Published ahead of print on June 23, 2005, doi:10.1164/rccm.200501-122OC Am. J. Respir. Crit. Care Med., Volume 172, Number 6, September 2005, 687-692 A more recent version of this article appeared on September 15, 2005
Submitted on January 26, 2005 Extended Haplotype in the TNF Gene Cluster is Associated with Asthma and Asthma Related PhenotypesAdrienne G Randolph1*,1 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Anesthesia, Children's Hospital and Harvard Medical School, Boston, MA, USA, 2 Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA, 3 Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA * To whom correspondence should be addressed. E-mail: adrienne.randolph{at}tch.harvard.edu.
Rationale: Tumor necrosis factor (TNF) 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 -308 and LTA NcoI polymorphisms are believed to influence TNF transcription and secretion, respectively. Objectives: To determine if polymorphisms in TNF or LTA, or 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 (CAMP)and their parents. Using an extension of the family based association tests in the PBAT program, each polymorphism was tested for association with asthma, age of onset of asthma and with time series data on baseline FEV1 % predicted, post-bronchodilator FEV1 % predicted, body mass index, and log of PC20. Measurements and Main Results: Although no associations were found for the individual SNPs, the haplotype analysis found the LTA NcoI_G/LTA 4371T/TNF -308G/TNF 1078G haplotype to be associated with asthma and with all 5 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 SNPs. Key words: TNF, LTA, asthma, haplotypes, polymorphism
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