Copy number variation of the beta-defensin genes in Europeans : no supporting evidence for association with lung function, chronic obstructive pulmonary disease or asthma
posted on 2014-03-20, 11:32authored byLouise V. Wain, Linda Odenthal-Hesse, Razan Abujaber, Ian Sayers, Caroline Beardsmore, Erol A. Gaillard, Sally Chappell, Cristian M. Dogaru, Tricia McKeever, Tamar Guetta-Baranes, Noor Kalsheker, Claudia E. Kuehni, Ian P. Hall, Martin D. Tobin, Edward J. Hollox
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.
Funding
DNA extraction from LRC samples and PRT DEFB genotyping of LRC and Gedling samples was funded by a Higher Education Innovation Fund (HEIF) funded Impact Award to Louise V. Wain. The Nottingham Gedling cohort collection was funded by Asthma UK and the British Lung Foundation. Leicester Respiratory Cohort (LRC) was funded by Swiss National Science Foundation grant 3200B0-122341 and Asthma UK grant 07/048. Martin D. Tobin holds a Medical Research Council Senior Clinical Fellowship (G0902313). The research was part-funded by the National Institute for Health Research (NIHR). Ian Hall and Ian Sayers hold a Medical Research Council programme grant (G1000861).
History
Citation
PLoS ONE, 2014, 9 (1), e84192
Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Genetics