Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM

Chowdhury, Tahseen A; Dronsfield, M. J.; Kumar, Sudesh; Gough, S; Gibson, S. P.; Khatoon, Anjum Sultana; Macdonald, Fiona; Rowe, B R; Dunger, D.B.; Dean, John; Davies, Simon; Webber, Jonathan; Smith, Paul; Mackin, Paul; Marshall, Sally M.; Adu, D.; Morris, Peter J.; Todd, John A.; Barnett, Anthony; Boulton, Andrew J.M.; Bain, Stephen C.

doi:10.1007/bf00400661

Cited by 62 publications

(38 citation statements)

References 35 publications

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“…Cases had Type 1 diabetes with overt proteinuria (≥300 mg 24 h −1 ), hypertension (BP>140/90) and diabetic retinopathy [4]. A cohort of Type 1 diabetic subjects who have been injecting themselves with insulin for 50 years or more were chosen as the control group.…”

Section: Methodsmentioning

confidence: 99%

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Nitric oxide synthase gene polymorphisms and diabetic nephropathy

et al. 2003

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Aims/hypothesis. Susceptibility to diabetic nephropathy in subjects with Type 1 diabetes is mainly genetically determined. Excess cardiovascular risk associated with diabetes is overwhelmingly concentrated in patients with nephropathy. Endothelial dysfunction is a feature of cardiovascular disease, hypertension, dyslipidaemia and smoking, all of which are associated with diabetic nephropathy. Nitric oxide regulates endothelial function and so genes encoding nitric oxide synthases could confer susceptibility to nephropathy. Recently positive associations have been reported. We examined polymorphisms within NOS3 and NOS2A, the genes encoding endothelial-and inducible nitric oxide synthase, for association with nephropathy. Methods. Large case-control studies of patients with Type 1 diabetes and overt nephropathy who had hypertension and diabetic retinopathy. The control group comprised Type 1 diabetic subjects who have been on insulin for 50 or more years and have an extremely low risk of nephropathy. Genotyping was by PCR and agarose-or automated polyacrylamide gel electrophoresis using fluorescence-labelled primers.Results. NOS3 intron 4 genotype frequencies (n=860: 464 cases, 396 control subjects) were 2.6%, 23.3%, 74.1% and 2.3%, 22.7%, 75.0% for aa, ab and bb genotypes; p=0.935. NOS2A promoter genotype frequencies (n=715: 358 cases, 357 control subjects) were 0.3%, 16.8%, 83.0% and 0.3% 17.6% and 82.1% for +/+, +/− and −/− genotypes (p=0.952). Conclusion/interpretation. In our cohort of Caucasian subjects with Type 1 diabetes there is no association between either of the polymorphisms studied and diabetic nephropathy. The previous suggestion from smaller studies that the intron 4 polymorphism in NOS3 could play a role in susceptibility to the disease is not confirmed. [Diabetologia (2003) 46:426-428]

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Section: Methodsmentioning

confidence: 99%

“…DNA was extracted by standard methods and genotype was determined using PCR and separation by agarose gel electrophoresis and automated gene scan analysis for the eNOS and iNOS polymorphisms respectively, as described elsewhere [4,5,6]. As one polymorphism was being investigated for each gene, a p value of 0.05 was defined as significant.…”

Section: Methodsmentioning

confidence: 99%

Nitric oxide synthase gene polymorphisms and diabetic nephropathy

et al. 2003

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“…The patients in this study have been previously described [5]. Three white Caucasian Type I diabetic cohorts were typed.…”

