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Extended Haplotype in the Tumor Necrosis Factor Gene Cluster Is Associated with Asthma and Asthma-related Phenotypes

Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School; Department of Anesthesia, Children's Hospital and Harvard Medical School; and Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Adrienne Randolph, M.D., M.Sc., Children's Hospital, MICU, FA-108, 300 Longwood Avenue, Boston, MA 02115. E-mail: adrienne.randolph{at}childrens.harvard.edu

Rationale: Tumor necrosis factor is a proinflammatory cytokine found in increased concentrations in asthmatic airways. The TNF- (TNF) and lymphotoxin- (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 FEV₁ % predicted, postbronchodilator FEV₁ % predicted, body mass index, and log of PC₂₀. 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.

Key Words: asthma • haplotypes • lymphotoxin- polymorphism • tumor necrosis factor

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