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Journal of Diabetes and Its Complications xx (2008) xxx – xxx Oxidative stress pathway genes and chronic renal insufficiency in Asian Arun K. Tiwaria, Pushplata Prasada, Thelma B.K.a,⁎, K.M. Prasanna Kumarb, A.C. Amminic, aDepartment of Genetics, University of Delhi South Campus, New Delhi 110 021, India bDepartment of Endocrinology and Metabolism, M.S. Ramiah Medical College, Bangalore, India cDepartment of Endocrinology, All India Institute of Medical Sciences, New Delhi, India dJaipur Diabetes Research Centre, Jaipur, India eMonilek Hospital and Research Centre, Jaipur, India Received 18 April 2007; received in revised form 16 July 2007; accepted 18 October 2007 Background: There are significant regional variations in prevalence of diabetes and diabetic chronic renal insufficiency (CRI) in India.
Oxidative stress plays an important role in the development of diabetic complications. To determine the importance of the polymorphisms inthe genes involved in maintenance of cellular redox balance, we performed a case control study in subjects from south and north India.
Methods: Successive cases presenting to the study centers with Type 2 diabetes of N2 years duration and moderate CRI (n=194, south India104, north India 90) diagnosed by serum creatinine ≥2 mg/dl after exclusion of nondiabetic causes of CRI were compared with diabetessubjects with no evidence of renal disease (n=224, south India 149, north India 75). Twenty-six polymorphisms from 13 genes from theoxidative stress pathway were analyzed using polymerase chain reaction–restriction fragment length polymorphism. Genes included weresuperoxide dismutases (SOD1, 2, 3), uncoupling proteins (UCP1, 2), endothelial nitric oxide synthase (NOS3), glutathione-S-transferases(GST) (M1, T1, P1), vascular endothelial growth factor (VEGF), paraoxonase (PON) 1 and 2, and nicotinamide adenine dinucleotidephosphate reduced, oxidase p22phox. Genes were tested for their association with CRI using χ2 test. Results: In south Indian (SI) subjectsthere was significant allelic and genotypic association of the wild-type allele in SOD2 (Ala9Val; P=.002 and P=.013, respectively), UCP1(−112 TNG, P=.012 and P=.009; Ala64Thr, P=.015 and P=.004), NOS3 (Glu298Asp, P=.002 and P=.009) and GSTP1 (Ile105Val, P=.003and P=.004) genes with development of CRI. None of these observations were replicated in the north Indian (NI) subjects. A genotypic butnot allelic association was observed for two markers, VEGF (−460 TNC) and PON1 (Arg192Gly) among NI diabetic CRI subjects.
Conclusion: The nonreplication of association suggests differential genetic susceptibility of the two populations to diabetic chronic renalinsufficiency. In the SI diabetic subjects, oxidative stress pathway genes might be an important predictor for the development of diabeticcomplications. Further, the association of wild-type alleles may suggest that they confer greater survival ability to comorbid complications andmay be nephroprotective.
2008 Elsevier Inc. All rights reserved.
Keywords: Oxidative stress; Candidate genes; Single nucleotide polymorphisms; Association; Chronic renal insufficiency; India This study received financial assistance through senior research fellowships to Arun K. Tiwari, from University Grants Commission, NewDelhi, and Pushplata Prasad, from Council of Scientific and Industrial Diabetic nephropathy (DN) with diabetic chronic renal insufficiency (CRI) is a leading cause of end stage renal No conflict of interest. This is an original research article and has not been published or under consideration in any other journal. All the authors involves myriad of factors including older age, male sex, have read through the manuscript and given consent for communication.
hyperglycaemia, and hyperlipidaemia. Ethnicity is the Corresponding author. Tel.: +91 11 24118201; fax: +91 11 24112761.
other major risk factor, with African Americans, Asians, 1056-8727/08/$ – see front matter 2008 Elsevier Inc. All rights reserved.
