Association of genetic variants in the promoter region of genes encoding p22phox (CYBA) and glutamate cysteine ligase catalytic subunit (GCLC) and renal disease in patients with type 1 diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Oxidative stress is recognized as a major pathogenic factor of cellular damage caused by hyperglycemia. NOX/NADPH oxidases generate reactive oxygen species and NOX1, NOX2 and NOX4 isoforms are expressed in kidney and require association with subunit p22phox (encoded by the <it>CYBA </it>gene). Increased expression of p22phox was described in animal models of diabetic nephropathy. In the opposite direction, glutathione is one of the main endogenous antioxidants whose plasmatic concentrations were reported to be reduced in diabetes patients. The aim of the present investigation was to test whether functional single nucleotide polymorphisms (SNPs) in genes involved in the generation of NADPH-dependent O₂^•-(-675 T → A in <it>CYBA</it>, unregistered) and in glutathione metabolism (-129 C → T in <it>GCLC </it>[rs17883901] and -65 T → C in <it>GPX3 </it>[rs8177412]) confer susceptibility to renal disease in type 1 diabetes patients.</p> <p>Methods</p> <p>401 patients were sorted into two groups according to the presence (n = 104) or absence (n = 196) of overt diabetic nephropathy or according to glomerular filtration rate (GFR) estimated by Modification of Diet in Renal Disease (MDRD) equation: ≥ 60 mL (n = 265) or < 60 mL/min/1.73 m²(n = 136) and were genotyped.</p> <p>Results</p> <p>No differences were found in the frequency of genotypes between diabetic and non-diabetic subjects. The frequency of GFR < 60 mL/min was significantly lower in the group of patients carrying <it>CYBA </it>genotypes T/A+A/A (18.7%) than in the group carrying the T/T genotype (35.3%) (P = 0.0143) and the frequency of GFR < 60 mL/min was significantly higher in the group of patients carrying <it>GCLC </it>genotypes C/T+T/T (47.1%) than in the group carrying the C/C genotype (31.1%) (<it>p </it>= 0.0082). Logistic regression analysis identified the presence of at least one A allele of the <it>CYBA </it>SNP as an independent protection factor against decreased GFR (OR = 0.38, CI95% 0.14-0.88, <it>p </it>= 0.0354) and the presence of at least one T allele of the <it>GCLC </it>rs17883901 SNP as an independent risk factor for decreased GFR (OR = 2.40, CI95% 1.27-4.56, <it>p </it>= 0.0068).</p> <p>Conclusions</p> <p>The functional SNPs <it>CYBA </it>-675 T → A and <it>GCLC </it>rs17883901, probably associated with cellular redox imbalances, modulate the risk for renal disease in the studied population of type 1 diabetes patients and require validation in additional cohorts.</p

A Worldwide Phylogeography for the Human X Chromosome

BACKGROUND: We reasoned that by identifying genetic markers on human X chromosome regions where recombination is rare or absent, we should be able to construct X chromosome genealogies analogous to those based on Y chromosome and mitochondrial DNA polymorphisms, with the advantage of providing information about both male and female components of the population. METHODOLOGY/PRINCIPAL FINDINGS: We identified a 47 Kb interval containing an Alu insertion polymorphism (DXS225) and four microsatellites in complete linkage disequilibrium in a low recombination rate region of the long arm of the human X chromosome. This haplotype block was studied in 667 males from the HGDP-CEPH Human Genome Diversity Panel. The haplotypic diversity was highest in Africa (0.992+/-0.0025) and lowest in the Americas (0.839+/-0.0378), where no insertion alleles of DXS225 were observed. Africa shared few haplotypes with other geographical areas, while those exhibited significant sharing among themselves. Median joining networks revealed that the African haplotypes were numerous, occupied the periphery of the graph and had low frequency, whereas those from the other continents were few, central and had high frequency. Altogether, our data support a single origin of modern man in Africa and migration to occupy the other continents by serial founder effects. Coalescent analysis permitted estimation of the time of the most recent common ancestor as 182,000 years (56,700-479,000) and the estimated time of the DXS225 Alu insertion of 94,400 years (24,300-310,000). These dates are fully compatible with the current widely accepted scenario of the origin of modern mankind in Africa within the last 195,000 years and migration out-of-Africa circa 55,000-65,000 years ago. CONCLUSIONS/SIGNIFICANCE: A haplotypic block combining an Alu insertion polymorphism and four microsatellite markers on the human X chromosome is a useful marker to evaluate genetic diversity of human populations and provides a highly informative tool for evolutionary studies

