Association of tumor necrosis factor polymorphisms with asthma and serum total IgE

Abstract

Tumor necrosis factors (TNF; TNFA and TNFB) are major pro-inflammatory cytokines that are thought to be important in the pathogenesis of asthma. However, the functions of genetic polymorphisms in these cytokines have not been thoroughly examined in the context of asthma pathology. In an effort to discover polymorphism(s) in genes whose variant(s) have been implicated in asthma phenotypes, we examined the genetic effects of TNF (TNFA and TNFB) polymorphisms on asthma and total serum IgE level. Seven common single-nucleotide polymorphisms (SNP) in TNF genes were genotyped in a Korean asthma cohort (asthmatics n=550, normal controls n=171). Six common haplotypes could be constructed in the TNF gene cluster due to very strong LD between TNFA and TNFB, located 13 kb apart on chromosome 6p21. One SNP (TNFA-308G>A) showed a significant association with the risk of asthma (P=0.0004). The frequency of TNFA-308A allele-containing genotype in asthmatics (9.8%) was much lower than that in normal controls (22.9%). The protective effects of this polymorphism on asthma were also evident in separated subgroups by atopic status (P=0.05 in non-atopic subjects and P=0.003 in atopic subjects). The most common haplotype of the TNF gene (TNF-ht1[GGTCCGG]) was associated with total serum IgE (immunoglobulin E) levels in asthma patients, especially in non-atopic patients (P=0.004). Genetic variants of TNF might be involved in development of asthma and total serum IgE level in bronchial asthma patients. The results of this study could be helpful to understand the function of important TNF genes in asthma and IgE production.

An association between asthma and TNF-308G/A polymorphism: meta-analysis

“…After omission of the study by Shin et al (2004), the homogeneity test result was not significant (P=0.60). The combined odds ratio with the fixed effects model and random effects model in the Asian population was 1.71 (95% CI, 1.29-2.25, P=0.0002) and 1.70 (95% CI, 1.29-2.25, P=0.00019) respectively.…”

“…To see the effect of the -308G/A polymorphism in specific ethnicities, we performed separate meta-analysis of Caucasian and Asian populations. The studies by Albuquerque et al (1998) in Caucasian populations and Shin et al (2004) in Asian populations contributed to heterogeneity in each ethnic group. After omission of these studies from our meta-analysis, results were consistent between the two ethnic groups, indicating that the -308A allele is associated with an increased risk of asthma.…”

“…The result of the heterogeneity test was no longer significant after omission of the study by Shin et al (2004), indicating that their study contributed disproportionately to the summary odds ratio, suggesting the existence of heterogeneity. The combined odds ratio with the fixed effects model and with the random effects model after removal of that study was 1.46 (95% CI, 1.27-1.68, P=0.0000001) and 1.46 (95% CI, 1.20-1.77, P=0.00014) respectively.…”

“…1; Moffatt and Cookson 1997;Albuquerque et al 1998;Louis et al 2000;Winchester et al 2000;Buckova et al 2002;Witte et al 2002;El Bahlawan et al 2003;Sandford et al 2004;Shin et al 2004;Wang et al 2004;Bilolikar et al 2005;Gupta et al 2005). Several studies were not included because allele frequency data were not available (Chagani et al 1999;Li Kam Wa et al 1999;Trabetti et al 1999;Lin et al 2002;Di Somma et al 2003;Li et al 2006) or because of an incomplete phenotype (probable asthma; Zhu et al 2000).…”

“…Some studies have supported an association with asthma (Moffatt and Cookson 1997;Albuquerque et al 1998;Chagani et al 1999;Li Kam Wa et al 1999;Winchester et al 2000;Witte et al 2002;Shin et al 2004;Wang et al 2004), whereas other studies have not (Louis et al 2000;Zhu et al 2000;Buckova et al 2002). Moffatt and Cookson (1997) first reported that -308G/A was significantly associated with asthma in an Australian population (Moffatt and Cookson 1997).…”