Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 88
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Ann Rheum Dis ; 76(1): 310-314, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27461236

RESUMO

OBJECTIVE: More than 40 loci have been associated with ankylosing spondylitis (AS), but less is known about genetic associations in spondyloarthritis (SpA) as a whole. We conducted a family-based genome-wide association study (GWAS) to identify new non-major histocompatibility complex (MHC) genetic factors associated with SpA. METHODS: 906 subjects from 156 French multiplex families, including 438 with SpA, were genotyped using Affymetrix 250K microarrays. Association was tested with Unphased. The best-associated non-MHC single nucleotide polymorphisms (SNPs) were then genotyped in two independent familial cohorts (including 215 French and 294 North American patients with SpA, respectively) to replicate associations. RESULTS: 43 non-MHC SNPs yielded an association signal with SpA in the discovery cohort (p<1×10-4). In the extension studies, association was replicated at a nominal p value of p<0.05 for 16 SNPs in the second cohort and for three SNPs in the third cohort. Combined analysis identified an association close to genome-wide significance between rs7761118, an intronic SNP of MAPK14, and SpA (p=3.5×10-7). Such association appeared to be independent of HLA-B27. CONCLUSIONS: We report here for the first time a family-based GWAS study on SpA and identified an associated polymorphism near MAPK14. Further analyses are needed to better understand the functional basis of this genetic association.


Assuntos
Proteína Quinase 14 Ativada por Mitógeno/genética , Espondilartrite/genética , Adulto , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
2.
Bone ; 92: 107-115, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27519970

RESUMO

SOST encodes sclerostin, an inhibitor of bone formation that antagonizes canonical Wnt signaling. Variations of SOST expression have an impact on bone mineral density (BMD) and bone strength. We hypothesized that genetic and epigenetic DNA modifications have an impact on SOST gene expression. By analyzing 43 bone samples from women, we found that rs851054 (G/A) is associated with SOST mRNA expression, donors with one or two G allele(s) displaying higher SOST expression (p<0.05). Beside this polymorphism, we also investigated the role of CpG methylation in SOST mRNA expression, and analyzed methylation variation at 13 CpG sites on the 1st exon of SOST in 14 human bone samples. Principal component analysis identified three groups of CpG sites that explained most of the methylation variation. We calculated the percentage of methylation in the main group of CpGs, and showed that higher rates of methylated CpGs are associated with higher SOST mRNA expression. To demonstrate that change in SOST expression might be related to human bone disease, we analyzed 131 patients with osteogenesis imperfecta (OI), a rare disease characterized by low BMD, bone fragility, and marked intra-familial variability of bone phenotypes. We found an association between rs851054 of the SOST promoter and the fracture rate only during childhood (p<0.01). In conclusion, genetic and epigenetic changes contribute to variation in SOST expression in human bone. Our data also indicate that these variations may be related to the severity of OI.


Assuntos
Densidade Óssea/genética , Proteínas Morfogenéticas Ósseas/genética , Metilação de DNA/genética , Marcadores Genéticos/genética , Variação Genética/genética , Polimorfismo Genético/genética , RNA Mensageiro/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas Morfogenéticas Ósseas/biossíntese , Estudos de Coortes , Feminino , Fraturas Ósseas/genética , Fraturas Ósseas/metabolismo , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/metabolismo , RNA Mensageiro/biossíntese , Adulto Jovem
3.
BMC Genet ; 17(1): 74, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27266705

RESUMO

BACKGROUND: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. RESULTS: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)). CONCLUSIONS: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar/genética , Análise de Sequência de RNA/métodos , Adulto , Idoso , Cromossomos Humanos Par 6/genética , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Loci Gênicos , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade
4.
Ann Rheum Dis ; 75(7): 1380-5, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26275432

