RESUMO
BACKGROUND: People at high risk of developing melanoma are usually identified by pigmentary and naevus phenotypes. OBJECTIVE: We examined whether associations of these phenotypes with melanoma risk differed by ambient sun exposure or participant characteristics in two population-based, case-control studies with comparable ancestry but different ambient sun exposure. METHODS: Data were analysed from 616 cases and 496 controls from the Australian Melanoma Family Study and 2012 cases and 504 controls from the Leeds (UK) case-control study. Questionnaire, interview and dermatological skin examination data were collected using the same measurement protocols. Relative risks were estimated as odds ratios using unconditional logistic regression, adjusted for potential confounders. RESULTS: Hair and skin colour were the strongest pigmentary phenotype risk factors. All associations of pigmentary phenotype with melanoma risk were similar across countries. The median number of clinically assessed naevi was approximately three times higher in Australia than Leeds, but the relative risks for melanoma associated with each additional common or dysplastic naevus were higher for Leeds than Australia, especially for naevi on the upper and lower limbs. Higher naevus counts on the head and neck were associated with a stronger relative risk for melanoma for women than men. The two countries had similar relative risks for melanoma based on self-reported naevus density categories, but personal perceptions of naevus number differed by country. There was no consistent evidence of interactions between phenotypes on risk. CONCLUSIONS: Classifying people at high risk of melanoma based on their number of naevi should ideally take into account their country of residence, type of counts (clinical or self-reported), body site on which the naevus counts are measured and sex. The presence of naevi may be a stronger indicator of a genetic predisposition in the UK than in Australia based on less opportunity for sun exposure to influence naevus development.
Assuntos
Exposição Ambiental , Melanoma/etnologia , Nevo Pigmentado/etnologia , Neoplasias Cutâneas/etnologia , Pigmentação da Pele , Luz Solar , Adolescente , Adulto , Idoso , Austrália/epidemiologia , Estudos de Casos e Controles , Extremidades , Feminino , Cor de Cabelo , Humanos , Masculino , Pessoa de Meia-Idade , Nevo Pigmentado/patologia , Fenótipo , Medição de Risco , Fatores de Risco , Fatores Sexuais , Neoplasias Cutâneas/patologia , Carga Tumoral , Reino Unido/epidemiologia , População Branca , Adulto JovemRESUMO
BACKGROUND: Genetic studies of eczema have identified many genes, which explain only 14% of the heritability. Missing heritability may be partly due to ignored gene-gene (G-G) interactions. OBJECTIVE: Our aim was to detect new interacting genes involved in eczema. METHODS: The search for G-G interaction in eczema was conducted using a two-step approach, which included as a first step, a biological selection of genes, which are involved either in the skin or epidermis development or in the collagen metabolism, and as a second step, an interaction analysis of the selected genes. Analyses were carried out at both SNP and gene levels in three asthma-ascertained family samples: the discovery dataset of 388 EGEA (Epidemiological study on the Genetics and Environment of Asthma) families and the two replication datasets of 253 SLSJ (Saguenay-Lac-Saint-Jean) families and 207 MRCA (Medical Research Council) families. RESULTS: One pair of SNPs, rs2287807 in COL5A3 and rs17576 in MMP9, that were detected in EGEA at P ≤ 10-5 showed significant interaction by meta-analysis of EGEA, SLSJ and MRCA samples (P = 1.1 × 10-8 under the significant threshold of 10-7 ). Gene-based analysis confirmed strong interaction between COL5A3 and MMP9 (P = 4 × 10-8 under the significant threshold of 4 × 10-6 ) by meta-analysis of the three datasets. When stratifying the data on asthma, this interaction remained in both groups of asthmatic and non-asthmatic subjects. CONCLUSION: This study identified significant interaction between two new genes, COL5A3 and MMP9, which may be accounted for by a degradation of COL5A3 by MMP9 influencing eczema susceptibility. Further confirmation of this interaction as well as functional studies is needed to better understand the role of these genes in eczema.
