Submitted on February 24, 2006
Revised on May 15, 2006
Association of TNF Haplotypes with Asthma, Serum IgE levels and Correlation with Serum TNF-
levels
Shilpy Sharma1, Amit Sharma1, Sarvesh Kumar1, Surendra K Sharma2, and Balaram Ghosh1*
1 Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative Biology, Delhi, Delhi, India,
2 Department of Medicine, All India Institute of Medical Sciences, Delhi, Delhi, India
* To whom correspondence should be addressed. E-mail: bghosh{at}igib.res.in.
Both biochemical and genetic evidence have implicated TNF-
(TNFA) and lymphotoxin- (LTA) in atopic asthma. Here we report for the first time the association of their genotypes and haplotypes with atopic asthma in Indian population. We genotyped seven SNPs, encompassing the two genes, in patients and controls in two independent cohorts. Serum TNF- levels of selected individuals were measured and correlated with genotypes and haplotypes. The A allele of the TNFA-863C>A polymorphism was associated with reduced risk of asthma (p=0.002 and 0.007 in cohort A and B, respectively), reduced TsIgE levels (p=0.0024 and p=0.0029 in cohort A and B, respectively) and reduced serum TNF- levels (p<0.05). A marginal association was also observed for LTA_NcoI polymorphism with asthma and TsIgE levels. Furthermore, analysis using HAPLO.STATS showed significant differences in the major haplotype frequencies (>3%) between cases and controls (p=0.002 and p=0.006 for cohort A and B, respectively). Individually, the haplotype GATCCG was the most frequent in patients (p=0.0029 and p=0.0025 for cohort A and B, respectively) and was associated with high TsIgE and serum TNF- levels while AACACG was the most frequent in the controls (p=0.0032 and p=0.022 for cohort A and B, respectively) and was associated with low TsIgE and serum TNF- levels. We also report here that the C>A substitution at position -863 of the TNFA influences the binding of nuclear proteins in EMSA experiments. Thus, the TNFA-863C>A polymorphism in the promoter region of TNFA may influence TNF- expression and affect TsIgE levels and susceptibility towards asthma.
