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首页> 外文期刊>PLoS Genetics >A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci
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A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci

机译：慢性阻塞性肺疾病（COPD）的全基因组关联研究：鉴定两个主要的易感基因座

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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.
机译：吸烟者患慢性阻塞性肺疾病（COPD）的敏感性差异很大。唯一已知的遗传风险因素是α1-抗胰蛋白酶的严重缺乏，在COPD患者中有1-2％存在α1-抗胰蛋白酶。我们在来自挪威卑尔根的同质病例对照队列（823个COPD病例和810个吸烟对照）中进行了全基因组关联研究（GWAS），并评估了基于家族的国际COPD遗传学中排名前100位的单核苷酸多态性（SNP）网络（ICGN;来自606家谱的1891位白人）研究。来自美国国家肺气肿治疗试验（NETT）的389名受试者和来自规范老化研究（NAS）的472名对照进一步评估了显示复制的多态性，然后从波士顿早期的127个扩展谱系的949名患者的第四组中进行了评估发病的COPD人群。调整协变量的逻辑回归模型用于分析病例对照人群。进行了基于家庭的关联分析，以诊断家庭人群中的COPD和肺功能。在全基因组关联研究中，确定了α-烟碱型乙酰胆碱受体（CHRNA 3/5）位点的两个SNP。他们在基于ICGN家族的分析和NETT病例对照分析中显示出明确的重复性，其组合p值分别为1.48×10？10，（rs8034191）和5.74×10？10（rs1051730）。此外，在ICGN和波士顿早发COPD人群中，这些SNP与肺功能显着相关。估计rs8034191 SNP的C等位基因的COPD归因于人群的风险为12.2％。刺猬相互作用蛋白（HHIP）基因座在第4号染色体上的协会也被一致地复制，但没有达到全基因组的显着性水平。在Framingham心脏研究中确定了HHIP基因座与肺功能在全基因组范围内的显着相关性（Wilk等人，本期《公共科学图书馆遗传学》（PLoS Genetics）的同伴文章; doi：10.1371 / journal.pgen.1000429）。 CHRNA 3/5和HHIP基因座对COPD的风险有重大贡献。 CHRNA3 / 5是与肺癌风险有关的同一基因座。

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