Section: Methodsmentioning

confidence: 99%

Human leucocyte antigen and insulin gene regions and nephropathy in Type I diabetes

et al. 1999

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The human leucocyte antigen (HLA) region has a major influence on susceptibility to Type I diabetes [1] and is possibly implicated in susceptibility to diabetic complications. Human leucocyte antigen-identical, non-diabetic siblings of diabetic probands have glomerular basement membrane expansion, which is not observed in HLA-non-identical siblings [2]. This is also observed in DR4 positive parents of diabetic patients, suggesting that even in the absence of diabetes, microangiopathy may occur due to HLA-related factors [2]. Previous examination of HLA in nephropathy has shown positive and negative associations with A2, B8, B15, DR4 and DR3/4 [3]. The insulin gene (INS) is also associated with Type I diabetes, and has been implicated in the onset of vascular disease [4]. As macrovascular disease is common in nephropathy, INS is a suitable candidate gene for susceptibility to nephropathy. Previous studies suggest an excess of class I allele homozygotes in patients with nephropathy [4].Studies examining the role of HLA or INS have often been small and ascertainment of nephropathy status has been poor. The aim of our study was to clarify the role of these genes in susceptibility to nephropathy in three large, well characterised cohorts with Type I diabetes. Diabetologia (1999) Abstract Aims/hypothesis. Diabetic nephropathy seems to have a strong genetic component. Genes involved in the genetic susceptibility to Type I (insulin-dependent) diabetes have been suggested to have a role in the development of diabetic nephropathy. This study aimed to examine the role of human leucocyte antigen and insulin genes in susceptibility to nephropathy in patients with Type I diabetes. Methods. We carried out a genetic association study examining insulin gene polymorphisms using three large cohorts of patients with Type I diabetes: nephropathy (n = 258), long duration non-nephropathy (n = 153) and a recently diagnosed (sporadic) diabetic cohort (n = 264). Human leucocyte antigen typing results were obtained in a smaller number due to assay failures (n = 182, 126 and 200 respectively).

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“…Genetic factors are thought to contribute to the pathogenesis of nephropathy, as demonstrated by familial clustering of nephropathy (10). Earlier studies from our group have evaluated a series of candidate genes including the angiotensin converting enzyme, angiotensinogen (11) and the angiotensin II type 1 receptor (12).…”

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confidence: 99%

Association studies between the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2), type 1 diabetes mellitus and diabetic nephropathy

Lavery

McTernan

Bain

et al. 2002

European Journal of Endocrinology

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Objective: Mutations in the HSD11B2 gene (encoding human 11b-hydroxysteroid dehydrogenase type 2) explain the syndrome of apparent mineralocorticoid excess where cortisol acts as a mineralocorticoid. A microsatellite marker within the HSD11B2 gene associates with salt sensitivity and hypertension -phenotypes characterising diabetic nephropathy. Here, we evaluate the HSD11B2 gene as a susceptibility locus for diabetic nephropathy. Design: 150 patients with type 1 diabetes and nephropathy (DN), 145 patients with type 1 diabetes with a long duration of non-nephropathy (LDNN) and 151 normal controls were studied. Methods: We determined allele frequencies for the (CA) n repeat marker within intron I of the HSD11B2 gene. Duration of type 1 diabetes, diabetic status and renal function were recorded. Results: 11 alleles (138 -158) for the marker were observed. Allele 152 was significantly increased in controls compared with LDNN (70.5% vs 57.6%, P c , 0:05 where P c is the P value corrected for multiple comparisons) but no difference was observed between DN and LDNN subjects. Allele 154 was significantly increased in the LDNN compared with the DN subjects (15.9% vs 7.0%, P c , 0:01) but no difference was observed between DN and controls. A greater proportion of subjects carried at least 1 allele ,152 in DN compared with control subjects (47.3% vs 28.5%, P c , 0:01), but no difference was observed in LDNN compared with control and DN subjects. Conclusions: Weak associations are reported between the HSD11B2 gene, type 1 diabetes mellitus and nephropathy. The increased frequency of HSD11B2 short alleles in the diabetic groups may reflect reduced renal 11b-hydroxysteroid dehydrogenase type 2 (11b-HSD2) activity and may, in part, explain the enhanced salt sensitivity observed in patients with type 1 diabetes.

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Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM

Cited by 62 publications

References 35 publications

Nitric oxide synthase gene polymorphisms and diabetic nephropathy

Nitric oxide synthase gene polymorphisms and diabetic nephropathy

Human leucocyte antigen and insulin gene regions and nephropathy in Type I diabetes

Association studies between the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2), type 1 diabetes mellitus and diabetic nephropathy

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