Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis.

Smolonska J1, Koppelman GH2, Wijmenga C3, Vonk JM4, Zanen P5, Bruinenberg M3, Curjuric I6, Imboden M6, Thun GA6, Franke L3, Probst-Hensch NM6,Nürnberg P7, Riemersma RA8, van Schayck CP9, Loth DW10, Brusselle GG11, Stricker BH12, Hofman A13, Uitterlinden AG14, Lahousse L15, London SJ16, Loehr LR17, Manichaikul A18, Barr RG19, Donohue KM19, Rich SS20, Pare P21, Bossé Y22, Hao K23, van den Berge M8, Groen HJ24, Lammers JW5, Mali W25, Boezen HM4, Postma DS26.

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Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background ("Dutch hypothesis"). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) κβ pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p = 9.96×10-9). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-κβ, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution.