社区获得性肺炎成人全基因组关联研究。

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-16 DOI:10.1186/s12931-024-03009-4
Eva Suarez-Pajes, Itahisa Marcelino-Rodriguez, Elisa Hernández Brito, Silvia Gonzalez-Barbuzano, Melody Ramirez-Falcon, Eva Tosco-Herrera, Luis A Rubio-Rodríguez, María Luisa Briones, Olga Rajas, Luis Borderías, Jose Ferreres, Antoni Payeras, Leonardo Lorente, Javier Aspa, Jose M Lorenzo Salazar, José Manuel Valencia-Gallardo, Nieves Carbonell, Jorge L Freixinet, Felipe Rodríguez de Castro, Jordi Solé Violán, Carlos Flores, Carlos Rodríguez-Gallego
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引用次数: 0

摘要

背景:社区获得性肺炎(CAP)的发病率和住院率都很高。在传染病中,宿主遗传学在易感性和免疫反应中起着关键作用,所涉及的免疫途径高度依赖于微生物及其感染途径。在此,我们旨在通过病例对照全基因组关联研究(GWAS)确定 CAP 的遗传风险位点:我们对 3,765 名西班牙人进行了 GWAS 研究,其中包括 257 名住院治疗的 CAP 成年患者和 3,508 名人群对照。有 30% 的患者被证实患有肺炎球菌性 CAP,其余 70% 的患者是在微生物病因不明的患者中挑选出来的。我们使用逻辑回归法测试了 760 万个估算基因型。英国生物库细菌性肺炎 GWAS 用于结果验证。随后,我们根据贝叶斯精细图谱和功能证据对基因和可能的因果变异进行了优先排序。我们还对经典的HLA等位基因和氨基酸进行了推算和关联分析:六个独立的哨点变异达到了全基因组显著性(p -8),其中三个位于染色体 6p21.32,4q28.2、11p12 和 20q11.22 各一个。只有 6p21.32 上的一个变异在细菌性肺炎和肺炎球菌性肺炎的独立 GWAS 中得到了验证。我们的分析优先考虑了 4q28.2 上的 C4orf33、6p21.32 上的 TAPBP 和 20q11.22 上的 ZNF341。有趣的是,TAPBP 和 ZNF341 的遗传缺陷是以前已知的易患细菌性肺炎(包括肺炎球菌和流感嗜血杆菌)的先天性免疫错误。经典的 HLA 等位基因的相关性均不显著:我们完成了一项关于 CAP 的基因组学分析,发现了四个与 CAP 易感性有关的新风险位点。
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A genome-wide association study of adults with community-acquired pneumonia.

Background: Community-acquired pneumonia (CAP) is associated with high morbidity and hospitalization rate. In infectious diseases, host genetics plays a critical role in susceptibility and immune response, and the immune pathways involved are highly dependent on the microorganism and its route of infection. Here we aimed to identify genetic risk loci for CAP using a case-control genome-wide association study (GWAS).

Methods: We performed a GWAS on 3,765 Spanish individuals, including 257 adult patients hospitalized with CAP and 3,508 population controls. Pneumococcal CAP was documented in 30% of patients; the remaining 70% were selected among patients with unidentified microbiological etiology. We tested 7,6 million imputed genotypes using logistic regressions. UK Biobank GWAS of bacterial pneumonia were used for results validation. Subsequently, we prioritized genes and likely causal variants based on Bayesian fine mapping and functional evidence. Imputation and association of classical HLA alleles and amino acids were also conducted.

Results: Six independent sentinel variants reached the genome-wide significance (p < 5 × 10-8), three on chromosome 6p21.32, and one for each of the chromosomes 4q28.2, 11p12, and 20q11.22. Only one variant at 6p21.32 was validated in independent GWAS of bacterial and pneumococcal pneumonia. Our analyses prioritized C4orf33 on 4q28.2, TAPBP on 6p21.32, and ZNF341 on 20q11.22. Interestingly, genetic defects of TAPBP and ZNF341 are previously known inborn errors of immunity predisposing to bacterial pneumonia, including pneumococcus and Haemophilus influenzae. Associations were all non-significant for the classical HLA alleles.

Conclusions: We completed a GWAS of CAP and identified four novel risk loci involved in CAP susceptibility.

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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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