Assuntos
Colágeno Tipo V/genética , Eczema/genética , Epistasia Genética/genética , Predisposição Genética para Doença/genética , Metaloproteinase 9 da Matriz/genética , Adulto , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Exhaled nitric oxide (FeNO) is a biomarker for eosinophilic inflammation in the airways and for responsiveness to corticosteroids in asthmatics. OBJECTIVE: We sought to identify in adults the genetic determinants of fractional exhaled nitric oxide (FeNO) levels and to assess whether environmental and disease-related factors influence these associations. METHODS: We performed a genome-wide association study of FeNO through meta-analysis of two independent discovery samples of European ancestry: the outbred EGEA study (French Epidemiological study on the Genetics and Environment of Asthma, N = 610 adults) and the Hutterites (N = 601 adults), a founder population living on communal farms. Replication of main findings was assessed in adults from an isolated village in Sardinia (Talana study, N = 450). We then investigated the influence of asthma, atopy and tobacco smoke exposure on these genetic associations, and whether they were also associated with FeNO values in children of the EAGLE (EArly Genetics & Lifecourse Epidemiology, N = 8858) consortium. RESULTS: We detected a common variant in RAB27A (rs2444043) associated with FeNO that reached the genome-wide significant level (P = 1.6 × 10(-7) ) in the combined discovery and replication adult data sets. This SNP belongs to member of RAS oncogene family (RAB27A) and was associated with an expression quantitative trait locus for RAB27A in lymphoblastoid cell lines from asthmatics. A second suggestive locus (rs2194437, P = 8.9 × 10(-7) ) located nearby the sodium/calcium exchanger 1 (SLC8A1) was mainly detected in atopic subjects and influenced by inhaled corticosteroid use. These two loci were not associated with childhood FeNO values. CONCLUSIONS AND CLINICAL RELEVANCE: This study identified a common variant located in RAB27A gene influencing FeNO levels specifically in adults and with a biological relevance to the regulation of FeNO levels. This study provides new insight into the biological mechanisms underlying FeNO levels in adults.
Assuntos
Estudos de Associação Genética , Variação Genética , Óxido Nítrico , Proteínas rab de Ligação ao GTP/genética , Adulto , Alelos , Asma/genética , Asma/imunologia , Asma/metabolismo , Biomarcadores , Mapeamento Cromossômico , Expiração , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores de Risco , Adulto Jovem , Proteínas rab27 de Ligação ao GTPRESUMO
Cutaneous melanoma is a multifactorial disease resulting from both environmental and genetic factors. Five susceptibility genes have been identified over the past years, comprising high-risk susceptibility genes (CDKN2A, CDK4, and BAP1 genes) and intermediate-risk susceptibility genes (MITF, and MC1R genes). The aim of this expert consensus was to define clinical contexts justifying genetic analyses, to describe the conduct of these analyses, and to propose surveillance recommendations. Given the regulatory constraints, it is recommended that dermatologists work in tandem with a geneticist. Genetic analysis may be prescribed when at least two episodes of histologically proven invasive cutaneous melanoma have been diagnosed before the age of 75 years in two 1st or 2nd degree relatives or in the same individual. The occurrence in the same individual or in a relative of invasive cutaneous melanoma with ocular melanoma, pancreatic cancer, renal cancer, mesothelioma or a central nervous system tumour are also indications for genetic testing. Management is based upon properly managed photoprotection and dermatological monitoring according to genetic status. Finally, depending on the mutated gene and the familial history, associated tumour risks require specific management (e.g. ocular melanoma, pancreatic cancer). Due to the rapid progress in genetics, these recommendations will need to be updated regularly.
