Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 172, Issue 6, Pages 687-692Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200501-122OC
Keywords
asthma; haplotypes; lymphotoxin-alpha polymorphism; tumor necrosis factor
Categories
Funding
- NHLBI NIH HHS [N01-HR-16049, K23HL04278, K23 HL004278, P01 HL67664, U01 HL66795, P50 HL67664, N01HR16049] Funding Source: Medline
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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 Ncol 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 Ncol 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 FEV1 % predicted, postbronchodilator FEV, % predicted, body mass index, and 109 Of PC20-Measurements and Main Results: Although no associations were found for the individual single-nucleotide polymorphisms, the haplotype analysis found the LTA Ncol_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 Ncol 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.
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