RESUMO

OBJECTIVE: Spondyloarthritis (SpA) is a chronic inflammatory disorder with high heritability but with complex genetics. Apart from HLA-B27, most of the underlying genetic components remain to be identified. We conducted a whole-genome high-density non-parametric linkage analysis to identify new genetic factors of susceptibility to SpA. METHODS: 914 subjects including 462 with SpA from 143 multiplex families were genotyped using Affymetrix 250K microarrays. After quality control, 189 368 single nucleotide polymorphisms (SNPs) were kept for further analyses. Both non-parametric and parametric linkage analyses were performed using Merlin software. Association was tested with Unphased. RESULTS: Non-parametric linkage analysis identified two regions significantly linked to SpA: the major histocompatibility complex (LODmax=24.77) and a new 13q13 locus (LODmax=5.03). Additionally, eight loci achieved suggestive LOD scores, including the previously identified SPA2 locus at 9q33 (LODmax=3.51). Parametric analysis supported a codominant model in 13q13 with a maximum heterogeneity LOD, 'HLOD' score of 3.084 (α=0.28). Identification of meiotic recombination events around the 13q13 linkage peak in affected subjects from the 43 best-linked families allowed us to map the disease interval between 38.753 and 40.040 Mb. Family-based association analysis of the SNPs inside this interval in the best-linked families identified a SNP near FREM2 (rs1945502) which reached a p value close to statistical significance (corrected p=0.08). CONCLUSION: We report here for the first time a significant linkage between 13q13 and SpA. Identification of susceptibility factor inside this chromosomal region through targeted sequencing in linked families is underway.


Assuntos
Cromossomos Humanos Par 13/genética , Ligação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Espondilartrite/genética , Adulto , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem
6.
Nat Genet ; 47(10): 1206-11, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26301497

RESUMO

Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1(-/-) mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.


Assuntos
Prolapso da Valva Mitral/genética , Animais , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Camundongos
7.
Am J Clin Nutr ; 102(2): 514-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26156739

RESUMO

BACKGROUND: Neuropeptide Y is a key peptide affecting adiposity and has been related to obesity risk. However, little is known about the role of NPY variations in diet-induced change in adiposity. OBJECTIVE: The objective was to examine the effects of NPY variant rs16147 on central obesity and abdominal fat distribution in response to dietary interventions. DESIGN: We genotyped a functional NPY variant rs16147 among 723 participants in the Preventing Overweight Using Novel Dietary Strategies trial. Changes in waist circumference (WC), total abdominal adipose tissue, visceral adipose tissue, and subcutaneous adipose tissue (SAT) from baseline to 6 and 24 mo were evaluated with respect to the rs16147 genotypes. Genotype-dietary fat interaction was also examined. RESULTS: The rs16147 C allele was associated with a greater reduction in WC at 6 mo (P < 0.001). In addition, the genotypes showed a statistically significant interaction with dietary fat in relation to WC and SAT (P-interaction = 0.01 and 0.04): the association was stronger in individuals with high-fat intake than in those with low-fat intake. At 24 mo, the association remained statistically significant for WC in the high-fat diet group (P = 0.02), although the gene-dietary fat interaction became nonsignificant (P = 0.30). In addition, we found statistically significant genotype-dietary fat interaction on the change in total abdominal adipose tissue, visceral adipose tissue, and SAT at 24 mo (P = 0.01, 0.05, and 0.04): the rs16147 T allele appeared to associate with more adverse change in the abdominal fat deposition in the high-fat diet group than in the low-fat diet group. CONCLUSION: Our data indicate that the NPY rs16147 genotypes affect the change in abdominal adiposity in response to dietary interventions, and the effects of the rs16147 single-nucleotide polymorphism on central obesity and abdominal fat distribution were modified by dietary fat.


Assuntos
Gordura Abdominal/patologia , Adiposidade , Dieta Redutora , Neuropeptídeo Y/genética , Obesidade Abdominal/dietoterapia , Obesidade Abdominal/genética , Polimorfismo de Nucleotídeo Único , Adulto , Índice de Massa Corporal , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Feminino , Estudos de Associação Genética , Humanos , Gordura Intra-Abdominal , Masculino , Pessoa de Meia-Idade , Neuropeptídeo Y/metabolismo , Obesidade Abdominal/metabolismo , Obesidade Abdominal/patologia , Gordura Subcutânea Abdominal , Circunferência da Cintura , Ganho de Peso , Perda de Peso
8.
Nat Commun ; 6: 7207, 2015 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-26068201

RESUMO

Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Neoplasias Encefálicas/genética , Mutação , Oligodendroglioma/genética , Regulação para Baixo , Humanos , Ativação Transcricional/genética
9.
Nat Genet ; 46(11): 1233-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25261932

RESUMO

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.