Assuntos
Predisposição Genética para Doença , Testes Genéticos , Melanoma/genética , Neoplasias Cutâneas/genética , Quinase 4 Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Genótipo , Humanos , Fator de Transcrição Associado à Microftalmia/genética , Mutação , Receptor Tipo 1 de Melanocortina/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
KIT mutations have been detected in different cancer subtypes, including melanoma. The gene also has been extensively studied in farm animals for its prominent role in coat color. The present work aimed at detecting KIT variants in a porcine model of cutaneous melanoma, the melanoblastoma-bearing Libechov Minipig (MeLiM). By sequencing exons and intron borders, 36 SNPs and one indel were identified. Of 10 coding SNPs, three were non-synonymous mutations, likely to affect the protein conformation. A promising variant, located in exon 19 (p.Val870Ala), was genotyped in a MeLiM × Duroc cross, and an association analysis was conducted on several melanoma-related traits. This variant showed a significant association with melanoma development, tumor ulceration and cutaneous invasion. In conclusion, although the KIT gene would not be a major causal gene for melanoma development in pig, its genetic variation could be influencing this trait.
Assuntos
Melanoma/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Cutâneas/genética , Suínos/genética , Animais , Suscetibilidade a Doenças/patologia , Suscetibilidade a Doenças/fisiopatologia , Melanoma/patologia , Melanoma/fisiopatologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/fisiopatologia , Porco MiniaturaRESUMO
BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.
Assuntos
Índice de Massa Corporal , Estudo de Associação Genômica Ampla , Adolescente , Adulto , Idoso , Alelos , Asma/complicações , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: Genital and anorectal mucosal melanomas (GAMMs) are rare compared with cutaneous melanoma (CM). Many epidemiological and genetic studies have been carried out on CM. In contrast, the genetic and environmental risk factors for GAMM have been poorly documented up to now. OBJECTIVES: To compare the distribution of pigmentation and naevus phenotypes, sun exposure and family history of melanoma between patients with GAMM and CM. METHODS: We compared two series of patients, 81 with GAMM and 293 with CM. RESULTS: Patients with GAMM and CM did not show significant differences for phenotypic risk factors. However, patients with GAMM tended to display red hair (11% vs. 5·5%, P = 0·08) and a poor tanning ability (22% vs. 13·3%, P = 0·06) at a higher frequency than patients with CM. A family history of melanoma was significantly more frequent with GAMM than with CM (18% vs. 7·5%, P = 0·005). Apart from the GAMM index case, affected relatives had CM except in one family. The frequency of multiple primary melanomas (MPMs) was similar in the GAMM and CM series (6% vs. 5·3%, P = 0·43). All patients with GAMM and MPM had only one GAMM primary, while the other primary was cutaneous. No CDKN2A germline mutation was detected in patients with GAMM. CONCLUSIONS: This study shows that GAMM and CM may occur in the same patient, and GAMM may develop in a familial setting. The association of both GAMM and CM in patients and families suggests shared genetic factors by these two types of melanoma.
Assuntos
Neoplasias do Ânus/genética , Neoplasias dos Genitais Femininos/genética , Melanoma/genética , Neoplasias Retais/genética , Neoplasias Cutâneas/genética , Neoplasias do Ânus/complicações , Feminino , Neoplasias dos Genitais Femininos/complicações , Mutação em Linhagem Germinativa/genética , Humanos , Mucosa Intestinal , Masculino , Melanoma/complicações , Pessoa de Meia-Idade , Nevo/complicações , Nevo/genética , Linhagem , Fenótipo , Transtornos da Pigmentação/complicações , Transtornos da Pigmentação/genética , Neoplasias Retais/complicações , Neoplasias Cutâneas/complicaçõesRESUMO
The changes in the type of haemoglobin (Hb) produced during embryonic, fetal and adult life, have served as a paradigm for understanding the developmental regulation of human genes. A genetically determined persistence of fetal Hb synthesis has an ameliorating effect on beta thalassaemia and sickle cell anaemia, globally the commonest single gene disorders. The search for the putative gene(s) controlling the level of fetal Hb production has been extremely difficult because this trait may be influenced by several factors. We have studied a large kindred with hereditary persistence of fetal haemoglobin (HPFH). Using a genetic mapping strategy and statistical methods that account simultaneously for the effects of several genetic factors, we have demonstrated that in addition to the two factors (beta thalassaemia and Xmn I-G gamma site) on chromosome 11p, there is a third major genetic determinant for fetal Hb production localized on chromosome 6q.