doi: A.K. Tiwari et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx and native Americans being more prone to develop DN than superoxide, primarily at the ubiquinone–semiubiquinone step, is increased. This effect of hyperglycaemia is abolished by overexpression of mitochondrial SOD (SOD2 or significant differences in prevalence of diabetes with high MnSOD), which converts harmful superoxide radical to prevalence in southern and western Indian populations, as H2O2, or overexpression of UCP-1, which causes a basal leak compared to northern and eastern Indians ( in the proton gradient reducing superoxide production ). The regional variation in prevalence of diabetes and variable propensity for renal disease along with reports of tion of ROS in the etiology of microvascular complications familial clustering of nephropathy, suggest a possible genetic genetic susceptibility conferred by these groups of genes has not been carried out. A few reports on the associations of evidences suggest that four pathways are involved in the SOD2, glutathione-S-transferase (GST)-T1 (GSTT1) and development of diabetic microvascular complications (for GSTMI, nicotinamide adenine dinucleotide phosphate reduced (NADPH) oxidase p22phox, paraoxonase (PON) 2, and endothelial nitric oxide synthase (NOS3) among type 2 by chronic hyperglycaemia include the polyol, advanced diabetes patients with diabetic nephropathy from a Japanese glycation end products, protein kinase C, and hexoseamine pathways. Inability of the inhibitors of these single pathways to block all the downstream events suggested that all the pathways could be possibly linked to a common upstream event and overproduction of superoxide by electron transport chain was proposed to be this single unifying mechanism activates the four pathways through DNA damage-mediated However, no such reports on these genes from the activation of polyadenosine diphosphate (ADP) ribose polymerase-1 (PARP-1); PARP-1 transfers polyADP-ribose Nearly 30% of the cases of end-stage renal disease in units to several nuclear proteins including glyceraldehyde-3- India are due to diabetes, and this group is more likely to phosphate dehydrogenase (GAPDH). GAPDH is a multi- develop this complication than the Caucasians functional enzyme, which, besides functioning as a glycolytic enzyme in the cytoplasm, plays an important role in DNA ). India has the unfortunate distinction of being repair in the nucleus. The transfer of polyADP-ribose units the country with the maximum number of diabetics world- prevents translocation of GAPDH from the nucleus to wide; 31.7 million people were estimated to be affected with cytoplasm. This prevents its function as a glycolytic enzyme, diabetes in the year 2000, with the projection for the year leading to the accumulation of the upstream intermediate compounds of the glycolytic pathway. These intermediates With such drastic increase, the risk of these such as fructose-6-phosphate, dihydroxyacetone phosphate patients developing diabetes specific complications will also along with glucose are substrates/activators of the above- rise enormously. Therefore, it is essential to identify the risk factors for the development and progression for such of these pathways, in turn, leads to the secondary production complications. Considering the central role of superoxide radical in the genesis of microvascular complications Several genes that detoxify or reduce the production of mentioned above, we analysed, in a pilot study, the role superoxide and other free radicals have been identified.
of 26 polymorphisms from 13 major genes involved in the Superoxide dismutase (SOD) is a family of enzymes involved maintenance of cellular redox balance and important in the conversion of superoxide to H2O2. Uncoupling physiological functions in the development of CRI in proteins (UCP) cause a leakage in the proton gradient. The two geographically distinct populations, one from south importance of these enzymes in diabetic complications is underscored by the observations made under hyperglycaemicconditions. During such condition, increased flux of glucosethrough the glycolytic and tricarboxylic acid (TCA) cycles leads to increase in the production of electron donors(Nicotinamide Adenine Dinucleotide, reduced [NADH] and Flavin Adenine Dinucleotide, reduced [FADH2]). This leadsto increased passage of electrons through the electron In this case control association study, consecutive south transport chain, causing an increase in the potential gradient Indian (SI) samples were recruited from M.S. Ramiah across the inner mitochondrial membrane. When the potential Medical College, Bangalore, and the north Indian (NI) gradient increases above a threshold value, the production of samples from All India Institute of Medical Sciences, New A.K. Tiwari et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx Table 1List of primers, annealing temperature and allelic profiles of the polymorphisms analysed A.K. Tiwari et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx CYBA, Cytochrome b-245, alpha polypeptide.