Assuntos
Grupo com Ancestrais do Continente Europeu/genética , Loci Gênicos/genética , Predisposição Genética para Doença/genética , Linfoma Difuso de Grandes Células B/genética , Mapeamento Cromossômico , Biologia Computacional , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Funções Verossimilhança , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
10.
PLoS Genet ; 10(9): e1004580, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25188300

RESUMO

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Transtornos Cognitivos/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Estudos de Casos e Controles , Criança , Cognição/fisiologia , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Neurônios/fisiologia , Sinapses/genética
11.
PLoS One ; 9(8): e104326, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25111785

RESUMO

Bipolar disorder is one of the most common and devastating psychiatric disorders whose mechanisms remain largely unknown. Despite a strong genetic contribution demonstrated by twin and adoption studies, a polygenic background influences this multifactorial and heterogeneous psychiatric disorder. To identify susceptibility genes on a severe and more familial sub-form of the disease, we conducted a genome-wide association study focused on 211 patients of French origin with an early age at onset and 1,719 controls, and then replicated our data on a German sample of 159 patients with early-onset bipolar disorder and 998 controls. Replication study and subsequent meta-analysis revealed two genes encoding proteins involved in phosphoinositide signalling pathway (PLEKHA5 and PLCXD3). We performed additional replication studies in two datasets from the WTCCC (764 patients and 2,938 controls) and the GAIN-TGen cohorts (1,524 patients and 1,436 controls) and found nominal P-values both in the PLCXD3 and PLEKHA5 loci with the WTCCC sample. In addition, we identified in the French cohort one affected individual with a deletion at the PLCXD3 locus and another one carrying a missense variation in PLCXD3 (p.R93H), both supporting a role of the phosphatidylinositol pathway in early-onset bipolar disorder vulnerability. Although the current nominally significant findings should be interpreted with caution and need replication in independent cohorts, this study supports the strategy to combine genetic approaches to determine the molecular mechanisms underlying bipolar disorder.


Assuntos
Transtorno Bipolar/epidemiologia , Transtorno Bipolar/genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Idade de Início , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Humanos , Masculino , Adulto Jovem
12.
Ann Hum Genet ; 78(6): 434-51, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25069958

RESUMO

HMIP-2 is a human quantitative trait locus affecting peripheral numbers, size and hemoglobin composition of red blood cells, with a marked effect on the persistence of the fetal form of hemoglobin, HbF, in adults. The locus consists of multiple common variants in an enhancer region for MYB (chr 6q23.3), which encodes the hematopoietic transcription factor cMYB. Studying a European population cohort and four African-descended groups of patients with sickle cell anemia, we found that all share a set of two spatially separate HbF-promoting alleles at HMIP-2, termed "A" and "B." These typically occurred together ("A-B") on European chromosomes, but existed on separate homologous chromosomes in Africans. Using haplotype signatures for "A" and "B," we interrogated public population datasets. Haplotypes carrying only "A" or "B" were typical for populations in Sub-Saharan Africa. The "A-B" combination was frequent in European, Asian, and Amerindian populations. Both alleles were infrequent in tropical regions, possibly undergoing negative selection by geographical factors, as has been reported for malaria with other hematological traits. We propose that the ascertainment of worldwide distribution patterns for common, HbF-promoting alleles can aid their further genetic characterization, including the investigation of gene-environment interaction during human migration and adaptation.


Assuntos
Anemia Falciforme/genética , Elementos Facilitadores Genéticos , Eritrócitos/citologia , Locos de Características Quantitativas , Grupo com Ancestrais do Continente Africano/genética , Alelos , Grupo com Ancestrais do Continente Europeu/genética , Interação Gene-Ambiente , Estudos de Associação Genética , Genética Populacional , Genoma Humano , Genótipo , Haplótipos , Humanos , Proteínas Proto-Oncogênicas c-myb/genética , Análise de Sequência de DNA
13.
PLoS One ; 9(6): e94661, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24922517

RESUMO

BACKGROUND: Alzheimer's disease is a common debilitating dementia with known heritability, for which 20 late onset susceptibility loci have been identified, but more remain to be discovered. This study sought to identify new susceptibility genes, using an alternative gene-wide analytical approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 m genotypes from 25,580 Alzheimer's cases and 48,466 controls. PRINCIPAL FINDINGS: In addition to earlier reported genes, we detected genome-wide significant loci on chromosomes 8 (TP53INP1, p = 1.4×10-6) and 14 (IGHV1-67 p = 7.9×10-8) which indexed novel susceptibility loci. SIGNIFICANCE: The additional genes identified in this study, have an array of functions previously implicated in Alzheimer's disease, including aspects of energy metabolism, protein degradation and the immune system and add further weight to these pathways as potential therapeutic targets in Alzheimer's disease.


