Smolonska Joanna, Koppelman Gerard H, Wijmenga Cisca, Vonk Judith M, Zanen Pieter, Bruinenberg Marcel, Curjuric Ivan, Imboden Medea, Thun Gian-Andri, Franke Lude, Probst-Hensch Nicole M, Nürnberg Peter, Riemersma Roland A, van Schayck Constant P, Loth Daan W, Brusselle Guy G, Stricker Bruno H, Hofman Albert, Uitterlinden André G, Lahousse Lies, London Stephanie J, Loehr Laura R, Manichaikul Ani, Barr R Graham, Donohue Kathleen M, Rich Stephen S, Pare Peter, Bossé Yohan, Hao Ke, van den Berge Maarten, Groen Harry J M, Lammers Jan-Willem J, Mali Willem, Boezen H Marike, Postma Dirkje S
Dept of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands Dept of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands.
GRIAC Research Institute, Groningen University Medical Center, University of Groningen, Groningen, The Netherlands Dept of Paediatric Pulmonology and Paediatric Allergology, Beatrix Children's Hospital, University Medical Center, University of Groningen, Groningen, The Netherlands.
Eur Respir J. 2014 Oct;44(4):860-72. doi: 10.1183/09031936.00001914. Epub 2014 Jul 3.
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.
哮喘和慢性阻塞性肺疾病（COPD）被认为具有共同的遗传背景（“荷兰假说”）。我们研究了哮喘和COPD是否具有共同的潜在遗传因素，对哮喘和COPD都进行了全基因组关联研究，并将结果合并进行荟萃分析。三个基因座显示可能与这两种疾病都有关：2号染色体p24.3区域、5号染色体q23.1区域和13号染色体q14.2区域，分别包含DDX1、COMMD10（两者均参与核因子（NF）κβ途径）和GNG5P5。在首次复制阶段后，GNG5P5中的单核苷酸多态性（SNP）rs9534578达到全基因组显著性水平（p = 9.96×10⁻⁹）。在七个独立队列中进行的第二次复制阶段研究未提供显著的重复验证结果。对前20个相关SNP在血细胞和肺组织中进行表达数量性状基因座（eQTL）分析，发现COMMD10中有两个SNP影响基因表达。哮喘和COPD中的炎症过程不同，且由NF-κβ介导，这可能由相同的潜在基因COMMD10和DDX1驱动。没有一个SNP达到全基因组显著性水平。我们的eQTL研究支持两个COMMD10 SNP具有功能作用，因为它们在血细胞和肺组织中均影响基因表达。我们的研究结果表明，哮喘和COPD要么没有共同的遗传成分，要么是不同的环境因素，例如不同国家和大陆的生活方式和职业，可能掩盖了遗传上的共同作用。