* Genotyping of GSTM1 and GSTT1 was carried out in a multiplex reaction using estrogen receptor-1 (ESR-1) amplicon as a control for amplification.
Delhi, Jaipur Diabetes and Research Center, Jaipur, and glucose, glycated hemoglobin, serum creatinine, triglycer- Monilek Hospital and Research Centre, Jaipur, following ides, total cholesterol, and albumin were carried out at the clearance from ethical committees of respective institutions.
respective centers using automated analyzers and similar Written informed consent was obtained from the participating protocols to ensure uniformity. Using serum creatinine as a subjects before sample collection. The samples were surrogate marker, we carried out a retrospective calculation of classified as SI or NI based on their ethnicity, mother tongue, glomerular filtration rate (GFR) by the online modified diet in ancestral history, and marital relationships; SIs are primarily of Dravidian origin, and the NI, of Indo-European origin ). Type 2 diabetes mellitus (T2DM) subjects blood from the four centeres was transported to the genetics having diabetes for ≥10 years and serum creatinine b2 mg/dl, with no history of kidney diseases, were included as controls.
The cases of T2DM with CRI were those with persistentlyelevated serum creatinine ≥2 mg/dl, diabetes of ≥2 year duration, and presence of diabetic retinopathy. All patientsunderwent either a fundoscopic examination or fluoroangio- Genomic DNA was isolated from whole blood using the graphic study for diagnosis of retinopathy. Patients with drug- conventional phenol chloroform extraction method and used induced nephrotoxic damage or secondary causes of renal for polymerase chain reaction (PCR)-based genotyping. A total insufficiency such as obstructive renal disease, renal stone of 26 polymorphisms from 13 genes were genotyped using the disease, and acute urinary tract infection were excluded.
PCR–restriction fragment length polymorphism method. The From south India, a total of 149 cases with T2DM and 106 details of primers used and expected allele profiles are provided cases with CRI were evaluated, and NI centers evaluated 75 in . Briefly, the PCR was performed in a total reaction cases of T2DM and 90 cases of diabetic CRI. Clinical data volume of 20 μl containing 100 ng of DNA template; 200 μM included information on duration of diabetes, presence of any deoxyribonucleotide triphosphates (dNTPs), 5 pmol of each complication, history of other disorders, weight (kg), height primer, 1.5 mM MgCl2, 0.5 U of Taq polymerase (Biotools, (cm), body mass index (kg/m2), and systolic and diastolic Madrid, Spain), and 1× PCR reaction buffer. For digestion, blood pressure. Reliable documentation of antidiabetic and PCR products were incubated with 1 U of restriction enzyme antihypertensive medication could not be obtained for the overnight. Depending on the size, the digestion products were large majority of patients and hence these data are not resolved on a 2.5–3.5% ethidium bromide-containing agarose reported. Ten milliliters of venous blood was collected from gel. Samples with known genotypes were included in each set each individual included in the study for biochemical and of digestion to ensure that the observed genotypes were not due genetic analysis. Biochemical analyses to determine fasting to partial/incomplete digestion. Some samples could not be A.K. Tiwari et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx Table 2Clinical characteristics of north India and south India sample sets genotyped due to failure of repeated PCRs due to unknown (for contingency table with low cell values, CLUMP was used; ). For SNPs that were found tobe significant, strength of association was tested by oddsratio estimates at 95% confidence interval. Haplotypes were reconstructed using PHASE version 2.0.2 (Power All statistical tests were done using SPSS version 11.0.
calculations were carried out using the Power and Precision Categorical variables such as gender were compared using χ2 test. Normally distributed continuous variables werecompared using t test. Continuous variables where skeweddistribution was observed were compared by Mann– Whitney U test, and values are reported as mean andrange. Individual single nucleotide polymorphism (SNP) The clinical and demographic characteristics of the two association (allelic and genotypic) was tested using χ2 test sample sets (SI and NI) are provided in Amongst the Table 3Distribution of allelic and genotypic frequencies among patients with T2DM without CRI (coded as 1) and T2DM with CRI (coded as 2) among SI patients a The 11 genotype corresponds to the first allele e.g. Ala9Val CNT 11=CC, 12=CT, 22=TT genotypes.
b Calculated by 2×2 contingency, table cells with cell values less than 5 were merged with the preceding column.