Assuntos
Doença de Alzheimer/genética , Proteínas de Transporte/genética , Proteínas de Choque Térmico/genética , Estudos de Casos e Controles , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos B/genética
14.
Eur J Hum Genet ; 22(3): 363-8, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23756445

RESUMO

MRXS5 or Pettigrew syndrome was described 20 years ago in a four generation family including nine affected individuals presenting with facial dysmorphism, intellectual disability, Dandy-Walker malformation and inconstant choreoathetosis. Four individuals had iron deposition in the basal ganglia seen on MRI or at autopsy. The mutation causing Pettigrew has remained elusive since the initial description of the condition. We report the identification of a mutation in the X-linked AP1S2 gene in the original Pettigrew syndrome family using X-chromosome exome sequencing. We report additional phenotype details for several of the affected individuals, allowing us to further refine the phenotype corresponding to this X-linked intellectual disability syndrome. The AP1S2 c.426+1 G>T mutation segregates with the disease in the Pettigrew syndrome family and results in loss of 46 amino acids in the clathrin adaptor complex small chain domain that spans most of the AP1S2 protein sequence. The mutation reported here in AP1S2 is the first mutation that is not predicted to cause a premature termination of the coding sequence or absence of the AP1S2 protein. Although most of the families affected by a mutation in AP1S2 were initially described as having different disorders assigned to at least three different OMIM numbers (MIM 300629, 300630 and 304340), our analysis of the phenotype shows that they are all the same syndrome with recognition complicated by highly variable expressivity that is seen within as well as between families and is probably not explained by differences in mutation severity.


Assuntos
Subunidades sigma do Complexo de Proteínas Adaptadoras/genética , Doenças dos Gânglios da Base/genética , Síndrome de Dandy-Walker/genética , Retardo Mental Ligado ao Cromossomo X/genética , Mutação , Convulsões/genética , Adolescente , Adulto , Sequência de Aminoácidos , Doenças dos Gânglios da Base/diagnóstico , Criança , Cromossomos Humanos X/genética , Síndrome de Dandy-Walker/diagnóstico , Exoma , Humanos , Masculino , Retardo Mental Ligado ao Cromossomo X/diagnóstico , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Convulsões/diagnóstico
15.
J Invest Dermatol ; 134(2): 481-487, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23892592

RESUMO

Dysplastic nevi (DN) is a strong risk factor for cutaneous malignant melanoma (CMM), and it frequently occurs in melanoma-prone families. To identify genetic variants for DN, we genotyped 677 tagSNPs in 38 melanoma candidate genes that are involved in pigmentation, DNA repair, cell cycle control, and melanocyte proliferation pathways in a total of 504 individuals (310 with DN, 194 without DN) from 53 melanoma-prone families (23 CDKN2A mutation positive and 30 negative). Conditional logistic regression, conditioning on families, was used to estimate the association between DN and each single-nucleotide polymorphism (SNP) separately, adjusted for age, sex, CMM, and CDKN2A status. P-values for SNPs in the same gene were combined to yield gene-specific P-values. Two genes, CDK6 (cyclin-dependent kinase 6) and XRCC1, were significantly associated with DN after Bonferroni correction for multiple testing (P=0.0001 and 0.00025, respectively), whereas neither gene was significantly associated with CMM. Associations for CDK6 SNPs were stronger in CDKN2A mutation-positive families (rs2079147, Pinteraction=0.0033), whereas XRCC1 SNPs had similar effects in mutation-positive and -negative families. The association for one of the associated SNPs in XRCC1 (rs25487) was replicated in two independent data sets (random-effect meta-analysis: P<0.0001). Our findings suggest that some genetic variants may contribute to DN risk independently of their association with CMM in melanoma-prone families.


