A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci.
A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci.
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DOI：
10.1371/journal.pgen.1000421
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发表时间：
2009-03
期刊：
影响因子：
4.5
通讯作者：
ICGN Investigators
中科院分区：
文献类型：
--
作者：
Pillai SG;Ge D;Zhu G;Kong X;Shianna KV;Need AC;Feng S;Hersh CP;Bakke P;Gulsvik A;Ruppert A;Lødrup Carlsen KC;Roses A;Anderson W;Rennard SI;Lomas DA;Silverman EK;Goldstein DB;ICGN Investigators
吸烟者患慢性阻塞性肺疾病(COPD)的易感性有相当大的差异。唯一已知的遗传风险因素是α-1抗胰蛋白酶严重缺乏，这存在于1-2%的慢性阻塞性肺疾病患者中。我们在挪威卑尔根的同质病例对照队列(823例COPD病例和810例吸烟对照)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遗传学网络(ICGN；来自606个家系的1891名高加索人)研究中排名前100的单核苷酸多态(SNPs)。在美国国家肺气肿治疗试验(NETT)的389名受试者和标准老龄化研究(NAS)的472名对照中，进一步评估了显示重复的多态，然后在来自波士顿早发性COPD人群的127个扩展家系的949人的第四个队列中进行了评估。采用调整协变量的Logistic回归模型对病例对照人群进行分析。在家庭人群中进行了基于家庭的关联分析，以诊断COPD和肺功能。在全基因组关联研究中，在α-烟碱型乙酰胆碱受体(CHRNA3/5)基因座上发现了两个SNP。在以ICGN家族为基础的分析和NETT病例对照分析中，它们具有明确的重复性，其组合p值分别为1.48×10−10(Rs8034191)和5.74×10−10(Rs1051730)。此外，在ICGN和波士顿早发性COPD人群中，这些SNP与肺功能显著相关。据估计，rs8034191 SNP的C等位基因具有12.2%的COPD人群归因风险。4号染色体上刺猬相互作用蛋白(HHIP)基因座的关联也被一致地复制，但没有达到全基因组显著水平。Framingham心脏研究(Wilk等人，本期《公共科学图书馆·遗传学》的配套文章；doi：10.1371/Joural.pgen.1000429)确认了HHIP基因座与肺功能在全基因组范围内的显著关联。CHRNA3/5和HHIP基因座对COPD的风险有显著贡献。CHRNA3/5是与肺癌风险有关的同一个基因座。吸烟者患慢性阻塞性肺疾病(COPD)的易感性有相当大的变异性，这是一种可遗传的多因素特征。确定COPD风险的遗传决定因素将具有巨大的公共卫生重要性。这项研究描述了首次在COPD中进行的全基因组关联研究。我们在一组来自挪威的同质病例对照队列中进行了GWAS研究，并评估了以家族为基础的国际COPD遗传学网络中排名前100位的单核苷酸多态。在美国国家肺气肿治疗试验的受试者和标准老龄化研究的对照组中，以及来自波士顿早发性COPD人群的第四个扩展家系队列中，进一步评估了显示重复的多态。15号染色体上α-烟碱型乙酰胆碱受体3/5基因座的两个多态表明与慢性阻塞性肺疾病有关。该基因座先前已被认为与吸烟行为和肺癌风险有关，提示该区域可能存在多种功能多态或单一多态，从而导致广泛的表型后果。与COPD相关的4号染色体上的HHIP基因座也是COPD的重要危险基因。
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. There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.
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影响因子：
120.7
作者：
Pearson, Thomas A.;Manolio, Teri A.
通讯作者：
Manolio, Teri A.
DOI：
10.1164/ajrccm.164.8.2105002
发表时间：
2001-10-15
影响因子：
24.7
作者：
McCloskey, SC;Patel, BD;Lomas, DA
通讯作者：
Lomas, DA
影响因子：
12.4
作者：
Carlsen, KCL;Håland, G;Carlsen, KH
通讯作者：
Carlsen, KH
影响因子：
3.5
作者：
Saccone, Scott F.;Hinrichs, Anthony L.;Bierut, Laura Jean
通讯作者：
Bierut, Laura Jean
DOI：
10.1164/ajrccm.153.2.8564146
发表时间：
1996-02-01
影响因子：
24.7
作者：
Hanrahan, JP;Sherman, CB;Mannino, DM
通讯作者：
Mannino, DM