RESUMO
To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.
Assuntos
Doença de Alzheimer/genética , Translocases Mitocondriais de ADP e ATP/genética , Idoso de 80 Anos ou mais , Estudos de Coortes , Simulação por Computador , Feminino , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Whole-genome epistasis analysis may add a new layer of knowledge to whole-genome association studies, permitting the identification of new candidate genes which are completely transparent during conventional single-locus analysis. We present the first whole-genome conditional two-locus analysis in Parkinson's disease (PD). We scanned the entire genome and selected markers that interacted with a set of well-known loci previously associated to PD (SNCA, Parkin, LRRK2, UCHL1, DJ-1, PINK and MAPT). Our work describes several loci potentially related to PD risk which interact with SNCA, PARK1 and LRRK2 markers. We propose conditional whole-genome two-locus association analysis as a valuable method that might be helpful in re-analysing and re-interpreting data from whole-genome association studies.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genoma , Doença de Parkinson , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Genéticas , Epistasia Genética , Marcadores Genéticos , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Doença de Parkinson/epidemiologia , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Colorectal cancer is one of the most prevalent cancers in developed countries. However, the genetic factors influencing its appearance remain far from being fully characterized. Recently, a G>A functional transition mapping the 3' untranslated region of the CXCL12 gene (rs1801157) has been found to be under-represented among rectal cancer patients when compared to colon cancer patients from a Swedish series. Here we present the results from an independent analysis of CXCL12 rs1801157 in a larger CRC series of Spanish origin in order to analyse the robustness of this association within a different European population. No significant difference was observed between controls and colon or rectal cancer patients. We were also unable to find a correlation between rs1801157 and different prognostic markers such as metastasis development or disease-free survival time. The epidemiologic data involving CXCL12 rs1801157 in colorectal cancer risk are discussed.
Assuntos
Regiões 3' não Traduzidas/genética , Quimiocina CXCL12/genética , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Colo/genética , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/genética , Valores de Referência , Análise de SobrevidaRESUMO
BACKGROUND: A specific haplotype (AGATA) in the estrogen receptor alpha (ER1) gene was recently described as a new risk factor for cryptorchidism in the Japanese population. In this ethnic group, single-nucleotide polymorphism 12 (SNP12) was concluded to be the tag SNP for the AGATA haplotype. MATERIALS AND METHODS: A large group of patients (total number=335) and controls (total number=567) of two Caucasian populations were analysed for the AGATA haplotype and SNP12 to verify whether this genetic variant and its tag SNP were associated with cryptorchidism or with severe spermatogenic failure. RESULTS: We confirm that SNP12 is the tag SNP for the AGATA haplotype also in Caucasians. However, in contrast with the Japanese population we found a protective effect for ESR1 SNP12 on cryptorchidism in the Italian population. No association between SNP12 and severe spermatogenic disturbances was observed. CONCLUSIONS: The observed associations (although with opposite effect) with cryptorchidism encourage future studies on independent cases and controls from different ethnic and geographic origins. On the other hand, in contrast with other ESR1 polymorphisms, SNP12 polymorphism is not associated with severe male factor infertility in two independent European population.
Assuntos
Criptorquidismo/genética , Receptor alfa de Estrogênio/genética , Infertilidade Masculina/genética , Polimorfismo de Nucleotídeo Único/genética , População Branca/genética , Frequência do Gene , Haplótipos , Humanos , Itália , Masculino , Espanha , Contagem de EspermatozoidesRESUMO
BACKGROUND: There is much evidence involving the KIT tyrosine kinase receptor and its ligand KITLG in the survival and proliferation of germ cells. Animal models and functional studies in humans suggest that this signalling pathway plays a role in male infertility. METHODS: We studied three and two single-nucleotide polymorphisms (SNPs) (rs3819392, rs3134885, rs2237012, rs10506957 and rs995030) located within the genomic region of the KIT and KITLG genes, respectively. A total of 167 idiopathic infertile men (sperm counts <5 million spz/ml) and 465 unrelated healthy controls from the same geographical region were genotyped for these SNPs. RESULTS: We found a statistically significant association of the rs3819392 polymorphism, which is located within the KIT gene, with idiopathic male infertility. In addition, a deviation from the Hardy-Weinberg equilibrium (HWE) law was observed for rs10506957 polymorphism within the KITLG gene only in the infertile group. CONCLUSIONS: Our data indicate that the KIT/KITLG system may be involved in a low sperm count trait in humans.
Assuntos
Marcadores Genéticos/genética , Infertilidade Masculina/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/genética , Fator de Células-Tronco/genética , Mapeamento Cromossômico , Frequência do Gene , Haplótipos , Humanos , Infertilidade Masculina/etiologia , MasculinoRESUMO
BACKGROUND: Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. The aim of the present study was to investigate the role of CALPAIN-5 (CAPN5) gene in PCOS susceptibility. METHODS: We analysed four intronic polymorphisms of the CAPN5 gene in 148 well-characterized women with PCOS and 606 unrelated controls. We performed a case-control study and an intracohort analysis of clinical characteristics associated with PCOS. RESULTS: Analysis of haplotypes distribution between PCOS population compared to controls showed a strong deviation (P = 0.00029). The haplotypes GGCA and GGTG were overrepresented in PCOS patients (P = 0.009 and P = 0.001, respectively). In addition, we identified several CAPN5 haplotypes associated with phenotypic differences observed between PCOS patients, such as the presence of obesity (P = 0.02), cardiovascular complications (P = 0.02), familial antecedents of obesity (P = 0.003) and of hypertension (P = 0.007) and type 2 diabetes mellitus aggregation (P = 0.04). CONCLUSIONS: These results suggest a role of CAPN5 gene in PCOS susceptibility in humans. Moreover, novel candidate risk alleles have been identified, within CAPN5 gene, which could be associated with important phenotypic and prognosis differences observed in PCOS patients.