Assuntos
Proteínas de Ligação a DNA/genética , Síndrome do Nevo Displásico/genética , Melanoma/genética , Neoplasias Cutâneas/genética , Adulto , Quinase 6 Dependente de Ciclina/genética , Síndrome do Nevo Displásico/epidemiologia , Saúde da Família , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Variação Genética , Humanos , Masculino , Melanoma/epidemiologia , Pessoa de Meia-Idade , Fatores de Risco , Neoplasias Cutâneas/epidemiologia , Proteína 1 Complementadora Cruzada de Reparo de Raio-X
16.
Ann Hum Genet ; 77(6): 465-71, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23937567

RESUMO

Angiotensin-I converting enzyme (ACE) occupies a pivotal role in cardiovascular homeostasis. Major loci for plasma ACE have been identified at ACE on Chromosome 17 and at ABO on Chromosome 9. We sought to characterise the genetic architecture of plasma ACE at finer resolution in two populations. We carried out a GWAS in 1810 individuals of Japanese ethnicity; this identified signals at ACE and ABO that together accounted for nearly half of the population variability of the trait. We conducted measured haplotype analysis at the ABO locus in 1425 members of 248 British families using haplotypes of three SNPs, which together tagged the alleles responsible for the principal blood group antigens A1, A2, B and O. Type O alleles were associated with intermediate plasma ACE activity compared to Type A1 alleles (in whom plasma ACE activity was ∼36% lower) and Type B alleles (in whom plasma ACE activity was ∼36% higher). We demonstrated heterogeneity among A alleles: A2 alleles were associated with plasma ACE activity that was very similar to the O alleles. Variation at ACE accounted for 35% of the trait variance, and variation at ABO accounted for 15%. A further 10% could be ascribed to polygenic effects.


Assuntos
Sistema do Grupo Sanguíneo ABO/genética , Alelos , Heterogeneidade Genética , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/genética , Locos de Características Quantitativas , Ativação Enzimática , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Estudos de Associação Genética , Estudo de Associação Genômica Ampla , Genótipo , Haplótipos , Humanos , Japão , Fenótipo , Polimorfismo de Nucleotídeo Único
17.
PLoS One ; 8(7): e68093, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23874506

RESUMO

None of the polymorphic variants of the IL2RA gene found associated with Type 1 Diabetes (T1D) was shown to have a functional effect. To test if the epigenetic variation could play a role at this locus, we studied the methylation of 6 CpGs located within the proximal promoter of IL2RA gene in 252 T1D patients compared with 286 age-matched controls. We found that DNA methylation at CpGs -373 and -456 was slightly but significantly higher in patients than in controls (40.4 ± 4.6 vs 38.3 ± 5.4, p=1.4E4; 91.4 ± 2.8 vs 89.5 ± 5.3, p=1.8E-6), while other CpG showed a strictly comparable methylation. Among 106 single nucleotide polymorphisms (SNPs) located in the neighboring 180 kb region, we found that 28 SNPs were associated with DNA methylation at CpG -373. Sixteen of these SNPs were known to be associated with T1D. Our findings suggest that the effect of IL2RA risk alleles on T1D may be partially mediated through epigenetic changes.


Assuntos
Ilhas de CpG/genética , Metilação de DNA/genética , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Subunidade alfa de Receptor de Interleucina-2/genética , Regiões Promotoras Genéticas , Idade de Início , Estudos de Casos e Controles , Criança , Feminino , França/epidemiologia , Estudos de Associação Genética , Loci Gênicos/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética
18.
Circ Cardiovasc Genet ; 6(4): 347-53, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23876493

RESUMO

BACKGROUND: Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. METHODS AND RESULTS: We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87-1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03-1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I(2)=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91-1.03]) without significant heterogeneity (I(2)=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87-1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. CONCLUSIONS: The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.


Assuntos
Cardiopatias Congênitas/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Alelos , Estudos de Coortes , Bases de Dados Genéticas , Ácido Fólico/sangue , Predisposição Genética para Doença , Genótipo , Cardiopatias Congênitas/patologia , Humanos , Razão de Chances , Fatores de Risco
19.
Nat Genet ; 45(7): 767-75, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23708188

RESUMO

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.


Assuntos
Ansiedade/genética , Mapeamento Cromossômico/métodos , Cardiopatias/genética , Esclerose Múltipla/genética , Análise de Sequência de DNA/métodos , Animais , Animais não Endogâmicos , Variação Genética/genética , Genótipo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas/genética , Ratos
20.
Nat Genet ; 45(7): 822-4, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23708191

RESUMO

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻5; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹°). Genotype accounted for ~9% of the population-attributable risk of ASD.


Assuntos
Cromossomos Humanos Par 4 , Loci Gênicos , Predisposição Genética para Doença , Cardiopatias Congênitas/genética , Cardiopatias/genética , Comunicação Interatrial/genética , Anormalidades Múltiplas/genética , Animais , Estudos de Casos e Controles , Cromossomos Humanos Par 4/genética , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias/congênito , Humanos , Masculino , Camundongos , Fenótipo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA