特发性肺纤维化患者的罕见变异与生存情况
Rare variants and survival of patients with idiopathic pulmonary fibrosis.
作者信息
Alonso-Gonzalez Aitana, Jáspez David, Lorenzo-Salazar José M, Ma Shwu-Fan, Strickland Emma, Mychaleckyj Josyf, Kim John S, Huang Yong, Adegunsoye Ayodeji, Oldham Justin M, Steward Iain, Molyneaux Philip L, Maher Toby M, Wain Louise V, Allen Richard J, Jenkins R Gisli, Kropski Jonathan A, Yaspan Brian, Blackwell Timothy S, Zhang David, Garcia Christine Kim, Martinez Fernando J, Noth Imre, Flores Carlos
机构信息
Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Instituto de Investigación Sanitaria de Canarias, Santa Cruz de Tenerife, Spain.
Genomics Division, Instituto Tecnológico y de Energías Renovables, Santa Cruz de Tenerife, Spain.
出版信息
medRxiv. 2024 Oct 15:2024.10.12.24315151. doi: 10.1101/2024.10.12.24315151.
BACKGROUND
The clinical course of idiopathic pulmonary fibrosis (IPF) is highly variable and unpredictable, with multiple genetic variants influencing IPF outcomes. Notably, rare pathogenic variants in telomere-related genes are associated with poorer clinical outcomes in these patients. Here we assessed whether rare qualifying variants (QVs) in monogenic adult-onset pulmonary fibrosis (PF) genes are associated with IPF survival. Using polygenic risk scores (PRS), we also evaluated the influence of common IPF risk variants in individuals carrying these QVs.
METHODS
We identified QVs in telomere and non-telomere genes linked to monogenic PF forms using whole-genome sequences (WGS) from 888 Pulmonary Fibrosis Foundation Patient Registry (PFFPR) individuals. We also derived a PRS for IPF (PRS-IPF) from 19 previously published common sentinel IPF variants. Using regression models, we then examined the mutual relationships of QVs and PRS-IPF and their association with survival. Validation of results was sought in WGS from an independent IPF study (PROFILE, n=472), and results from the two cohorts were meta-analyzed.
RESULTS
Carriers of QVs in monogenic adult-onset PF genes, representing nearly 1 out of 6 IPF patients, were associated with lower PRS-IPF (Odds Ratio [OR]: 1.79; 95% Confidence Interval [CI]: 1.15-2.81; p=0.010) and shorter survival (Hazard Ratio [HR]: 1.53; 95% CI: 1.12-2.10; p=7.3×10). Notably, carriers of pathogenic variants at telomere genes showed the strongest association with survival (HR: 1.76; 95% CI: 1.13-2.76; p=0.013). The meta-analysis of the results showed a consistent direction of effect across both cohorts.
CONCLUSIONS
We revealed the opposite effects of QVs and PRS-IPF on IPF survival. Thus, a distinct IPF molecular subtype might be defined by QVs in monogenic adult-onset PF genes. Assessing the carrier status for QVs and modelling PRS-IPF promises to further contribute to predicting disease progression among IPF patients.
背景
特发性肺纤维化（IPF）的临床病程高度可变且不可预测，多种基因变异会影响IPF的预后。值得注意的是，端粒相关基因中的罕见致病变异与这些患者较差的临床预后相关。在此，我们评估单基因成年发病型肺纤维化（PF）基因中的罕见合格变异（QV）是否与IPF患者的生存相关。我们还使用多基因风险评分（PRS）评估了携带这些QV的个体中常见IPF风险变异的影响。
方法
我们使用来自888名肺纤维化基金会患者登记处（PFFPR）个体的全基因组序列（WGS），鉴定了与单基因PF形式相关的端粒和非端粒基因中的QV。我们还从19个先前发表的常见哨兵IPF变异中得出了IPF的PRS（PRS-IPF）。然后，我们使用回归模型研究了QV与PRS-IPF之间的相互关系及其与生存的关联。在一项独立的IPF研究（PROFILE，n = 472）的WGS中寻求结果验证，并对两个队列的结果进行荟萃分析。
结果
单基因成年发病型PF基因中QV的携带者（约占6名IPF患者中的1名）与较低的PRS-IPF相关（优势比[OR]：1.79；95%置信区间[CI]：1.15 - 2.81；p = 0.010）且生存期较短（风险比[HR]：1.53；95% CI：1.12 - 2.10；p = 7.3×10）。值得注意的是，端粒基因致病变异的携带者与生存的关联最强（HR：1.76；95% CI：1.13 - 2.76；p = 0.013）。结果的荟萃分析表明两个队列的效应方向一致。
结论
我们揭示了QV和PRS-IPF对IPF生存的相反影响。因此，单基因成年发病型PF基因中的QV可能定义了一种独特的IPF分子亚型。评估QV的携带者状态并构建PRS-IPF模型有望进一步有助于预测IPF患者的疾病进展。
Zotero 插件