A.K. Tiwari et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx Table 4Distribution of haplotype(s) carrying the risk allele(s) among patients with T2DM without CRI (DM) and T2DM with CRI (CRI) in SI and NI sample sets South IndiaUCP1 (−T3826C-T112G-Ala64Thr) SI samples, no significant difference in the distribution of sample set, SOD2 Ala9Val (in DM), VEGF −460 CNT and gender, duration of diabetes, and glycated hemoglobin was 936CNT, and PON1 rs662 (only in CRI) were not in HWE observed between cases and controls. The other clinical characteristics were significantly different between the twogroups. On the other hand, among the NI case-control group,except for serum cholesterol, all the other clinical variables were significantly different. Hardy–Weinberg equilibrium(HWE) was estimated for both diabetes mellitus (DM) and Of the 26 polymorphisms in 13 genes analyzed in the SI CRI groups in both the sample sets. In the SI sample set, NOS3 subjects, significant association of SOD2 (Ala9Val), UCP1 Glu298Asp (only in DM) and NADPH oxidase p22phox −930 −112 TNG; Ala64Thr, CNT), UCP2 (−866ANG), NOS3 ANG (both in DM and CRI) were not in HWE. In the NI (Glu298Asp, GNT), and GSTP1 (Ile105Val) with CRI was Table 5Distribution of allelic and genotypic frequencies among patients with T2DM without CRI (coded as 1) and T2DM with CRI (coded as 2) from North India a The 11 genotype corresponds to the first allele e.g. Ala9Val CNT 11=CC, 12=CT, 22=TT genotypes.
b Calculated by 2×2 contingency table cells with cell values less than 5 was merged with the preceding column.
A.K. Tiwari et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx observed (Significant observations in all these observed for these two polymorphisms (PN.05, The markers except UCP2 were the excess of wild-type allele and distribution of haplotypes in VEGF gene was not signifi- wild-type genotype and their association with CRI.
cantly different between DM and CRI categories. A The distribution of SOD2 Ala9Val genotypes was found haplotype in PON1 was found to be protective to CRI to be significantly different between DM and CRI groups development [A-A-A; OR=0.512 (0.261–1.005), P=.048].
There was an excess of the wild-type allele Ala(OR=1.780, 95%CI=1.233–2.569; P=.001) and Ala/Ala genotype (OR=1.927, 95%CI=1.157–3.210; P=.011) in theCRI category. Similar association and excess of the wild- Hyperglycaemia-induced oxidative stress is a crucial factor type allele and genotype in CRI category was observed for in the development of diabetic complications UCP1 −112 TNG [OR=1.849, 95% CI=1.142–2.994 for T allele, P =.012; OR=2.076, 95%CI=1.189–3.625, P=.0089 possible role of oxidative stress gene polymorphisms in the for TT) and UCP1 Ala64Thr (OR=2.099 95%CI=1.146– progression of diabetes related complications, using CRI as a 3.844, P =.015 for Ala, C allele; OR=2.585, 95%CI=1.318– phenotype. Few markers namely, NOS3 Glu298Asp (only in 5.072; P =.0048 for CC (Ala/Ala) genotype] ).
SI-DM) and NADPH oxidase p22phox −930 ANG (both in SI- Excess of the wild-type allele and genotype was seen for DM and CRI); SOD2 Ala9Val (in NI-DM); VEGF −460 CNT NOS3 Glu298Asp in CRI category [OR=2.101, 95% & 936CNT; and PON1 rs662 (only in NI-CRI) were not in CI=1.293–3.415, P=.002 for allele G (Glu); OR=2.103, HWE in the study populations. Such deviations, in literature, 95%CI=1.197–3.695; P=.009 for GG genotype) ().
