Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis
Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis
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DOI：
10.1164/rccm.201903-0511oc
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发表时间：
2019-12-01
影响因子：
24.7
通讯作者：
Viviano, Lisa
中科院分区：
文献类型：
--
作者：
Hobbs, Brian D.;Putman, Rachel K.;Viviano, Lisa
理由：间质性肺异常（ILAs）与特发性肺纤维化（IPF）的最高遗传风险位点相关；然而，ILAs个体之间的独特关联程度或与IPF的额外重叠程度尚不清楚。目的：进行ila全基因组关联研究（GWAS）。方法：在AGES（年龄基因/环境易感性）、COPDGene（慢性阻塞性肺疾病[COPD]的遗传流行病学）、Framingham Heart、ECLIPSE （COPD纵向评估以确定预测替代终点）、MESA（动脉粥样硬化多民族研究）和SPIROMICS （COPD研究的亚群和中间结果测量）研究中，通过胸部计算机断层扫描（CT）评估ILAs和胸膜下显性亚型。我们对每个队列的ILAs进行了GWAS，并使用荟萃分析合并结果。我们评估了IPF独立GWASs的重叠关联。测量结果和主要结果：获得了1699名ILAs患者和10274名对照组的全基因组基因分型数据。MUC5B（粘蛋白5B）启动子变异rs35705950与ILAs （P = 2.6x10(-27)）和胸膜下ILAs （P = 1.6x10(-29)）均显著相关。我们发现IPO11 （rs6886640, P = 3.8x10(-8)）和FCF1P3 （rs73199442, P = 4.8x10(-8)）附近与ILAs以及HTRE1 （rs7744971, P = 4.2x10(-8)）附近与胸膜下主要ILAs存在新的全基因组关联。这些新的关联与IPF无关。在先前报道的12个IPFGWAS基因座中，有5个（DPP9、DSP、FAM13A、IVD和MUC5B）与ILAs显著相关（P < 0.05/12）。结论：在六项研究的ILAs的GWAS中，我们证实了与MUC5B启动子变异的关联，并发现了先前描述的IPF位点的作用的有力证据；然而，新的ILA关联与IPF无关。这些发现强调了ILAs和IPF之间共同的遗传驱动的生物学途径，也提出了不同的途径。
Rationale: Interstitial lung abnormalities (ILAs) are associated with the highest genetic risk locus for idiopathic pulmonary fibrosis (IPF); however, the extent to which there are unique associations among individuals with ILAs or additional overlap with IPF is not known.Objectives: To perform a genome-wide association study (GWAS) of ILAs.Methods: ILAs and a subpleural-predominant subtype were assessed on chest computed tomography (CT) scans in the AGES (Age Gene/Environment Susceptibility), COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]), Framingham Heart, ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points), MESA (Multi-Ethnic Study of Atherosclerosis), and SPIROMICS (Subpopulations and Intermediate Outcome Measures in COPD Study) studies. We performed a GWAS of ILAs in each cohort and combined the results using a meta-analysis. We assessed for overlapping associations in independent GWASs of IPF.Measurements and Main Results: Genome-wide genotyping data were available for 1,699 individuals with ILAs and 10,274 control subjects. The MUC5B (mucin 5B) promoter variant rs35705950 was significantly associated with both ILAs (P = 2.6x10(-27)) and subpleural ILAs (P = 1.6x10(-29)). We discovered novel genome-wide associations near IPO11 (rs6886640, P = 3.8x10(-8)) and FCF1P3 (rs73199442, P = 4.8x10(-8)) with ILAs, and near HTRE1 (rs7744971, P = 4.2x10(-8)) with subpleural-predominant ILAs. These novel associations were not associated with IPF. Among 12 previously reported IPFGWAS loci, five (DPP9, DSP, FAM13A, IVD, and MUC5B) were significantly associated (P < 0.05/12) with ILAs.Conclusions: In a GWAS of ILAs in six studies, we confirmed the association with a MUC5B promoter variant and found strong evidence for an effect of previously described IPF loci; however, novel ILA associations were not associated with IPF. These findings highlight common genetically driven biologic pathways between ILAs and IPF, and also suggest distinct ones.