Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease
Genomewide linkage analysis of quantitative spirometric phenotypes in severe early-onset chronic obstructive pulmonary disease
复制标题
DOI：
10.1086/340316
复制
发表时间：
2002-05-01
影响因子：
9.8
通讯作者：
Weiss, ST
中科院分区：
文献类型：
--
作者：
Silverman, EK;Palmer, LJ;Weiss, ST
慢性阻塞性肺疾病（COPD）是一种常见、复杂的疾病，发病率和死亡率很高。 COPD 的定义是不可逆的气流阻塞；气流阻塞通常通过定量肺活量指数的降低来确定，包括 1 秒用力呼气量 (FEV1) 以及 FEV1 与用力肺活量 (FVC) 的比率。为了确定定量肺活量表型的遗传决定因素，对 72 个家系（585 名个体）进行了短串联重复 (STR) 多态性标记的常染色体 10-cM 全基因组扫描，通过患有严重早发性 COPD 的先证者进行了确定。对定量表型（包括 FEV1、FVC 和 FEV1/FVC）进行多点方差分量连锁分析（使用 SOLAR）。在最初的全基因组扫描中，在染色体 2q 上证明了与 FEV1/FVC 关联的重要证据（222 cM 处的 LOD 评分为 4.12）。发现了与 1 号染色体（120 cM 处 LOD 得分 1.92）和 17 号染色体（67 cM 处 LOD 得分 2.03）上的 FEV1/FVC 以及 1 号染色体上的 FEV1/FVC（13 cM 处 LOD 得分 2.05）相关的暗示性证据。在初始全基因组扫描中，FEV1 的最高 LOD 得分为 1.53，位于 12 号染色体上，位于 36 cM。在染色体 12p 上添加 12 个额外的 STR 标记（之前已在该群体中进行过基因分型）后，证明了 FEV1（37 cM 时 LOD 评分为 2.43）与该区域连锁的暗示性证据。这些观察结果既提供了 2 号染色体上早发型 COPD 易感位点的重要证据，也提供了肺活量测定相关表型与其他几个基因组区域的联系的提示性证据。 FEV1/FVC 与染色体 2q 的显着关联可能反映了影响气流阻塞或呼吸障碍发生的一个或多个基因。
Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with substantial morbidity and mortality. COPD is defined by irreversible airflow obstruction; airflow obstruction is typically determined by reductions in quantitative spirometric indices, including forced expiratory volume at 1 s (FEV1) and the ratio of FEV1 to forced vital capacity (FVC). To identify genetic determinants of quantitative spirometric phenotypes, an autosomal 10-cM genomewide scan of short tandem repeat (STR) polymorphic markers was performed in 72 pedigrees (585 individuals) ascertained through probands with severe early-onset COPD. Multipoint variance-component linkage analysis (using SOLAR) was performed for quantitative phenotypes, including FEV1, FVC, and FEV1/FVC. In the initial genomewide scan, significant evidence for linkage to FEV1/FVC was demonstrated on chromosome 2q (LOD score 4.12 at 222 cM). Suggestive evidence was found for linkage to FEV1/FVC on chromosomes 1 (LOD score 1.92 at 120 cM) and 17 (LOD score 2.03 at 67 cM) and to FVC on chromosome 1 (LOD score 2.05 at 13 cM). The highest LOD score for FEV1 in the initial genomewide scan was 1.53, on chromosome 12, at 36 cM. After inclusion of 12 additional STR markers on chromosome 12p, which had been previously genotyped in this population, suggestive evidence for linkage of FEV1 (LOD score 2.43 at 37 cM) to this region was demonstrated. These observations provide both significant evidence for an early-onset COPD-susceptibility locus on chromosome 2 and suggestive evidence for linkage of spirometry-related phenotypes to several other genomic regions. The significant linkage of FEV1/FVC to chromosome 2q could reflect one or more genes influencing the development of airflow obstruction or dysanapsis.