Polymorphisms in a disintegrin and metalloprotease 33 (ADAM33) predict impaired early-life lung function.
BACKGROUND
Asthma commonly originates in early life in association with impaired lung function, which tracks to adulthood.


OBJECTIVE
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 FEV(1). SNPs were analyzed individually using logistic regression, followed by linkage disequilibrium mapping to identify the causal locus.


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 FEV(1) (F+1, M+1, T1, and T2; p < or = 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.
Simpson
Angela
A
North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK. asimpson@fs1.with.man.ac.uk
Maniatis
Nikolas
N
Jury
Francine
F
Cakebread
Julie A
JA
Lowe
Lesley A
LA
Holgate
Stephen T
ST
Woodcock
Ashley
A
Ollier
William E R
WE
Collins
Andrew
A
Custovic
Adnan
A
Holloway
John W
JW
John
Sally L
SL
D051722:ADAM Proteins; D001249:Asthma / Q000235:genetics* / Q000503:physiopathology; D002675:Child, Preschool; D015331:Cohort Studies; D019483:Disintegrins / Q000235:genetics*; D005260:Female; D005333:Fetus; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008666:Metalloendopeptidases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011247:Pregnancy; D011379:Prognosis; D011446:Prospective Studies; D012129:Respiratory Function Tests / Q000379:methods; D018709:Statistics, Nonparametric; D011795:Surveys and Questionnaires
D019483:Disintegrins; D051722:ADAM Proteins; C450441:ADAM33 protein, human; D008666:Metalloendopeptidases