Published ahead of print on April 1, 2005, doi:10.1164/rccm.200412-1708OC
Am. J. Respir. Crit. Care Med., Volume 172, Number 1, July 2005, 55-60
A more recent version of this article appeared on July 1, 2005
Submitted on December 20, 2004
Accepted on March 30, 2005
Polymorphisms in A Disintegrin and Metalloprotease 33 Predict Impaired Early-Life Lung Function
Angela Simpson1*, Nikolas Maniatis2, Francine Jury3, Julie A Cakebread4, Lesley A Lowe1, Stephen T Holgate5, Ashley Woodcock1, William ER Ollier3, Andrew Collins2, Adnan Custovic1, John W Holloway4, and Sally L John3
1 North West Lung Centre and Academic Division of Medicine and Surgery South, University of Manchester and Wythenshawe Hospital, Manchester, United Kingdom,
2 Human Genetics Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, United Kingdom,
3 Centre for Integrated Genomic Medical Research (CIGMR), University of Manchester, Manchester, United Kingdom,
4 Infection, Inflammation and Repair Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, United Kingdom; Human Genetics Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, United Kingdom,
5 Infection, Inflammation and Repair Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, United Kingdom
* To whom correspondence should be addressed. E-mail: asimpson{at}fs1.with.man.ac.uk.
Rationale: Asthma commonly originates in early life in association with impaired lung function that 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 three (n=285) and five years (n=470) was assessed using plethysmographic measurement of specific airway resistance (sRaw). At age five we also measured FEV1. SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium (LD) mapping to identify the causal locus.
Main Results: Carriers of the rare allele of F+1 SNP had reduced lung function at age three years (p=0.003). When the recessive model was considered, four SNPs (F+1, S1, ST+5, V4) showed association with sRaw at age five years (p<0.04). Using LD 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 amongst 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: asthma, genetics, lung function, ADAM33
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