Genome-Wide Association Studies in Idiopathic Pulmonary Fibrosis: Bridging the Gap between Sequence and Consequence.
Genome-Wide Association Studies in Idiopathic Pulmonary Fibrosis: Bridging the Gap between Sequence and Consequence.
复制标题
特发性肺纤维化的全基因组关联研究：弥合序列和后果之间的差距。
DOI：
10.1164/rccm.201911-2286ed
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发表时间：
2020
影响因子：
24.7
通讯作者：
Kropski,JonathanA
中科院分区：
文献类型：
--
作者：
Spagnolo,Paolo;Kropski,JonathanA
全基因组关联研究（GWASs）的发展旨在提高我们对疾病生物学的理解，并通过鉴定受影响个体基因组中与疾病或感兴趣的性状相关的序列变异来发现新的治疗靶点(1)。自2005年以来，GWASs已经确定了数千个与数百种复杂疾病相关的基因座（即由多个基因的变异决定的疾病，通常与环境因素相互作用，每个基因的影响不同，但相对较小）。然而，与早期的预期相反，GWAS将识别功能性（即蛋白质破坏）变异，90%与疾病风险相关的GWAS位点位于基因组的非编码区域。许多与疾病相关的风险变异的功能仍然难以捉摸，尽管一般认为这些变异发挥顺式或跨式调节作用。显然，需要快速、高通量的方法来定义这些调节变异的功能，以加速将这些遗传发现转化为与疾病相关的生物学理解。特发性肺纤维化（IPF）是一种慢性、进行性、几乎总是致命的间质性肺疾病（ILD），原因不明，主要发生在老年人(2)。虽然IPF中纤维化的机制尚不完全清楚，但该疾病被认为是由重复微损伤后肺泡上皮的异常修复引起的，吸烟、病毒感染、环境污染物和慢性胃内容物微吸入是纤维化反应的可能诱发因素(3)。肌成纤维细胞（表达成纤维细胞和平滑肌细胞特征的细胞）过度的无对抗细胞外基质合成会导致肺进行性瘢痕形成、实质扭曲和不可逆的功能丧失(4)。遗传因素在家族性和散发性IPF病例中的作用越来越受到重视(5)。具体来说，家族性研究已经确定了与端粒生物学和表面活性剂产生相关的基因的关联，而零星病例的GWASs，包括相关位点的高分辨率重测序(6)，已经报道了与含有肺防御、端粒维持和细胞-细胞粘附相关基因的位点的关联(7)。然而，据估计，这些遗传异常仅占IPF遗传风险的30%，而它们促进疾病发展的分子机制在很大程度上是未知的(8)。在这一期的期刊上，Allen和他的同事（第564-574页）报道了一项迄今为止最大的IPF易感性GWAS的合作研究结果(9)。研究人群包括所有被招募到任何先前报道的IPF GWAS（10-12）的欧洲血统的患者和对照受试者（即2668名IPF患者和8591名对照受试者）。作者对这些GWASs（发现队列）的结果进行了荟萃分析。两个独立的病例/对照数据集被纳入复制队列（1467例IPF患者和11874例对照受试者）。该研究证实了先前报道的11个位点的相关性，条件分析证实11p15位点的风险是由MUC5B启动子变异驱动的。3p21中KIF15附近的三个新的关联信号。31), MAD1L1 （in 7p22）。3)和detor （DEP结构域含mtor相互作用蛋白）(在8q24。12)也被识别出来，并且在调整多重性后仍然显著，并且在所有的发现和复制数据集中被复制。用三…
Genome-wide association studies (GWASs) have been developed with the aim of improving our understanding of disease biology and discovering novel therapeutic targets through the identification of sequence variants associated with the disease or trait of interest across the genome of affected individuals (1). Since 2005, GWASs have identified several thousands of loci associated with hundreds of complex diseases (ie, those determined by variations across multiple genes, often interacting with environmental factors, and each contributing an effect of varying yet relatively modest magnitude). However, contrary to early expectations that GWASs would identify functional (ie, proteindisrupting) variants, z90% of GWAS loci linked to disease risk lie in noncoding regions of the genome. The functions of many such diseaseassociated risk variants have remained elusive, although it is generally presumed that these variants play cis-or trans-regulatory roles. Rapid, high-throughput approaches for defining the function of such regulatory variants are clearly needed to accelerate the translation of these genetic discoveries to disease-relevant biological understanding. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and almost invariably fatal interstitial lung disease (ILD) of unknown origin that occurs primarily in older adults (2). Although the mechanisms of fibrosis in IPF remain incompletely understood, the disease is believed to result from aberrant repair of the alveolar epithelium after repetitive microinjuries, with smoking, viral infection, environmental pollutants, and chronic microaspiration of gastric content representing plausible putative triggers of the fibrotic response (3). Excessive unopposed extracellular matrix synthesis by myofibroblasts—cells that express features of both fibroblasts and smooth muscle cells—leads to progressive scarring of the lung, parenchymal distortion, and irreversible loss of function (4). The role of genetic factors in both familial and sporadic cases of IPF is increasingly appreciated (5). Specifically, familial studies have identified associations with genes related to telomere biology and surfactant production, whereas GWASs of sporadic cases, including high-resolution resequencing of implicated loci (6), have reported associations with loci containing genes related to lung defense, telomere maintenance, and cell–cell adhesion (7). However, these genetic abnormalities have been estimated to account for only z30% of the genetic risk of IPF, and the molecular mechanisms through which they promote disease development are largely unknown (8). In this issue of the Journal, Allen and colleagues (pp. 564–574) report findings from a collaborative effort to perform the largest GWAS of IPF susceptibility to date (9). The study population included all patients and control subjects of European ancestry who had been recruited to any previously reported IPF GWAS (10–12)(ie, 2,668 patients with IPF and 8,591 control subjects). The authors conducted a meta-analysis of the results of these GWASs (the discovery cohort). Two independent case/control datasets were included as a replication cohort (1,467 patients with IPF and 11,874 control subjects). The study confirmed associations at 11 previously reported loci, and conditional analyses confirmed that risk at the 11p15 locus is driven by the MUC5B promoter variant. Three novel association signals near KIF15 (in 3p21. 31), MAD1L1 (in 7p22. 3), and DEPTOR (DEP domain-containing mTOR-interacting protein)(in 8q24. 12) were also identified and remained significant after adjustment for multiplicity, and were replicated in all of the discovery and replication datasets. Using three …