Assuntos
Hemoglobina Fetal/genética , Hemoglobinopatias/genética , Cromossomos Humanos Par 11 , Cromossomos Humanos Par 6 , Desoxirribonucleases de Sítio Específico do Tipo II , Feminino , Regulação da Expressão Gênica , Ligação Genética , Marcadores Genéticos , Humanos , Masculino , Polimorfismo de Fragmento de Restrição , Análise de Regressão , Talassemia beta/genéticaRESUMO
Single nucleotide polymorphisms (SNPs) at chromosome 17q21 confer an increased risk of early-onset asthma. The objective was to study whether 17q21 SNPs modify associations between early respiratory infections and asthma. Association analysis was conducted in 499 children (268 with asthma, median age 11 yrs) from the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). The 12-yr follow-up data were used to assess persistent or remittent asthma in young adulthood. Respiratory infection before 2 yrs of age was assessed retrospectively. For the 12 17q21 SNPs studied, the odds ratios (OR) for association between infection and early-onset asthma (age at onset Assuntos
Asma/etiologia
, Asma/genética
, Cromossomos Humanos Par 17/genética
, Infecções Respiratórias/complicações
, Infecções Respiratórias/genética
, Adolescente
, Idade de Início
, Criança
, Feminino
, Seguimentos
, Estudos de Associação Genética
, Predisposição Genética para Doença
, Humanos
, Masculino
, Proteínas de Membrana/genética
, Proteínas de Neoplasias/genética
, Polimorfismo de Nucleotídeo Único
, Estudos Retrospectivos
, Fatores de Risco
, Fatores Sexuais
, Poluição por Fumaça de Tabaco/efeitos adversos
RESUMO
Sex differences in asthma-associated phenotypes are well known but the genetic factors that may account for these differences have received little attention. This study aimed to characterize sex-specific and pleiotropic genetic factors underlying four quantitative phenotypes involved in the main asthma physiopathological pathways: immunoglobulin E levels, a measure of polysensitization (SPTQ), eosinophil counts and a measure of lung function FEV(1)/H(2) (forced expiratory volume in one second divided by height square). Sex-stratified univariate and bivariate linkage analyses were conducted in 295 families from the Epidemiological study on the Genetics and Environment of Asthma study. We found genome-wide significant evidence for a male-specific pleiotropic QTL (quantitative trait loci) on 5q31 (P=7 x 10(-9)) influencing both FEV(1)/H(2) and SPTQ and for a female-specific pleiotropic QTL on 11q23 underlying SPTQ and immunoglobulin E (P=2 x 10(-5)). Three other sex-specific regions of linkage were detected for eosinophil: 4q24 and 22q13 in females, and 3p25 in males. Further, bivariate association analysis of FEV(1)/H(2) and SPTQ with 5q31 candidate genes in males showed a significant association with two single-nucleotide polymorphisms within IL9 gene, rs2069885 and rs2069882 (P=0.02 and P=0.002, respectively, after Bonferroni's correction). This study underlies the importance of taking into account complex mechanisms, such as heterogeneity according to sex and pleiotropy to unravel the genes involved in asthma phenotypes.
