RESUMO
BACKGROUND: The Interleukin (IL)-10 polymorphic variants -1082G/A, -819C/T and -592C/A were linked with obesity, metabolic syndrome, and type 2 diabetes (T2DM). We investigated the hypothesis that IL-10 promoter polymorphisms may be associated with the progression of diabetic nephropathy (DN). DESIGN: Case-controlled study. PATIENTS: Study subjects comprised of 515 DN patients, and 402 normoalbuminuric (DWN) T2DM patients. MEASUREMENTS: IL-10 genotyping was done by PCR-based assays, and the contributions of the IL-10 polymorphic variants to DN were analysed by haplotype analysis and multivariate regression analysis. RESULTS: Decreased prevalence of (mutant) -819T allele and -819C/T genotype was seen in DN patients; neither the -1082G/A nor the -592C/A polymorphism was associated with DN. Three-loci haplotype (-1082GA/-819CT/-592CA) analysis identified GTC as DN-protective haplotype. Multivariate regression analysis confirmed the association of GTC haplotype (P = 0.045; OR = 0.56, 95% CI: 0.31-0.99), and in addition identified GTA haplotype (P = 0.044; OR = 0.54, 95% CI: 0.30-0.98) as independent predictors of DN after controlling for a number of covariates (age, sex, BMI; hypertension, glucose, HbA1c, DN duration, total cholesterol, medications). CONCLUSION: This study suggests that IL-10 promoter polymorphism influence the risk of nephropathy in Tunisian T2DM patients.
Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Predisposição Genética para Doença/genética , Interleucina-10/genética , Polimorfismo Genético/genética , Regiões Promotoras Genéticas/genética , Idoso , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus Tipo 2/etnologia , Nefropatias Diabéticas/etnologia , Feminino , Genótipo , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , TunísiaRESUMO
BACKGROUND: Nitric oxide (NO) produced by endothelial NO synthase (eNOS) mediates a wide range of processes, and abnormal NO production mediated diabetes complications, including diabetic nephropathy (DN). In view of their impact on eNOS activity, polymorphisms in eNOS gene were described as candidates for atherosclerosis and DN. AIMS: We evaluated the association of -786T>C (promoter region), Glu298Asp (Exon 7), and 4b4a (Intron 4) polymorphisms in eNOS gene with Type 2 diabetes mellitus (T2DM) and DN by haplotype analysis. SUBJECTS AND METHODS: Study subjects comprised 515 DN patients, 402 normoalbuminuric [diabetes with no nephropathy (DWN)] T2DM patients, and 748 healthy subjects. -786T>C and Glu298Asp genotyping were done by PCR-RFLP analysis. RESULTS: Higher prevalence of mutant Asp298, 4a, and -786C alleles and homozygous Asp298/Asp298 and 4a/4a genotypes were seen in T2DM patients compared to healthy subjects, with increased Asp298/Asp298 seen in DN compared to DWN patients (P<.05). Three-loci haplotype analysis demonstrated significant association between eNOS variants and T2DM, with protective, neutral, T2DM, and DN-susceptible haplotypes identified, the latter including Asp298/4b/-786T and the Asp298/4a/-786C haplotypes that were present at higher frequencies among DN than among DWN patients. Multivariate regression analysis identified only Asp298/4a/-786T haplotype to be associated with DN (P=.047) after controlling for potential covariates. CONCLUSION: Genetic variation at the eNOS locus is associated with T2DM. It can serve as a useful genetic marker of increased susceptibility to T2DM and its complications, including the risk of nephropathy.
Assuntos
Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Ligação Genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Idoso , Ácido Aspártico/genética , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Ácido Glutâmico/genética , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: The possible association between the endothelial nitric oxide (eNOS) gene T-786C (promoter region), 27-bp repeat 4b/4a (intron 4), and Glu298Asp (exon 7) polymorphisms with diabetic retinopathy (DR) was investigated. DESIGN: A retrospective case-control study. PATIENTS: A total of 872 type 2 diabetes (T2DM) patients were studied, of whom 383 presented with preproliferative/proliferative retinopathy (DR group), and 489 with absent/mild retinopathy (DWR group). MEASUREMENTS: Glu298Asp and T-786C genotyping was carried out by PCR-RFLP analysis, while 4b/4a was assessed by PCR. Genotype distribution was compared using the chi(2)-test, and the contributions of the polymorphisms to DR were analysed by haplotype analysis and multivariate regression analysis. RESULTS: Lower prevalence of mutant 4a (P = 0.011), and heterozygous 4b/4a (P = 0.042) were seen in the DR compared to the DWR groups; the allele and genotype distribution of the Glu298Asp and T-786C polymorphisms were comparable between DR and DWR groups. Three-loci haplotype analysis demonstrated significant association between eNOS variants and DR, with protective [haplotype 122 (Glu298/4a/-786C)], and susceptible haplotypes [haplotypes 112 (Glu298/4b/-786C) and 222 (Asp298/4a/-786C)] identified. Multivariate regression analysis confirmed the association between haplotypes 122 (P = 0.015); 112 (P = 0.027), and 222 (P = 0.048) and DR, after controlling for potential covariates (including age, sex, age of disease onset; HbA1c; hypertension, total cholesterol). CONCLUSIONS: This study identifies genetic variation at the eNOS locus as genetic risk factor for diabetic retinopathy, which may serve as a useful marker of increased susceptibility to the risk of retinopathy.
