Department of Epidemiology, Johns Hopkins School of Public Health, 615 N. Wolfe Street, Baltimore, MD, 21205, USA.
Channing Division of Network Medicine Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Respir Res. 2019 Jul 19;20(1):160. doi: 10.1186/s12931-019-1097-8.
Emphysema, characterized by lung destruction, is a key component of Chronic Obstructive Pulmonary Disease (COPD) and is associated with increased morbidity and mortality. Genome-wide association studies (GWAS) have identified multiple genetic factors associated with cross-sectional measures of quantitative emphysema, but the genetic determinants of longitudinal change in quantitative measures of emphysema remain largely unknown. Our study aims to identify genetic variants associated with longitudinal change in quantitative emphysema measured by computed tomography (CT) imaging.
We included current and ex-smokers from two longitudinal cohorts: COPDGene, a study of Non-Hispanic Whites (NHW) and African Americans (AA), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). We calculated annual change in two quantitative measures of emphysema based on chest CT imaging: percent low attenuation area (≤ - 950HU) (%LAA-950) and adjusted lung density (ALD). We conducted GWAS, separately in 3030 NHW and 1158 AA from COPDGene and 1397 Whites from ECLIPSE. We further explored effects of 360 previously reported variants and a lung function based polygenic risk score on annual change in quantitative emphysema.
In the genome-wide association analysis, no variants achieved genome-wide significance (P < 5e-08). However, in the candidate region analysis, rs2076295 in the DSP gene, previously associated with COPD, lung function and idiopathic pulmonary fibrosis, was associated with change in %LAA-950 (β (SE) = 0.09 (0.02), P = 3.79e-05) and in ALD (β (SE) = - 0.06 (0.02), P = 2.88e-03). A lung function based polygenic risk score was associated with annual change in %LAA-950 (P = 4.03e-02) and with baseline measures of quantitative emphysema (P < 1e-03) and showed a trend toward association with annual change in ALD (P = 7.31e-02).
DSP variants may be associated with longitudinal change in quantitative emphysema. Additional investigation of the DSP gene are likely to provide further insights into the disease progression in emphysema and COPD.
Clinicaltrials.gov Identifier: NCT00608764 , NCT00292552 .
肺气肿以肺破坏为特征，是慢性阻塞性肺疾病（COPD）的一个关键组成部分，与发病率和死亡率的增加有关。全基因组关联研究（GWAS）已经确定了多个与定量肺气肿的横断面测量相关的遗传因素，但定量肺气肿纵向变化的遗传决定因素在很大程度上仍不清楚。我们的研究旨在确定与 CT 成像定量肺气肿纵向变化相关的遗传变异。
我们纳入了来自两个纵向队列的现吸烟者和前吸烟者：COPDGene，一项对非西班牙裔白人（NHW）和非裔美国人（AA）的研究，以及评估 COPD longitudinally 以确定预测替代终点（ECLIPSE）。我们根据胸部 CT 成像计算了两种定量肺气肿指标的年度变化：低衰减区百分比（≤-950HU）（%LAA-950）和调整后的肺密度（ALD）。我们在 COPDGene 中对 3030 名 NHW 和 1158 名 AA 进行了全基因组关联研究，在 ECLIPSE 中对 1397 名白人进行了全基因组关联研究。我们进一步探讨了 360 个先前报道的变异和基于肺功能的多基因风险评分对定量肺气肿年度变化的影响。
在全基因组关联分析中，没有变异达到全基因组显著性（P<5e-08）。然而，在候选区域分析中，先前与 COPD、肺功能和特发性肺纤维化相关的 DSP 基因中的 rs2076295 与 %LAA-950 的变化相关（β（SE）=0.09（0.02），P=3.79e-05）和 ALD 的变化（β（SE）=-0.06（0.02），P=2.88e-03）。基于肺功能的多基因风险评分与 %LAA-950 的年度变化相关（P=4.03e-02），与定量肺气肿的基线测量值相关（P<1e-03），与 ALD 的年度变化呈趋势相关（P=7.31e-02）。
DSP 变异可能与定量肺气肿的纵向变化相关。对 DSP 基因的进一步研究可能会进一步深入了解肺气肿和 COPD 的疾病进展。
Clinicaltrials.gov 标识符：NCT00608764，NCT00292552。
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