Assuntos
Asma/genética , Eosinófilos/patologia , Ligação Genética , Imunoglobulina E/sangue , Interleucina-9/genética , Pulmão/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Asma/sangue , Hiper-Reatividade Brônquica , Contagem de Células , Criança , Mapeamento Cromossômico , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 4/genética , Feminino , Volume Expiratório Forçado/genética , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Repetições de Microssatélites , Fenótipo , Locos de Características Quantitativas , Testes de Função Respiratória , Fatores SexuaisRESUMO
Allergic diseases represent a major health problem in Europe. They are increasing in prevalence, severity and costs. GA2LEN (Global Allergy and Asthma European Network), an FP6 Network of Excellence, was created in 2005 as a vehicle to ensure excellence in research bringing together research and clinical institutions to combat fragmentation in the European research area and to tackle Allergy in its globality. GA2LEN benefited greatly from the voluntary efforts of researchers who are strongly committed to this model of pan-European collaboration. The network was organized in order to increase networking for scientific projects in allergy and asthma around Europe and to make GA2LEN the world leader in the field. Besides these activities, research has been jointly made and the first papers are being published. GA2LEN achievements in general can be grouped as those for a durable infrastructure built up during the project phase those which are project-related work based on these novel infrastructures, and the development and implementations of guidelines. The major achievements of GA2LEN are reported in this paper.
Assuntos
Asma , Hipersensibilidade , Cooperação Internacional , Pesquisa , Alergia e Imunologia , Europa (Continente) , HumanosRESUMO
Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.
Assuntos
Proteínas de Ligação a DNA , Diabetes Mellitus Tipo 2/genética , Proteínas Nucleares , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Mutação Puntual , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional , Idade de Início , Animais , Apolipoproteína C-III , Apolipoproteínas C/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Células COS , Feminino , Teste de Tolerância a Glucose , Fator 1 Nuclear de Hepatócito , Fator 1-alfa Nuclear de Hepatócito , Fator 1-beta Nuclear de Hepatócito , Fator 4 Nuclear de Hepatócito , Humanos , Insulina/metabolismo , Secreção de Insulina , Isoleucina/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Timidina Quinase/genética , Distribuição Tecidual , Valina/genéticaRESUMO
OBJECTIVE: Comprehensive analysis of the 9p21 locus including the CDKN2A, ARF, and CDKN2B genes in 53 individuals from melanoma index cases considered to be at heightened risk of melanoma. METHODS AND RESULTS: Using a combination of DNA sequencing, gene copy number by real time quantitative PCR, linkage analysis, and transcript analysis in haploid somatic cell hybrids, we found no evidence for germline alteration in either coding or non-coding domains of CDKN2A and CDKN2B. However, we identified a p14ARF exon 1beta missense germline mutation (G16D) in a melanoma-neural system tumour syndrome (CMM+NST) family and a 8474 bp germline deletion from 196 bp upstream of p14ARF exon 1beta initiation codon to 11233 bp upstream of exon 1alpha of p16(INK4A) in a family with five melanoma cases. For three out of 10 families with at least three melanoma cases, the disease gene was unlinked to the 9p21 region, while linkage analysis was not fully conclusive for seven families. CONCLUSIONS: These data reinforce the hypothesis that ARF is a melanoma susceptibility gene and suggest that germline deletions specifically affecting p14ARF may not be solely responsible for NST susceptibility. Predisposition to CMM+NST could either be due to complete disruption of the CDKN2A locus or be the result of more complex genetic inheritance. In addition, the absence of any genetic alteration in 50 melanoma prone families or patients suggests the presence of additional tumour suppressor genes possibly in the 9p21 region, and on other chromosomes.
Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Melanoma/genética , Proteína Supressora de Tumor p14ARF/genética , Linhagem Celular Tumoral , Cromossomos Humanos Par 9/genética , Análise Mutacional de DNA , Éxons/genética , Deleção de Genes , Genes Neoplásicos , Ligação Genética , Mutação em Linhagem Germinativa/genética , Humanos , Mutação de Sentido Incorreto/genética , Linhagem , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA não Traduzido/genética , Fatores de RiscoRESUMO
The number of genetic factors associated with asthma remains limited. To identify new genes with an undetected individual effect but collectively influencing asthma risk, we conducted a network-assisted analysis that integrates outcomes of genome-wide association studies (GWAS) and protein-protein interaction networks. We used two GWAS datasets, each consisting of the results of a meta-analysis of nine childhood-onset asthma GWASs (5,924 and 6,043 subjects, respectively). We developed a novel method to compute gene-level P-values (fastCGP), and proposed a parallel dense-module search and cross-selection strategy to identify an asthma-associated gene module. We identified a module of 91 genes with a significant joint effect on childhood-onset asthma (P < 10-5). This module contained a core subnetwork including genes at known asthma loci and five peripheral subnetworks including relevant candidates. Notably, the core genes were connected to APP (encoding amyloid beta precursor protein), a major player in Alzheimer's disease that is known to have immune and inflammatory components. Functional analysis of the module genes revealed four gene clusters involved in innate and adaptive immunity, chemotaxis, cell-adhesion and transcription regulation, which are biologically meaningful processes that may underlie asthma risk. Our findings provide important clues for future research into asthma aetiology.
