Extended haplotype in the tumor necrosis factor gene cluster is associated with asthma and asthma-related phenotypes

Abstract

Rationale: Tumor necrosis factor is a proinflammatory cytokine found in increased concentrations in asthmatic airways. The TNF-alpha (TNF) and lymphotoxin-alpha (LTA) genes belong to the TNF gene superfamily located within the human major histocompatibility complex on chromosome 6p in a region repeatedly linked to asthma. The TNF position -308 and LTA NcoI polymorphisms are believed to influence TNF transcription and secretion, respectively.

Objectives: This study sought to determine whether polymorphisms in TNF or LTA, or in TNF-LTA haplotypes, are associated with asthma and asthma phenotypes.

Methods: We genotyped the TNF -308 and LTA NcoI polymorphisms, and two other haplotype-tagging polymorphisms in the TNF and LTA genes, in 708 children with mild to moderate asthma enrolled in the Childhood Asthma Management Program and in their parents. Using an extension of the family-based association tests in the PBAT program, each polymorphism was tested for association with asthma, age at onset of asthma, and time series data on baseline FEV(1) % predicted, postbronchodilator FEV(1) % predicted, body mass index, and log of PC(20).

Measurements and main results: Although no associations were found for the individual single-nucleotide polymorphisms, the haplotype analysis found the LTA NcoI_G/LTA 4371T/TNF -308G/TNF 1078G haplotype to be associated with asthma and with all five phenotype groups.

Conclusions: We conclude that it is unlikely that the TNF -308 or LTA NcoI polymorphisms influence asthma susceptibility individually, but that this haplotype of variants may be functional or may be in linkage disequilibrium with other functional single-nucleotide polymorphisms.

Figures

Figure 1.

Top: Schematic representation of the TNF genes on chromosome 6 in relation to other important innate immunity genes in the area. TNF includes lymphotoxin-α (LTA), tumor necrosis factor-α (TNF), and lymphotoxin-β (LTB). COMP = complement; HSP = heat shock 70-kD protein-1 and 90-kD protein-1; MHC = major histocompatibility complex (human leukocyte antigens DP, DQ, DR); SNP = single-nucleotide polymorphism. Bottom: TNF and LTA with SNP locations; the solid boxes denote exons and the open boxes denote the 5′ and 3′ untranslated regions. Not drawn to scale. (The top portion of this diagram was modified from Reference 39.)

Figure 2.

Kaplan-Meier curve of reported asthma age of onset by the presence (x = 1) or the absence (x = 0) of the LTA NcoI_G/LTA 4371T/TNF –308G/TNF 1078G haplotype. A statistically significant association for later age of asthma onset in carriers of the haplotype was found (p = 0.007).