RESUMO
AIMS/HYPOTHESIS: The slit diaphragm is an adhesion and signalling protein complex linking the interdigitating podocyte foot processes in the kidney glomerulus, and mutations in slit diaphragm-associated genes result in severe proteinuria. Here we report a genetic association analysis of four slit diaphragm genes, LRRC7, KIRREL, NPHS2 and ACTN4, in a Finnish diabetic nephropathy cohort. MATERIALS AND METHODS: A total of 40 single nucleotide polymorphisms (SNPs) were genotyped in 1103 patients with type 1 diabetes. The patients were classified according to their renal status, and the genotype data were analysed in a cross-sectional case-control setting. To confirm positive associations, four SNPs were genotyped in 1,025 additional patients with type 1 diabetes. RESULTS: No associations with diabetic nephropathy were observed for any of the analysed SNPs. The SNPs were not associated with the time from the onset of diabetes to the diagnosis of nephropathy or with glomerular filtration rate or AER as quantitative variables. In a sex-specific sub-analysis, the variants rs979972 and rs749701 in the first intron of ACTN4 were nominally associated with diabetic nephropathy in females, with odds ratios of 1.81 (95% CI 1.18-2.79, p = 0.007) and 1.93 (95% CI 1.26-2.96, p = 0.003) respectively. CONCLUSIONS/INTERPRETATION: Our study has not found any evidence that common variants in LRRC7, KIRREL, NPHS2 and ACTN4 contribute to susceptibility to diabetic nephropathy in Finnish patients with type 1 diabetes.
Assuntos
Actinina/genética , Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/genética , Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Podócitos/metabolismo , Polimorfismo de Nucleotídeo Único , Sialoglicoproteínas/genética , Adulto , Estudos Transversais , Feminino , Finlândia , Humanos , MasculinoRESUMO
Among the few independently replicated genetic associations in migraine are polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) and oestrogen receptor (ESR1) genes. We studied the contribution of these genes to migraine susceptibility by genotyping six MTHFR and 26 ESR1 polymorphisms in 898 unrelated migraine with aura (MA) patients and in 900 unrelated healthy controls. There were no differences in the genotype distributions of the previously migraine-associated SNPs C677T (MTHFR) and G2014A (ESR1) between cases and controls (P-values 0.83 and 0.55, respectively). Thus, we were not able to replicate the previous findings, although our study had considerable power. However, five of the ESR1 SNPs (rs6557170, rs2347867, rs6557171, rs4870062 and rs1801132) that were in strong linkage disequilibrium were nominally associated with MA (uncorrected P-values 0.007-0.034). These results did not, however, remain significant after taking multiple testing into account. Thus it seems unlikely that the studied genes are involved in migraine susceptibility, at least in this sample.
Assuntos
Receptor alfa de Estrogênio/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Enxaqueca com Aura/genética , Feminino , Finlândia , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
AIMS/HYPOTHESIS: Substantial evidence exists for the involvement of the renin-angiotensin system (RAS) in diabetic nephropathy. Angiotensin I converting enzyme 2 (ACE2), a new component of the RAS, has been implicated in kidney disease, hypertension and cardiac function. Based on this, the aim of the present study was to evaluate whether variations in ACE2 are associated with diabetic nephropathy. MATERIALS AND METHODS: We used a cross-sectional, case-control study design to investigate 823 Finnish type 1 diabetic patients (365 with and 458 without nephropathy). Five single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan technology. Haplotypes were estimated using PHASE software, and haplotype frequency differences were analysed using a chi(2)-test-based tool. RESULTS: None of the ACE2 polymorphisms was associated with diabetic nephropathy, and this finding was supported by the haplotype analysis. The ACE2 polymorphisms were not associated with blood pressure, BMI or HbA(1)c. CONCLUSIONS/INTERPRETATION: In Finnish type 1 diabetic patients, ACE2 polymorphisms are not associated with diabetic nephropathy or any studied risk factor for this complication. Further studies are necessary to assess a minor effect of ACE2.
Assuntos
Carboxipeptidases/genética , Diabetes Mellitus Tipo 1/genética , Nefropatias Diabéticas/genética , Polimorfismo de Nucleotídeo Único , Adulto , Enzima de Conversão de Angiotensina 2 , Estudos de Casos e Controles , Estudos Transversais , Feminino , Finlândia , Predisposição Genética para Doença , Haplótipos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Peptidil Dipeptidase ARESUMO
We introduce a novel Bayesian approach to estimate and account for population structure simultaneously with association mapping of multiple quantitative trait loci. The method is designed for an analysis of unrelated individuals from a mixture of two populations (no admixture), where the individual population memberships are unknown. In our approach, the population structure is estimated and accounted for by using data on additional "grouping" markers which are assumed to be in Hardy-Weinberg equilibrium within the populations but have different allele frequencies between the populations. We use Bayesian hierarchical modeling and Markov chain Monte Carlo estimation, where we allow both population stratification and genetic heterogeneity. In our model the number of quantitative trait loci and their positions are treated as random variables, and we obtain their posterior distributions. Here we select the candidate and the grouping markers based on results from a preliminary SOLAR analysis.