have been attributed primarily to a possibility of genotyping For GSTP1 (Ile105Val, ANG), significant excess of wild- type Ile (A allele, OR=1.888, 95%CI=1.227–2.904; ruled out this possibility by inclusion of samples of known P =.003) and Ile/Ile genotype was observed in CRI category genotypes, as positive Restriction Fragment Length Poly- (OR=2.407, 95%CI=1.425–4.068; P=.0008). A trend morphism (RFLP) controls and two independent workers towards significance was observed for UCP2 −866 ANG, confirmed genotypes. The other possible reason for the and unlike the other markers, an excess of the rarer allele observed deviations could be either genetic drift, recent was seen in the CRI category (OR=1.524, 95%CI=1.037– origin/introduction of the polymorphism, absence of random 2.239, P=.031 for allele A), and the wild-type genotype was mating, and/or a stratification bias. The last two possibilities found to be protective (OR=0.563, 95%CI=0.339–0.934, can be ruled out as our sample collection consisted of randomly collected unrelated individuals of known ethnicity. However, Other polymorphisms investigated in SOD1 (rs2070424), the other factors cannot be ruled out, as our current sample set SOD3 (rs699473 and Ala58Thr), UCP1 (−3826 TNC), is not appropriate to comment on the selection forces operating UCP2 (45-bp duplication), NOS3 (T −786C, 27 bp duplication), VEGF (18-bp ins/del, −460CNT, C −634G, and The two major observations in this study are (a) the 936CNT), PON1 (rs854573, rs854560, rs662), PON2 (Cys311- excess of the wild-type/functionally efficient alleles of all the Ser), GSTMI (null), GSTTI (null), and NADPH oxidase associated markers with CRI in SI subjects and (b) p22phox (Cytochrome b-245, alpha polypeptide [CYBA], −930 the significant association of a few genes with CRI among ANG, C242T, A640G) genes were not associated with the the SI subjects which was not replicated in the NI cohort.
development of the disease in this sample set (data not shown).
Targeted analysis for distribution of haplotypes carrying the risk alleles identified in the above allelic associations wascarried out. In agreement with the observation of allelic as 9. Association of the wild-type alleles with diabetic renal well as genotypic associations, the haplotypes carrying the risk alleles (of UCP1, UCP2, and NOS3) were significantlyin excess in the CRI patients ().
We observed a significant association of polymorphisms in SOD2 (Ala9Val), UCP1 (−112 TNG and Ala64Thr), NOS3(Glu298Asp), and GSTP1 (Ile105Val) genes with the development of CRI in the SI population. A common featurein these observations was the excess of the wild-type allele Genotypic distributions of VEGF-460 and PON1 amongst the patients with CRI (). These observed Arg192Gly polymorphisms were significantly different associations may be a distinct risk factor for SI population and between DM and CRI categories (This significance are discussed further. Overexpression of SOD2 (MnSOD) could be attributed to the presence of an excess of and UCP1 prevent hyperglycaemia induced superoxide heterozygote in the patients with DM in VEGF −460 [for CT genotype, OR=2.23 (1.87–4.18), P=.012] and PON1 Functional polymorphisms altering expression levels are [Arg192Gly, ANG (for AG) genotype, OR=2.643 (1.347– known in these, as well as other genes found associated with 5.186); P =.004]. However, no allelic associations were CRI in the SI population. The presence of the variant allele of A.K. Tiwari et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx any of these polymorphisms can potentially lead to lowered level of gene product, finally leading to reduced activity of the specific enzyme and consequently reduced detoxification capacity. Logically, these variants should be the predisposing factors to the development of CRI. On the contrary, we have ). In addition, the haplotypes carrying the wild-type observed an excess of the wild-type or the functionally alleles were in excess in CRI patients (UCP1, T-T-C and C-T- efficient allele predisposing to CRI. This is intriguing C; UCP2 A-del; The possibility of the wild-type considering the well-defined and important role of these allele/haplotype in each of these situations leading to better genes in the maintenance of cellular homeostasis. Though, it survival of the CRI patients seems most likely and thus is often difficult to correlate the association of the wild-type alleles with a disease phenotype, a possible explanation forthe current observation could be attributed to lower survivalof CRI subjects carrying the variant allele.
