Boxi Lin, Jiafen Gong, Katherine Keenan, Fan Lin, Yu-Chung Lin, Julie Mésinèle, Claire Calmel, Badreddine Mohand Oumoussa, Pierre-Yves Boëlle, Loïc Guillot, Harriet Corvol, Valerie Waters, Lei Sun, Lisa J Strug
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Our objective is to advance understanding of the genetic basis of host susceptibility to <i>P. aeruginosa</i> infection.</p><p><strong>Materials and methods: </strong>We conducted a genome-wide association study of chronic <i>P. aeruginosa</i> infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic <i>P. aeruginosa</i> infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis.</p><p><strong>Results: </strong>Two novel genome-wide significant loci with lead single nucleotide polymorphisms (SNPs) rs62369766 (chr5p12; p=1.98×10<sup>-8</sup>) and rs927553 (chr13q12.12; p=1.91×10<sup>-8</sup>) were associated with chronic <i>P. aeruginosa</i> infection age. The rs62369766 locus was validated using an independent French cohort (n=501). Furthermore, the PRS constructed from CF lung function-associated SNPs was significantly associated with chronic <i>P. aeruginosa</i> infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic <i>P. aeruginosa</i> infection age (β=0.782 years, p=4.24×10<sup>-4</sup>). In the reverse direction, we observed a moderate effect (β=0.002, p=0.012).</p><p><strong>Conclusions: </strong>We identified two novel loci that are associated with chronic <i>P. aeruginosa</i> infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between <i>P. aeruginosa</i> infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections, which account for significant remaining morbidity in CF.</p>","PeriodicalId":12265,"journal":{"name":"European Respiratory Journal","volume":null,"pages":null},"PeriodicalIF":16.6000,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540985/pdf/","citationCount":"0","resultStr":"{\"title\":\"Genome-wide association study of susceptibility to <i>Pseudomonas aeruginosa</i> infection in cystic fibrosis.\",\"authors\":\"Boxi Lin, Jiafen Gong, Katherine Keenan, Fan Lin, Yu-Chung Lin, Julie Mésinèle, Claire Calmel, Badreddine Mohand Oumoussa, Pierre-Yves Boëlle, Loïc Guillot, Harriet Corvol, Valerie Waters, Lei Sun, Lisa J Strug\",\"doi\":\"10.1183/13993003.00062-2024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong><i>Pseudomonas aeruginosa</i> is a common pathogen that contributes to progressive lung disease in cystic fibrosis (CF). Genetic factors other than CF-causing <i>CFTR</i> (CF transmembrane conductance regulator) variations contribute ∼85% of the variation in chronic <i>P. aeruginosa</i> infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to <i>P. aeruginosa</i> infection.</p><p><strong>Materials and methods: </strong>We conducted a genome-wide association study of chronic <i>P. aeruginosa</i> infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic <i>P. aeruginosa</i> infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis.</p><p><strong>Results: </strong>Two novel genome-wide significant loci with lead single nucleotide polymorphisms (SNPs) rs62369766 (chr5p12; p=1.98×10<sup>-8</sup>) and rs927553 (chr13q12.12; p=1.91×10<sup>-8</sup>) were associated with chronic <i>P. aeruginosa</i> infection age. The rs62369766 locus was validated using an independent French cohort (n=501). Furthermore, the PRS constructed from CF lung function-associated SNPs was significantly associated with chronic <i>P. aeruginosa</i> infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic <i>P. aeruginosa</i> infection age (β=0.782 years, p=4.24×10<sup>-4</sup>). In the reverse direction, we observed a moderate effect (β=0.002, p=0.012).</p><p><strong>Conclusions: </strong>We identified two novel loci that are associated with chronic <i>P. aeruginosa</i> infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between <i>P. aeruginosa</i> infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections, which account for significant remaining morbidity in CF.