A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.

吸烟者罹患慢性阻塞性肺疾病（chronic obstructive pulmonary disease, COPD）的易感性存在显著异质性。目前已知的唯一遗传风险因子为α1-抗胰蛋白酶（α1-antitrypsin）严重缺乏，该情况在COPD患者中占比1%~2%。本研究在来自挪威卑尔根的同质病例-对照队列（823例COPD病例与810例吸烟对照）中开展全基因组关联研究（genome-wide association study, GWAS），并在基于家系的国际COPD遗传网络（International COPD Genetics Network, ICGN；纳入来自606个家系的1891名高加索裔个体）研究中对排名前100的单核苷酸多态性（single nucleotide polymorphisms, SNPs）进行验证。对显示出复制效应的多态性，本研究进一步在美国全国肺气肿治疗试验（National Emphysema Treatment Trial, NETT）的389名受试者与正常衰老研究（Normative Aging Study, NAS）的472名对照中开展评估，随后在来自波士顿早发性COPD队列的127个扩展家系的949名个体组成的第四组队列中进行验证。针对病例-对照队列的分析采用校正协变量的逻辑回归模型；针对家系队列，则开展针对COPD诊断与肺功能的基于家系的关联分析。全基因组关联研究中，研究人员在烟碱型乙酰胆碱受体（nicotinic acetylcholine receptor, CHRNA 3/5）位点鉴定出两个SNPs。二者在ICGN基于家系的分析与NETT病例-对照分析中均得到明确验证，合并P值分别为1.48×10⁻¹⁰（rs8034191）与5.74×10⁻¹⁰（rs1051730）。此外，这两个SNPs在ICGN与波士顿早发性COPD队列中均与肺功能显著相关。经估算，rs8034191的C等位基因对应的COPD人群归因风险为12.2%。4号染色体上的刺猬相互作用蛋白（hedgehog interacting protein, HHIP）位点的关联也得到了一致性验证，但未达到全基因组显著性水平。弗雷明汉心脏研究（Wilk等，《PLoS遗传学》本期配套研究论文；doi:10.1371/journal.pgen.1000429）中已鉴定出HHIP位点与肺功能存在全基因组显著性关联。CHRNA 3/5与HHIP位点对COPD的发病风险具有显著贡献。CHRNA3/5同样是与肺癌风险相关的位点。