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


OBJECTIVE
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).


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.
Randolph
Adrienne G
AG
Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. adrienne.randolph@childrens.harvard.edu
Lange
Christoph
C
Silverman
Edwin K
EK
Lazarus
Ross
R
Weiss
Scott T
ST
D001249:Asthma / Q000235:genetics*; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D015337:Multicenter Studies as Topic; D005810:Multigene Family; D010641:Phenotype; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha