RESUMO
BACKGROUND: Asthma genome-wide association studies (GWAS) have identified several asthma susceptibility genes with confidence; however the relative contribution of these genetic variants or single nucleotide polymorphisms (SNPs) to clinical endpoints (as opposed to disease diagnosis) remains largely unknown. Thus the aim of this study was to firstly bridge this gap in knowledge and secondly investigate whether these SNPs or those that are in linkage disequilibrium are likely to be functional candidates with respect to regulation of gene expression, using reported data from the ENCODE project. METHODS: Eleven of the key SNPs identified in eight loci from recent asthma GWAS were evaluated for association with asthma and clinical outcomes, including percent predicted FEV1, bronchial hyperresponsiveness (BHR) to methacholine, severity defined by British Thoracic Society steps and positive response to skin prick test, using the family based association test additive model in a well characterised UK cohort consisting of 370 families with at least two asthmatic children. RESULTS: GSDMB SNP rs2305480 (Ser311Pro) was associated with asthma diagnosis (p = 8.9×10-4), BHR (p = 8.2×10-4) and severity (p = 1.5×10-4) with supporting evidence from a second GSDMB SNP rs11078927 (intronic). SNPs evaluated in IL33, IL18R1, IL1RL1, SMAD3, IL2RB, PDE4D, CRB1 and RAD50 did not show association with any phenotype tested when corrected for multiple testing. Analysis using ENCODE data provides further insight into the functional relevance of these SNPs. CONCLUSIONS: Our results provide further support for the role of GSDMB SNPs in determining multiple asthma related phenotypes in childhood asthma including associations with lung function and disease severity.
Assuntos
Asma/genética , Estudo de Associação Genômica Ampla , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Asma/patologia , Criança , Estudos de Coortes , Biologia Computacional , Feminino , Loci Gênicos , Genótipo , Humanos , Masculino , Fenótipo , Locos de Características Quantitativas , Índice de Gravidade de DoençaRESUMO
BACKGROUND: Polymorphisms spanning genes involved in the production of leukotriene B4 (LTB4) e.g. ALOX5AP and LTA4H are associated with asthma susceptibility, suggesting a role for LTB4 in disease. The contribution of LTB4receptor polymorphism is currently unknown. The aim of this study was to characterise the genes for the two pivotal LTB4 receptors, LTB4R1 and LTB4R2 in lung tissue and determine if polymorphisms spanning these genes are associated with asthma and disease severity. METHODS: Rapid amplification of cDNA ends (RACE) was used to characterise the LTB4R1 and LTB4R2 gene structure in lung. The LTB4R1/2 locus on chromosome 14q11.2 was screened for polymorphic variation. Six LTB4R single nucleotide polymorphisms (SNPs) were genotyped in 370 Caucasian asthma families and 299 Adult Asthma Individuals (n=1877 total) and were evaluated for association with asthma and severity (BTS) outcome measures using Family Based Association Test, linear regression and chi square. RESULTS: LTB4R1 has complex mRNA arrangement including multiple 5'-untranslated exons, suggesting additional levels of regulation. Three potential promoter regions across the LTB4R1/2 locus were identified with some airway cell specificity. 22 SNPs (MAF>0.01) were validated across the LTB4R locus in the Caucasian population. LTB4R1 and LTB4R2 SNPs were not associated with asthma susceptibility, FEV1 or severity. CONCLUSIONS: LTB4R1 and LTB4R2 shows splice variation in the 5'-untranslated region and multiple promoter regions. The functional significance of this is yet to be determined. Both receptor genes were shown to be polymorphic. LTB4R polymorphisms do not appear to be susceptibility markers for the development of asthma in Caucasian subjects.
Assuntos
Leucotrieno B4/genética , Polimorfismo de Nucleotídeo Único , Receptores do Leucotrieno B4/genética , Regiões 5' não Traduzidas , Adolescente , Adulto , Processamento Alternativo , Asma/genética , Moléculas de Adesão Celular , Cromossomos Humanos Par 14 , Éxons , Família , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Lineares , Desequilíbrio de Ligação , Pulmão/fisiologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso , Índice de Gravidade de Doença , População Branca/genética , Adulto JovemRESUMO
BACKGROUND: We have previously shown evidence that polymorphisms within genes controlling leukotriene B4 (LTB4) production (ALOX5AP and LTA4H) are associated with asthma susceptibility in children. Evidence also suggests a potential role of LTB4 in COPD disease mechanisms including recruitment of neutrophils to the lung. The aim of the current study was to see if these SNPs and those spanning the receptor genes for LTB4 (LTB4R1 and LTB4R2) influence baseline lung function and COPD susceptibility/severity in smokers. METHODS: Eight ALOX5AP, six LTA4H and six LTB4R single nucleotide polymorphisms (SNPs) were genotyped in a UK Smoking Cohort (n = 992). Association with baseline lung function (FEV1 and FEV1/FVC ratio) was determined by linear regression. Logistic regression was used to compare smoking controls (n = 176) with spirometry-defined COPD cases (n = 599) and to more severe COPD cases (GOLD stage 3 and 4, n = 389). RESULTS: No association with ALOX5AP, LTA4H or LTB4R survived correction for multiple testing. However, we showed modest association with LTA4H rs1978331C (intron 11) with increased FEV1 (p = 0.029) and with increased FEV1/FVC ratio (p = 0.020). CONCLUSIONS: These data suggest that polymorphisms spanning ALOX5AP, LTA4H and the LTB4R locus are not major determinants of baseline lung function in smokers, but provide tentative evidence for LTA4H rs1978331C (intron 11) in determining baseline FEV1 and FEV1/FVC ratio in Caucasian Smokers in addition to our previously identified role in asthma susceptibility.
Assuntos
Proteínas Ativadoras de 5-Lipoxigenase/genética , Epóxido Hidrolases/genética , Pulmão/fisiopatologia , Polimorfismo de Nucleotídeo Único , Doença Pulmonar Obstrutiva Crônica/genética , Receptores do Leucotrieno B4/genética , População Branca/genética , Proteínas Ativadoras de 5-Lipoxigenase/metabolismo , Adulto , Idoso , Estudos de Coortes , Epóxido Hidrolases/metabolismo , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Receptores do Leucotrieno B4/metabolismo , Testes de Função Respiratória , Fumar/genética , Reino UnidoRESUMO
Mitochondrial DNA damage has been used as a successful and unique biomarker of tissue stress. A valuable example of this is sun damage in human skin which leads to ageing and skin cancer. The skin is constantly exposed to the harmful effects of sunlight, such as ultraviolet radiation, which causes it to age with observable characteristic features as well as clinical precancerous lesions and skin cancer. Formation of free radicals by the sun's harmful rays which contribute to oxidative stress has been linked to the induction of deletions and mutations in the mitochondrial DNA. These markers of mitochondrial DNA damage have been proposed to contribute to the mechanisms of ageing in many tissues including skin and are associated with many diseases including cancer. In this article we highlight the role of this important organelle in ageing and cancer with particular emphasis on experimental strategies in the skin.