</p>\",\"PeriodicalId\":12265,\"journal\":{\"name\":\"European Respiratory Journal\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":16.6000,\"publicationDate\":\"2024-11-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540985/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Respiratory Journal\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1183/13993003.00062-2024\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/11/1 0:00:00\",\"PubModel\":\"Print\",\"JCR\":\"Q1\",\"JCRName\":\"RESPIRATORY SYSTEM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Respiratory Journal","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1183/13993003.00062-2024","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/11/1 0:00:00","PubModel":"Print","JCR":"Q1","JCRName":"RESPIRATORY SYSTEM","Score":null,"Total":0}
引用次数: 0
摘要
问题：铜绿假单胞菌（Pa）是导致囊性纤维化（CF）患者肺部疾病进展的常见病原体。根据双生子研究，除导致 CF 的 CFTR 变异外，其他遗传因素约占 CF 慢性 Pa 感染年龄变异的 85%，但易感性位点仍然未知。我们的目标是进一步了解宿主对 Pa 感染易感性的遗传基础：我们对 1037 名加拿大 CF 患者进行了慢性 Pa 感染年龄的全基因组关联研究（GWAS）。随后，我们通过多基因风险评分（PRS）分析评估了慢性 Pa 感染年龄与肺功能之间的遗传相关性，并通过双向孟德尔随机分析推断了它们之间的因果关系：结果：两个新的全基因组显著位点（主导 SNPs rs62369766（chr5p12；p-value= 1.98 ×10-8）和 rs927553（chr13q12.12；p-value= 1.91 ×10-8）与慢性 Pa 感染年龄相关。一个独立的法国队列（N=501）对 rs62369766 位点进行了验证。此外，由 CF 肺功能相关 SNPs 构建的 PRS 与慢性 Pa 感染年龄显著相关（p 值=0.002）。最后，我们的分析证明了肺功能对慢性 Pa 感染年龄的因果效应（Beta=0.782 年，p 值= 4.24 × 10-4）。在反方向上，我们观察到中等程度的影响（Beta=0.002，p 值=0.012）：结论：我们发现了两个与 CF 患者慢性 Pa 感染年龄相关的新基因位点。结论：我们发现了两个与 CF 患者慢性 Pa 感染年龄相关的新基因位点。此外，我们还提供了 CF 患者 Pa 感染易感性与肺功能之间常见遗传因素和潜在因果关系的证据。针对这些遗传因素的治疗方法可能会延缓慢性感染的发生，而慢性感染是 CF 剩余发病率的主要原因。
Genome-wide association study of susceptibility to Pseudomonas aeruginosa infection in cystic fibrosis.
Background: Pseudomonas aeruginosa is a common pathogen that contributes to progressive lung disease in cystic fibrosis (CF). Genetic factors other than CF-causing CFTR (CF transmembrane conductance regulator) variations contribute ∼85% of the variation in chronic P. aeruginosa infection age in CF according to twin studies, but the susceptibility loci remain unknown. Our objective is to advance understanding of the genetic basis of host susceptibility to P. aeruginosa infection.
Materials and methods: We conducted a genome-wide association study of chronic P. aeruginosa infection age in 1037 Canadians with CF. We subsequently assessed the genetic correlation between chronic P. aeruginosa infection age and lung function through polygenic risk score (PRS) analysis and inferred their causal relationship through bidirectional Mendelian randomisation analysis.
Results: Two novel genome-wide significant loci with lead single nucleotide polymorphisms (SNPs) rs62369766 (chr5p12; p=1.98×10-8) and rs927553 (chr13q12.12; p=1.91×10-8) were associated with chronic P. aeruginosa infection age. The rs62369766 locus was validated using an independent French cohort (n=501). Furthermore, the PRS constructed from CF lung function-associated SNPs was significantly associated with chronic P. aeruginosa infection age (p=0.002). Finally, our analysis presented evidence for a causal effect of lung function on chronic P. aeruginosa infection age (β=0.782 years, p=4.24×10-4). In the reverse direction, we observed a moderate effect (β=0.002, p=0.012).
Conclusions: We identified two novel loci that are associated with chronic P. aeruginosa infection age in individuals with CF. Additionally, we provided evidence of common genetic contributors and a potential causal relationship between P. aeruginosa infection susceptibility and lung function in CF. Therapeutics targeting these genetic factors may delay the onset of chronic infections, which account for significant remaining morbidity in CF.
期刊介绍：
The European Respiratory Journal (ERJ) is the flagship journal of the European Respiratory Society. It has a current impact factor of 24.9. The journal covers various aspects of adult and paediatric respiratory medicine, including cell biology, epidemiology, immunology, oncology, pathophysiology, imaging, occupational medicine, intensive care, sleep medicine, and thoracic surgery. In addition to original research material, the ERJ publishes editorial commentaries, reviews, short research letters, and correspondence to the editor. The articles are published continuously and collected into 12 monthly issues in two volumes per year.
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