Nationwide multicenter study on the prevalence of overweight and obesity in type 2 diabetes mellitus in the Brazilian population

AIM: To evaluate the prevalence of overweight and obesity in type 2 diabetic (DM2) outpatients from different regions of Brazil. PATIENTS AND METHODS: We studied 2,519 randomly selected patients, from 11 hospitals, 2 endocrine and one general public care clinics from 10 cities. Overweight was defined as body-mass index (BMI) > 25 and obesity as BMI > 30 kg/m². Glycemic control (GC) was evaluated by GC index (GCI= patient's HbA1 or HbA1c/upper limit of normal for the method x 100). RESULTS: 39% of the population studied was male, the mean age was 58.8 &plusmn; 11.6 y, the duration from clinical diagnosis of DM2 was 9.0 &plusmn; 7.3y, and BMI was 28.3 &plusmn; 5.2 kg/m². No measurements of BMI were recorded from 265 patients (10.5%). Patients from the Northeast presented lower BMI as compared with those from the Midwest, Southeast and South areas, respectively (26.4 &plusmn; 4.7 vs. 27.9 &plusmn; 4.8 vs. 29.2 &plusmn; 5.1 vs. 29.4 &plusmn; 5.4 kg/m²; p< 0.001). A greater prevalence of obesity was observed in the Southeast and South areas as compared to the Northeast (p< 0.001), as well as in the female group, respectively (69% vs. 31%; p< 0.001). Normal weight patients presented lower GCI. Patients being treated with two or more oral drugs and an association of insulin plus oral drug presented greater BMI values than those being treated with diet, oral hypoglycemic agents and insulin p< 0.001. The BMI of patients treated by a specialist did not differ from those treated by a generalist. CONCLUSIONS: 75% of our sample was out of adequate BMI and 30% was obese. The percentage of patients with overweight and obesity was comparable to those found in similar European studies but still lower than those found in the USA. The prevalence of obesity in diabetic patients was three times higher than in the overall Brazilian population according to data from the Brazilian Institute of Geography and Statistics (IBGE).OBJETIVO: Avaliar a prevalência de sobrepeso e obesidade em pacientes ambulatoriais com diabetes mellitus tipo 2 (DM2) em diferentes regiões do Brasil. PACIENTES E MÉTODOS: Avaliamos aleatoriamente 2.519 pacientes em 11 hospitais, 2 ambulatórios especializados e um posto de saúde em 10 cidades brasileiras. Consideramos sobrepeso um índice de massa corporal (IMC) > 25 e obesidade um IMC > 30 kg/m². O controle glicêmico (CG) foi avaliado pelo índice de CG [ICG= HbA1 e ou HbA1c do paciente/limite superior de normalidade do método x 100]. RESULTADOS: Os pacientes tinham idade de 58,8 &plusmn; 11,6 anos, tempo de diagnóstico clínico de DM de 9,0 &plusmn; 7,3 anos, IMC de 28,3 &plusmn; 5,2 kg/m², e 39% eram do sexo masculino. Do total da amostra, 265 pacientes (10,5%) não apresentavam avaliação do IMC. Os pacientes da região Nordeste apresentaram menor IMC em comparação com os das regiões Centro-Oeste, Sudeste e Sul, respectivamente (26,4 &plusmn; 4,7 vs. 27,9 &plusmn; 4,8 vs. 29,2 &plusmn; 5,1 vs. 29,4 &plusmn; 5,4 kg/m²; p< 0,001). Houve maior prevalência de obesidade na região Sudeste e Sul em comparação à região Nordeste (p< 0,001) e nos pacientes do sexo feminino, respectivamente (69 vs. 31%; p< 0,001). Os pacientes com peso normal apresentaram menor ICG. Aqueles em tratamento com associação de duas ou mais drogas orais e associação de insulina + droga oral apresentaram maior IMC do que aqueles em tratamento com dieta, hipoglicemiante oral e insulina; p< 0,001. O IMC não diferiu entre os pacientes assistidos ou não por especialistas. CONCLUSÕES: Da população estudada, 75% não estava na faixa de peso ideal, sendo que um terço tinha obesidade. Nossos dados indicam que o sobrepeso e a obesidade já atingem um percentual de pacientes com DM2 no Brasil semelhante ao relatado em estudos europeus, mas ainda menor do que o observado nos EUA. A prevalência de obesidade nos pacientes diabéticos foi três vezes maior do que a observada na população brasileira em geral de acordo com os dados do IBGE.13614