage renal failure, and dyslipidemia is a critical risk factor in the occurrence of DN. In the light of recent reports emphasizing the importance of angiotensin I-converting enzyme (ACE) in the modulation of plasma lipids, we sought to evaluate the influence of ACE I/D gene polymorphism with dyslipidemia status among type 2 diabetic (T2D) patients with and without nephropathy in the genetic predisposition and the progression to DN. METHOD: This study comprised of 600 subjects, which include patients with DN, T2D, and healthy controls (HC). Polymerase chain reaction based genotyping of ACE I/D polymorphism was performed and appropriate statistical analysis was done. RESULTS: Out of the 600 subjects, 20 (10%) of the HC, 73 (36.5%) of the T2D group, and 125 (62.5%) of the DN subjects had dyslipidemia. The D allele (0.62) and DD (42.5) genotype frequencies were higher in the DN group in comparison with T2D and HC (P < 0.05). The genotypes also varied among patients with dyslipidemia (χ2 5.04; P < 0.05) but not in the non-dyslipidemia group. Under the co-dominant model, DD genotype conferred a risk of 1.26 (P < 0.001) toward DN, whereas the ID genotype offered protection from DN among the dyslipidemic subjects (OR = 0.05; P < 0.01). In addition, genotype-dependent difference was seen in the plasma lipid levels among study groups. A multiple logistic regression analysis revealed male gender, BMI, HbA1c, TG, HDL, and ACE DD genotype as independent risk factors for the development of DN. CONCLUSION: The study showed a significant predisposing association of ACE DD genotype with DN and protective effect of ID genotype on DN in the dyslipidemia subgroup.

Association Analysis of Polymorphisms in Genes Related to Oxidative Stress in South Indian Type 2 Diabetic Patients with Retinopathy.

BACKGROUND: Diabetic Retinopathy (DR) is one of the most common microvascular complications of type 2 diabetes mellitus (T2DM) and is polygenic with a multitude of genes contributing to disease susceptibility. The present study aimed at exploring the association between DR and seven polymorphisms in oxidative stress-related genes, i.e. ACE, eNOS, p22phox subunit of NAD(P)H oxidase, PARP-1 and XRCC1 in South Indian T2DM subjects. MATERIALS AND METHODS: The study included 149 T2DM subjects with DR (diagnosed through funduscopic examination) and 162 T2DM patients with no evidence of DR. The selected polymorphisms were genotyped by polymerase chain reaction (PCR) and Taqman allele discrimination assay. RESULTS: There was no significant difference in the genotype and allele distribution of ACE ins/del, eNOS-786T>C, 894G>T, 4a4b and p22phox 242C>T polymorphisms between T2DM groups with and without DR. Contrastingly, there appeared to be a significant association of PARP-1 Val762Ala and XRCC1 Arg399Gln polymorphisms with DR, wherein 762Ala allele seemed to confer significant protection against DR (p = 0.01; OR = 0.51 [0.3-0.86]), while the presence of 399Gln allele was associated with an enhanced risk for DR (p = 0.02; OR = 1.52 [1.07-2.15]). Multiple logistic regression analysis revealed a significant and independent association of Val762Ala and Arg399Gln polymorphisms and other putative risk factors with DR in T2DM individuals. CONCLUSIONS: The polymorphisms in the DNA repair genes PARP-1 and XRCC1 tended to associate significantly with DR. While Val762Ala polymorphism was associated with reduced susceptibility to DR, the Arg399Gln polymorphism contributed an elevated to risk for DR in South-Indian T2DM individuals.

Association of the genetic variants of endothelial nitric oxide synthase gene with angiographically defined coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus.