Assuntos
Asma/genética , Redes Reguladoras de Genes , Mapas de Interação de Proteínas , Idade de Início , Precursor de Proteína beta-Amiloide/genética , Asma/patologia , Criança , Estudo de Associação Genômica Ampla , HumanosRESUMO
BACKGROUND: Genome-wide association studies have identified novel genetic associations for asthma, but without taking into account the role of active tobacco smoking. This study aimed to identify novel genes that interact with ever active tobacco smoking in adult onset asthma. METHODS: We performed a genome-wide interaction analysis in six studies participating in the GABRIEL consortium following two meta-analyses approaches based on 1) the overall interaction effect and 2) the genetic effect in subjects with and without smoking exposure. We performed a discovery meta-analysis including 4,057 subjects of European descent and replicated our findings in an independent cohort (LifeLines Cohort Study), including 12,475 subjects. RESULTS: First approach: 50 SNPs were selected based on an overall interaction effect at p<10-4. The most pronounced interaction effect was observed for rs9969775 on chromosome 9 (discovery meta-analysis: ORint = 0.50, p = 7.63*10-5, replication: ORint = 0.65, p = 0.02). Second approach: 35 SNPs were selected based on the overall genetic effect in exposed subjects (p <10-4). The most pronounced genetic effect was observed for rs5011804 on chromosome 12 (discovery meta-analysis ORint = 1.50, p = 1.21*10-4; replication: ORint = 1.40, p = 0.03). CONCLUSIONS: Using two genome-wide interaction approaches, we identified novel polymorphisms in non-annotated intergenic regions on chromosomes 9 and 12, that showed suggestive evidence for interaction with active tobacco smoking in the onset of adult asthma.
Assuntos
Asma/induzido quimicamente , Asma/genética , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla , Fumar/efeitos adversos , Adulto , Estudos de Coortes , Predisposição Genética para Doença/genética , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Melanoma/genética , Doença de Parkinson/genética , Neoplasias Cutâneas/genética , Estudos de Coortes , Receptor DCC , Dopamina/biossíntese , Genótipo , Humanos , Melaninas/biossíntese , Glicoproteínas de Membrana/genética , Monofenol Mono-Oxigenase , Oxirredutases/genética , Pigmentação/genética , Receptor ErbB-4/genética , Receptores de Superfície Celular/genética , Risco , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
Mutations in the glucokinase gene are a major cause of maturity-onset diabetes of the young. To evaluate the contribution of this gene to the development of late-onset NIDDM, linkage analyses between DNA polymorphisms at the glucokinase locus and NIDDM were performed in 79 multigenerational French families. In addition, all exons and the islet promoter region of glucokinase gene from 1 affected member from each family as well as from 17 unrelated women with previous gestational diabetes were amplified by polymerase chain reaction and screened for mutations by single-strand conformational polymorphism and DNA sequencing. Linkage of glucokinase and NIDDM was significantly rejected under all models tested. However, in 1 family, the lod score was 2.30, and we found a nucleotide substitution at the position -30 in the islet promoter region that cosegregated with diabetes. The proband of this family was a gestational diabetic individual. No other mutation in glucokinase was found in the 79 NIDDM families. We identified a missense mutation (TGG257-->CGG257) in exon 7 of glucokinase gene from 1 of 17 women with gestational diabetes, which was present in all diabetic members of her family. This family is likely to be a cryptic maturity-onset diabetes of the young, as 4 younger members, carrying this mutation, were subsequently found to be hyperglycemic. In conclusion, no evidence was obtained to incriminate glucokinase as a major gene for late age of onset NIDDM. Diabetic families with mutations in glucokinase must be carefully investigated, to differentiate cryptic maturity-onset diabetes of the young from late-onset NIDDM. Furthermore, pregnancy reveals diabetes in women carrying a glucokinase defect.
