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Abstract:
Lung function measures are heritable, predict mortality and are relevant in diagnosis of chronic obstructive pulmonary
disease (COPD). COPD and asthma are diseases of the airways with major public health impacts and each have a heritable
component. Genome-wide association studies of SNPs have revealed novel genetic associations with both diseases but only
account for a small proportion of the heritability. Complex copy number variation may account for some of the missing
heritability. A well-characterised genomic region of complex copy number variation contains beta-defensin genes (DEFB103,
DEFB104 and DEFB4), which have a role in the innate immune response. Previous studies have implicated these and related
genes as being associated with asthma or COPD. We hypothesised that copy number variation of these genes may play a
role in lung function in the general population and in COPD and asthma risk. We undertook copy number typing of this
locus in 1149 adult and 689 children using a paralogue ratio test and investigated association with COPD, asthma and lung
function. Replication of findings was assessed in a larger independent sample of COPD cases and smoking controls. We
found evidence for an association of beta-defensin copy number with COPD in the adult cohort (OR = 1.4, 95%CI:1.02–1.92,
P = 0.039) but this finding, and findings from a previous study, were not replicated in a larger follow-up sample(OR = 0.89,
95%CI:0.72–1.07, P = 0.217). No robust evidence of association with asthma in children was observed. We found no evidence
for association between beta-defensin copy number and lung function in the general populations. Our findings suggest
that previous reports of association of beta-defensin copy number with COPD should be viewed with caution. Suboptimal
measurement of copy number can lead to spurious associations. Further beta-defensin copy number measurement in larger
sample sizes of COPD cases and children with asthma are needed.