INTRODUCTION: The polymorphic variants of endothelial nitric oxide synthase (eNOS) gene have been implicated in endothelial dysfunction and are highly relevant to macroangiopathies. We investigated the relationship between eNOS gene T-786C, G894T, intron 4a/b polymorphisms and coronary artery disease (CAD) in South Indian type 2 diabetic (T2DM) individuals. METHODS: We screened 283 T2DM patients, inclusive of 160 with angiographically defined CAD, 73 with myocardial infarction (MI), 89 without MI and 121 T2DM individuals with no evidence of CAD for eNOS gene polymorphisms. RESULTS: There appeared to be a significant difference in the genotype and allele distribution of eNOS T-786C polymorphism between T2DM groups with and without CAD (p=0.004), albeit no significant association with MI was observed. The frequencies of TC and CC genotypes and -786C allele were considerably higher in patients with triple vessel disease (TVD) as compared to those without CAD (p=0.003), thereby associating this polymorphism with severity of CAD. Genotype and allele distributions of G894T and intron 4a/b polymorphisms were not significantly different between T2DM subjects with and without CAD/MI. Significant linkage disequilibrium was observed between intron 4a/b and T-786C polymorphisms. Multiple logistic regression analysis revealed a significant and independent association of eNOS T-786C polymorphism and other putative risk factors with CAD/TVD in T2DM individuals. CONCLUSIONS: These findings reveal a significant association between eNOS T-786C polymorphism, CAD/TVD and coincident putative risk factors in T2DM individuals in South Indian population.

Arg399Gln polymorphism of X-ray repair cross-complementing group 1 gene is associated with angiographically documented coronary artery disease in South Indian type 2 diabetic patients.

AIMS: DNA damage resulting from oxidative stress contributes significantly to the development and progression of atherosclerosis in type 2 diabetic (T2DM) individuals, thereby implicating polymorphisms in DNA repair genes in the modulation of DNA repair efficiency. Based on this premise, we explored the association between X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphism, coronary artery disease (CAD), and myocardial infarction (MI) in type 2 diabetic patients. We screened 283 T2DM patients, inclusive of 160 with angiographically defined CAD, 73 with MI, 89 without MI, and 121 T2DM individuals with no evidence of CAD for XRCC1 Arg399Gln polymorphism. RESULTS: There appeared to be a significant difference in the distribution of genotype and allele frequencies of XRCC1 Arg399Gln polymorphism between T2DM groups with and without CAD (p=0.03), albeit no significant association with MI was observed (p=0.055). A further analysis revealed that the frequencies of the Arg/Gln, Gln/Gln genotypes and 399Gln allele were considerably higher in patients with triple vessel disease (TVD) as compared with those with the single and double vessel disease (p=0.03), thereby associating this polymorphism with severity of CAD in T2DM individuals. Multiple logistic regression analysis revealed a significant and independent association of XRCC1 Arg399Gln polymorphism and other putative risk factors with CAD/TVD in T2DM individuals. CONCLUSIONS: These findings reveal a significant association between XRCC1 gene Arg399Gln polymorphism, CAD/TVD, and coincident putative risk factors in T2DM individuals in the South Indian population.

Relationship between NADPH oxidase p22phox C242T, PARP-1 Val762Ala polymorphisms, angiographically verified coronary artery disease and myocardial infarction in South Indian patients with type 2 diabetes mellitus.

INTRODUCTION: There has been compelling evidence for the role of oxidative stress in the pathogenesis of cardiovascular complications in type 2 diabetes mellitus (T2DM). We analyzed the association of C242T and Val762Ala polymorphisms of NADPH oxidase p22phox and poly (ADP-ribose) polymerase-1 (PARP-1) genes respectively with coronary artery disease (CAD) and its severity, myocardial infarction (MI) and cardiovascular risk factors in T2DM patients. MATERIALS AND METHODS: We screened 283 T2DM patients, inclusive of 160 with angiographically defined CAD, 73 with and 89 without MI and 121 T2DM individuals with no evidence of CAD for the two gene polymorphisms. RESULTS: The 242T and 762Ala alleles were significantly more frequent in T2DM subjects without CAD than those with CAD, thereby associating them with a significant protective effect against development of CAD [p=0.002 (C242T); 0.02 (Val762Ala)]. The association was further characterized by a relatively lower frequency of 242T and 762Ala alleles in T2DM patients with multi (MVD)/triple vessel disease respectively [p=0.003 (C242T); 0.02 (Val762Ala)]. Conversely, the genotype and allele frequencies of these polymorphisms were not significantly different in T2DM+CAD patients with or without MI. Stratification of risk by putative risk factors for CAD revealed a significant interaction with these polymorphisms. Multiple logistic regression analysis revealed a significant and independent association of C242T and Val762Ala polymorphisms and other putative risk factors with CAD/MVD in T2DM individuals. CONCLUSIONS: Our observations indicate a significant relationship between p22phox C242T and PARP-1 Val762Ala polymorphisms, CAD and its severity, but not with occurrence of MI in T2DM individuals with significant coronary stenoses.