Mohammed Ishaq

Relationship between angiotensin-converting enzyme gene insertion/deletion polymorphism, angiographically defined coronary artery disease and myocardial infarction in patients with type 2 diabetes mellitus.

Introduction: The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been implicated in the pathogenesis of cardiovascular diseases. The objective of the present study was to investigate the influence of ACE gene I/D polymorphism on the development and progression of coronary artery disease (CAD) and myocardial infarction (MI) in type 2 diabetic (T2DM) patients. Materials and Methods: We screened 283 T2DM patients, inclusive of 160 patients with angiographically defined CAD, 73 patients with MI, 89 patients without MI and 121 T2DM individuals with no evidence of CAD for ACE gene I /D polymorphism. Results: There was no significant difference in the distribution of genotypes and alleles of ACE gene I/D polymorphism between T2DM+CAD and T2DM (non-CAD) groups. However, a significant association of this polymorphism with MI in T2DM+CAD patients (p=0.024) was observed. Further analysis revealed that the frequencies of the DD and ID genotypes increased with the number of stenosed coronary vessels (p=0.026). The DD genotype and the D allele were more frequent in the subgroup of T2DM patients with multivessel CAD (p=0.01) than in individuals with single vessel stenosis. Conclusions: These findings reveal a significant relationship between ACE gene I/D polymorphism, multivessel CAD and also the occurrence of MI in T2DM individuals with significant coronary stenoses in our population.

Association of FOXP3 (rs3761548) promoter polymorphism with nondermatomal vitiligo: A study from India.

BACKGROUND The rs3761548 polymorphism (-3279 C>A) of FOXP3 gene is associated with several autoimmune disorders. OBJECTIVE We sought to determine whether rs3761548 polymorphism is associated with nondermatomal vitiligo in Indian subjects. METHODS Genomic DNA was isolated from blood samples of 303 patients and 305 control subjects and genotyping was done by allele-specific primers. Data analysis was carried out for the entire cohort and separately for male and female participants as FOXP3 is an X-linked marker. Statistics were performed using software. RESULTS The genotype frequencies differed significantly from patients to control subjects (P = .002). Further analysis demonstrated female participants with CC genotype were protected (CC vs CA+AA; odds ratio 0.38, 95% confidence interval 0.238-0.615) and those with CA genotype were at higher risk to develop vitiligo (CA vs CC+AA; odds ratio 2.634, 95% confidence interval 1.604-4.325). However, no such statistical difference was observed in male participants. LIMITATIONS Our study is, to our knowledge, the first report from India with respect to vitiligo and rs3761548; however, we lack adequate literature assistance. CONCLUSIONS The rs3761548 of FOXP3 gene in our population may be associated with susceptibility to vitiligo because of altered expression. CC genotype appears to be protective and CA genotype seems to impart nearly 3-fold risk to develop vitiligo in women and girls.

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.

Angiotensin converting enzyme (ACE) gene polymorphism in vitiligo: protective and predisposing effects of genotypes in disease susceptibility and progression

Vitiligo is a depigmenting skin disorder with profound heterogenity in its aetio-pathophysiology, and is associated with inter-individual variation in progression of disease. Angiotensin converting enzyme (ACE) is a regulator of renin angiotensin system (RAS) that plays an important role in the physiology of the vasculature, blood pressure, inflammation, adipocyte distribution of various diseases. The present study was carried out in 243 vitiligo patients (132 males and 111 females), aged between 3-62 years with a mean age at onset of 21.6  ±  13.6 yrs, and in 205 healthy controls of south Indian origin. The main objectives of the present study were to evaluate the ACE I/D (insertion/deletion) polymorphism in the patient and control groups. Further, I/D genotypes were compared among the patients with and without the family history of vitiligo as well as the progression of the disease, through polymerase chain reaction (PCR) methods.The results revealed a highly significant association of DD genotype with disease susceptibility (p < 0.01) in patients with a family history of vitiligo (p < 0.05) in terms of early age at onset. Further, the pre-dominance of ID genotype among patients revealed its association with a slow progression of the disease (p < 0.05). The present study is the first report to highlight the protective role of II genotype and the significant association of ID genotype with slow progression of the disease.

Role of Foxp3 Gene in Maternal Susceptibility to Pre‐eclampsia – A Study From South India

Pre‐eclampsia (PE) is a multifactorial pregnancy‐specific vascular disorder characterized by hypertension and proteinuria and affects around 3–8% of pregnancies worldwide. Defective placentation during the early stage of pregnancy most likely in combination with maternal and environmental factors could lead to systemic inflammation, endothelial dysfunction and the manifestation of the clinical symptoms. Inadequate number of regulatory T cells (Tregs) or their functional deficiency is linked with infertility, miscarriage and PE. It is well identified that forkhead box P3 (Foxp3) gene is a master control gene for the development and function of Tregs that play an important role in the maintenance of self‐tolerance and mediate maternal tolerance to the foetus. The main objective of this study was to assess the maternal susceptibility to PE with respect to a deletion mutation in exon‐2 and ‐3279 C > A polymorphism (rs3761548) in the promoter region within the Foxp3 gene in a total of 282 PE patients and 215 normal pregnant women. The results showed that exon‐2 deletion mutation is present in 1.06% of patients and none in the controls, indicating that it was not a common gene polymorphism associated with PE. With respect to rs3761548, the C allele frequency was observed to be higher in patients than in controls (49% versus 27%; OR = 2.81, P < 0.01). In conclusion, our results are suggestive of A allele to be protective against PE and C allele as predisposing in a dose‐dependent manner in our population.

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.

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

Abstract 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.

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

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.

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.

Parent‐of‐origin effect: A hint from vitiligo epidemiology

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