Assuntos
Diabetes Mellitus Tipo 2/genética , Ligação Genética , Glucoquinase/genética , Mutação , Adolescente , Adulto , Idoso , Sequência de Bases , Criança , DNA de Cadeia Simples/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo Genético , Gravidez , Gravidez em Diabéticas/genéticaRESUMO
Non-insulin-dependent diabetes mellitus (NIDDM) is a clinically and genetically heterogeneous disorder. Maturity-onset diabetes of the young (MODY), an autosomal dominant form of NIDDM, has been used as a model for genetic studies of NIDDM. We recently reported linkage between markers on chromosome 12q and diabetes in 25% of our French MODY families. To evaluate if this gene is also implicated in late-onset NIDDM, we performed linkage studies between two markers of the MODY region and diabetes in 172 families with late-onset NIDDM. Both parametric and nonparametric methods were used in a total of 600 affected sib-pairs. Linkage was rejected in this population by all methods, implying that the MODY gene on chromosome 12q is not a major gene for late-onset NIDDM in this population. However, we cannot exclude a modifying role in a polygenic disorder or an important role in some families.
Assuntos
Mapeamento Cromossômico , Cromossomos Humanos Par 12 , Diabetes Mellitus Tipo 2/genética , Ligação Genética , Adulto , Fatores Etários , Idade de Início , Sequência de Bases , Primers do DNA , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Genes Dominantes , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Pais , Reação em Cadeia da Polimerase , Caracteres SexuaisRESUMO
As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affected sib pairs defined as having a fasting plasma glucose value of >6.1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load. No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 years of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further analyses.
Assuntos
Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 2/genética , Diabetes Mellitus Tipo 2/genética , Fatores Etários , Alelos , Sequência de Bases , Índice de Massa Corporal , Estudos de Coortes , Primers do DNA/química , Família , França , Ligação Genética , Marcadores Genéticos/genética , Humanos , Modelos Genéticos , Modelos Estatísticos , Dados de Sequência Molecular , Polimorfismo Genético , Sequências Repetitivas de Ácido NucleicoRESUMO
The sulfonylurea receptor (SUR) is a key component in glucose-stimulated insulin secretion. Obesity and NIDDM are frequently associated and share some metabolic abnormalities, suggesting that they might also share some susceptibility genes. Thus, the SUR encoding gene is a plausible candidate for a primary pancreatic beta-cell defect and thus for hyperglycemia and weight gain. Through association and linkage studies, we have investigated the potential role of the SUR gene in families with NIDDM and in two independent sets of morbidly obese families. The exon 22 T-allele at codon 761 was more common in patients with NIDDM (7.7%) and morbid obesity (7.8%) than in control subjects (1.8%, P = 0.030 and P = 0.023, respectively). This variant was associated with morbid obesity (odds ratio 3.71, P = 0.017) and NIDDM (odds ratio 2.20, P = 0.04; association dependent on BMI). Although the frequencies for intron 24 variant were similar in all groups, morbidly obese patients homozygous for the c-allele had a more deleterious form of obesity. Sib-pair linkage studies with NIDDM in French Caucasian families gave no evidence for linkage to the SUR locus. However, in one set of the obese families, we found an indication for linkage with a SUR-linked microsatellite marker (D11S419, P = 0.0032). We conclude that in Caucasians, the SUR locus may contribute to the genetic susceptibility to NIDDM and obesity.