TNFA-308G>A in two international population-based cohorts and risk of asthma

Abstract

Genetic association studies have related the tumour necrosis factor-a gene (TNFA) guanine to adenine substitution of nucleotide -308 (-308G.A) polymorphism to increased risk of asthma, but results are inconsistent. The aim of the present study was to test whether two singlenucleotide polymorphisms, of TNFA and of the lymphotoxin-a gene (LTA), are associated with asthma, bronchial hyperresponsiveness and atopy in adults, by combining the results of two large population-based multicentric studies and conducting a meta-analysis of previously published studies.The European Community Respiratory Health Survey (ECRHS) and Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) used comparable protocols, including questionnaires for respiratory symptoms and measures of lung function and atopy. DNA samples from 11,136 participants were genotyped at TNFA -308 and LTA 252. Logistic regression employing fixed and random effects models and nonparametric techniques were used.The prevalence of asthma was 6%. The TNFA -308G.A polymorphism was associated with increased asthma prevalence and with bronchial hyperresponsiveness. No consistent association was found for atopy. The LTA 252A.G polymorphism was not associated with any of the outcomes. A meta-analysis of 17 studies showed an increased asthma risk for the TNFA -308 adenine allele.The tumour necrosis factor-a gene nucleotide -308 polymorphism is associated with a moderately increased risk of asthma and bronchial hyperresponsiveness, but not with atopy. These results are supported by a meta-analysis of previously published studies.

Joint effect of obesity andTNFAvariability on asthma: two international cohort studies

“…The median length of follow-up was 8.9 yrs. The asthma definitions used in the present analysis were similar to those used in previous publications [12,17]. All subjects defined as having asthma had responded positively to an initial question ''Have you ever had asthma?''…”

“…The LTA +252 A/G polymorphism, located in the first intron of the LTA gene, seems to be associated with a high LTA expression [11]. A recent meta-analysis that included the population reported in the current study has shown that the TNFA -308 A and LTA +252 G alleles are both positively associated with asthma [12].…”

“…Genotype distribution for both alleles was consistent with Hardy-Weinberg equilibrium (HWE) in the control group (p.0.05). A previous analysis of these cohorts [12] found similar effects of TNFA -308 and LTA +252 on asthma, possibly due to strong linkage disequilibrium between the loci (Chi-squared57516.29, disequilibrium ASTHMA, OBESITY AND TNFA POLYMORPHISMS F. CASTRO-GINER ET AL.…”

“…The population-based Swiss Cohort Study on Air Pollution and Lung and Heart Disease in Adults (SAPALDIA) was conducted in eight Swiss communities [15,16]. Initially, 5,065 participants from ECRHS and 6,071 participants from SAPALDIA with complete interview data and DNA samples for genotyping were included [12]. Some subjects from Basel, Switzerland (n5400), were initially included in both datasets, but remained only in the SAPALDIA cohort during the analyses.…”

“…Candidate single nucleotide polymorphism selection and genotyping On the basis of previous studies and functional data [10][11][12], two single nucleotide polymorphisms (SNPs) were selected for genetic analysis in the two cohorts, TNFA -308 (rs1800629) and LTA +252 (rs909253). In SAPALDIA, these polymorphisms were genotyped by real-time PCR.…”