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Polymorphisms in A Disintegrin and Metalloprotease 33 (ADAM33) Predict Impaired Early-Life Lung Function

Academic Division of Medicine and Surgery South, and Centre for Integrated Genomic Medical Research, University of Manchester, Manchester; Infection, Inflammation, and Repair, and Human Genetics Divisions, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, United Kingdom

Correspondence and requests for reprints should be addressed to Angela Simpson, M.D., North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK. E-mail: asimpson{at}fs1.with.man.ac.uk

Rationale: Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood. Objectives: Within the context of a prospective birth cohort study, we investigated the association between single nucleotide polymorphisms (SNPs) in a disintegrin and metalloprotease 33 (ADAM33) gene and early-life lung function. Methods: Children were genotyped for 17 SNPs in ADAM33. Lung function at age 3 (n = 285) and 5 years (n = 470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age 5, we also measured FEV₁. SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus. Main Results: Carriers of the rare allele of F+1 SNP had reduced lung function at age 3 years (p = 0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age 5 years (p < 0.04). Using linkage disequilibrium mapping, we found evidence of a significant causal location between BC+1 and F1 SNPs, at the 5' end of the gene. Four SNPs were associated with lower FEV₁ (F+1, M+1, T1, and T2; p 0.04). The risk of transient early wheezing more than doubled among children homozygous for the A allele of F+1 (odds ratio, 2.39; 95% confidence intervals, 1.18–4.86; p = 0.02), but there was no association between any SNP and allergic sensitization or physician-diagnosed asthma. Conclusions: Polymorphisms in ADAM33 predict impaired early-life lung function. The functionally relevant polymorphism is likely to be at the 5' end of the gene.

Key Words: ADAM33 • asthma • genetics • lung function

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