¹Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, USA

²Channing Laboratory, Harvard Medical School, 181 Longwood Avenue, Boston, Massachusetts, USA

³Sharp Rees-Stealy Medical Group, San Diego, California, USA

⁴Department of Pediatrics, University of California at San Diego, California, USA

⁵PPGx, Inc. La Jolla, California, USA

Correspondence to: J S Witte, Department of Epidemiology and Biostatistics, Case Western Reserve University, W-G72, 2109 Adelbert Road, Cleveland, Ohio 44106-4945, USA Tel: 216 368 6839; Fax: 216 368 3970; E-mail: witte@darwin.cwru.edu

Tumour necrosis factor (TNF) alpha affects immune response and airway inflammation, which are characteristics of asthma. Genetic factors may impact TNF levels, and several polymorphisms in the TNF gene cluster on chromosome 6p21 have been associated with TNF production and potential increased risk of asthma. The present paper evaluates the relation between two single nucleotide polymorphisms (SNPs) in the TNF gene cluster and asthma risk. The SNPs investigated here are guanine (G) to adenosine (A) substitutions in the TNF and lymphotoxin alpha (LT) genes. The TNF SNP is at position -308 in the promoter region (TNF-308), while the LT SNP is in the first intron NcoI recognition sequence (LT-NcoI). (For both SNPs the G allele is denoted as 1, and the A allele 2.) We determined TNF-308 and LT-NcoI genotypes in 511 individuals: 236 asthma cases and 275 non-asthmatic controls. Data were analysed by logistic regression of asthma status on the genotypes and potential confounders. TNF-308*2 was positively associated with asthma, and this relation was strengthened when restricting cases to individuals reporting acute asthma: the adjusted odds ratio (OR) comparing carriers of one or two TNF-308*2 alleles versus none was 1.86 (95% confidence interval (CI)=1.03-3.34, P=0.04). Further restricting the subjects to those with a family history of asthma, and those of European-American ancestry strengthened the association even more: adjusted OR=3.16 (95% CI=1.04-9.66; P=0.04). LT-NcoI*1 was weakly associated with asthma, and analysis of both genes suggests that only the TNF-308*2 allele increases risk of asthma.

European Journal of Human Genetics (2002) 10, 82-85 DOI: 10.1038/sj/ejhg/5200746

asthma; candidate gene; case-control study; genetics; tumour necrosis factor alpha; single nucleotide polymorphism