Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease
Genome-wide linkage analysis of bronchodilator responsiveness and post-bronchodilator spirometric phenotypes in chronic obstructive pulmonary disease
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DOI：
10.1093/hmg/ddg125
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发表时间：
2003-05-15
影响因子：
3.5
通讯作者：
Silverman, EK
中科院分区：
文献类型：
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作者：
Palmer, LJ;Celedón, JC;Silverman, EK
慢性阻塞性肺病（COPD）是一种常见、复杂的疾病，其发病率和死亡率显着且不断增加。COPD的主要特征是持续性气流阻塞，通过定量肺量测定指标的减少来测量，包括一秒用力呼气量（FEV 1）和FEV 1与用力肺活量（FEV 1/FVC）的比值。然而，许多患者在吸入支气管扩张剂药物后肺量测定指标有实质性改善，支气管扩张剂反应性（BDR）与疾病严重程度和进展相关。为了确定BDR表型的易感基因座，我们对72个家系（n = 560名成员）进行了9 cM的基因组扫描，这些家系通过患有严重早发性COPD的先证者确定。对定量表型进行多点方差分量连锁分析，包括BDR指标和使用支气管扩张剂后FEV 1和FEV 1/FVC。使用支气管扩张剂后的FEV 1与多个区域相关，最显著的是与染色体8 p（LOD = 3.30）和1 q（LOD = 2.24）上的标记物相关。使用支气管扩张剂后的FEV 1/FVC也与多个区域相关，最显著的是与染色体2 q（LOD = 4.42）和1 q（LOD = 2.52）上的标记物相关。当与使用支气管扩张剂前的肺量测定指数相比时，使用支气管扩张剂后的数值显示多个基因组区域中的连锁证据增加。特别是，8 p与FEV 1连锁的LOD评分从1.58增加到3.30。染色体4p（LOD = 1.28）、4 q（LOD = 1.56）和3q（LOD = 1.50）上的候选区域给出了与BDR措施连锁的最强证据。我们的研究结果为染色体2 q和8 p上气流阻塞易感基因位点的显著连锁提供了证据，并进一步表明支气管扩张剂后肺量测定是COPD遗传学研究的最佳表型。这项研究还确定了几个基因组区域，可能含有基因座调控BDR早发性COPD家庭。
Chronic obstructive pulmonary disease (COPD) is a common, complex disease associated with significant and increasing morbidity and mortality. The cardinal feature of COPD is persistent airflow obstruction, measured by reductions in quantitative spirometric indices including forced expiratory volume at one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC). However, many patients have substantial improvement in spirometric measures with inhaled bronchodilator medications, and bronchodilator responsiveness (BDR) has been associated with disease severity and progression. To identify susceptibility loci for BDR phenotypes, we performed a 9 cM genome scan in 72 pedigrees (n = 560 members) ascertained through probands with severe, early-onset COPD. Multipoint variance component linkage analysis was performed for quantitative phenotypes including BDR measures and post-bronchodilator FEV1 and FEV1/FVC. Post-bronchodilator FEV1 was linked to multiple regions, most significantly to markers on chromosome 8p (LOD = 3.30) and 1q (LOD = 2.24). Post-bronchodilator FEV1/FVC was also linked to multiple regions, most significantly to markers on chromosome 2q (LOD = 4.42) and 1q (LOD = 2.52). When compared with pre-bronchodilator spirometric indices, the post-bronchodilator values demonstrated increased evidence of linkage in multiple genomic regions. In particular, the LOD score for the 8p linkage to FEV1 roughly doubled from 1.58 to 3.30. Candidate regions on chromosomes 4p (LOD = 1.28), 4q (LOD = 1.56), and 3q (LOD = 1.50) gave the strongest evidence for linkage to BDR measures. Our results provide evidence for significant linkage to airflow obstruction susceptibility loci on chromosomes 2q and 8p, and further suggest that post-bronchodilator spirometric measures are optimal phenotypes for COPD genetic studies. This study has also identified several genomic regions that could contain loci regulating BDR in early-onset COPD families.