Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene
Multistudy Fine Mapping of Chromosome 2q Identifies XRCC5 as a Chronic Obstructive Pulmonary Disease Susceptibility Gene
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DOI：
10.1164/rccm.200910-1586oc
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发表时间：
2010-09-01
影响因子：
24.7
通讯作者：
Silverman, Edwin K.
中科院分区：
文献类型：
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作者：
Hersh, Craig P.;Pillai, Sreekumar G.;Silverman, Edwin K.
基本原理：一些以家族为基础的研究已经确定了肺功能和气流阻塞与染色体2 q的遗传连锁。目的：我们假设合并四个独立人群的高分辨率单核苷酸多态性（SNP）作图结果将导致染色体2 q上慢性阻塞性肺疾病（COPD）易感基因的鉴定。在染色体2 q连锁区域内，在来自挪威的806例COPD病例和779例对照受试者中对2，843个SNP进行了基因分型，在来自国家肺气肿治疗试验的309例重度COPD患者和330例社区对照受试者中对2，484个SNP进行了基因分型。对来自国际COPD遗传学网络（ICGN）的603个家庭的1，839名个体以及波士顿早发性COPD研究中来自127个家庭的949名个体进行了随访，发现两项病例对照研究的综合结果存在显着关联。测量和主要结果：合并两个病例对照分析的结果，790个重叠SNP中有14个具有组合P < 0.01。这14个SNP中的两个与ICGN家族中的COPD一致相关。在波士顿早发性COPD研究中，与位于基因XRCC 5中的一个SNP的关联被复制，在四项研究中的组合P = 2.51 x 10（-5），当调整多重检验时仍然显著（P = 0.02）。基因型插补证实了与XRCC 5中SNP的关联。结论：通过结合在四个独立的患者样本中进行的COPD遗传关联研究的数据，我们确定了XRCC 5，一种ATP依赖性DNA解旋酶，作为一个潜在的COPD易感基因。
Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 x 10(-5) across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5. Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.