10. Nonreplication of association across SI and Both diabetic nephropathy and CRI, as determined by elevated creatinine, are risk factors for development ofcardiovascular diseases ( All the above-discussed associations were observed in SI population, but none of these were replicated in the NI population. However, only a genotypic but not allelic association was observed for two other markers (VEGF mg/dl) has been reported to be an independent risk factor for −460 TNC and PON1 Arg192Gly) among NIs. Further, no the incidence of cardiovascular death, myocardial infarction, association was observed for haplotypes carrying the VEGF −460 TNC polymorphism, and only marginal association of a decreased GFR has been independently associated with risk haplotype in PON1 [A-A-A; uninformative OR; OR=0.512 (0.261–1.005)] was observed in our study sample. This makes it difficult to correlate the relevance of these SNPs in end-stage renal disease has been attributed to enhanced CRI manifestation for NI population. It is relevant to mention survival of T2DM, DN, and CRI patients, living long enough here that prior to the initiation of this study, allelic and to develop such complications, as a consequence of intensive genotypic frequencies of all the markers tested were analysed in 96 individuals each from the two populations (SI and NI).
In the SI population, a threefold higher risk We observed similar allelic and genotypic frequencies for for the development of cardiovascular disease in patients with majority of the markers (except SOD3 Ala58Thr and UCP1 diabetic nephropathy compared to normoalbuminuric T2DM −3826 C/T; data not shown). Therefore, the differences observed between the two populations may reflect a Thus, we may hypothesize that in our study, the patients differential susceptibility of the two groups to the develop- carrying the variant alleles, associated with reduced function, ment of this disorder [SI being at higher risk, ( might not have survived to reach the stage of CRI, possibly but with no comparable data on NI population].
due to premature mortality caused by cardiovascular events.
This may be mediated by gene environment interactions such Consequently, enrichment of the wild-type allele may be due as exposure of the two populations to different kinds of to higher survival rates of carriers of the wild-type allele.
environments and lifestyle [including physical activity Support for this hypothesis comes from the observation of (food habits, etc.]. The SI sample set is association of NOS3 Glu298Asp polymorphism, the T allele predominantly of rural and semiurban origin, whereas the NI (Asp) of which has been reported to be associated with centers receive a very heterogeneous population (predomi- hypertension, coronary artery disease and myocardial infarc- nantly urban). Thus genetic, environmental, as well as sample heterogeneity might be responsible for the nonreplication of associations observed in the SI population.
Alternatively, the nonreplication of associations between wild-type [Glu, G] allele in the CRI patients from south India.
NI and SI populations could be due to the sample size. Power Thus, patients carrying the mutant allele (less efficient allele) calculations for the SI sample set revealed that only 35% of might not have survived the comorbid complications the studies using a similar sample size would be able to detect (cardiovascular death, myocardial infarction and stroke).
similar differences of small effect size (w=0.10). However, The observation of excess of the haplotype carrying the Glu this study has adequate power to detect a medium effect size allele (T-4b-Glu) and deficit of the haplotype carrying the (w=0.25, 98% power in SI and 90% in NI population; Power Asp (T-4b-Asp) allele among CRI patients provides addi- and Precision software). These are limitations of the present tional support to the hypothesis. Further, in case of SOD2 study, and it is essential to replicate these observations in a Ala9Val or UCP1 −112TNG or UCP2 −866 ANG or GSTP1 prospective study and/or also in independent sample sets Ile105Val SNPs, decreased activity of the variant allele has A.K. Tiwari et al. / Journal of Diabetes and Its Complications xx (2008) xxx–xxx In conclusion, oxidative stress might be an important Hu, X., Xia, H., Srivastava, S. K., Pal, A., Awasthi, Y. C., Zimniak, P., & predictor of development of complications in type 2 diabetes Singh, S. V. (1998). Catalytic efficiencies of allelic variants of humanglutathione S-transferase P1-1 toward carcinogenic anti-diol epoxides of subjects. The carriers of wild-type and efficient alleles of enzo[c]phenanthrene and benzo[g]chrysene. Cancer Research, 58, oxidative stress genes are more likely to survive the comorbid complications and these alleles may be nephroprotective.
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