Genetic Modifiers of Cystic Fibrosis Lung Disease Severity: Whole-Genome Analysis of 7,840 Patients.

Autor:	Zhou YH; Bioinformatics Research Center.; Department of Biological Sciences, and., Gallins PJ; Bioinformatics Research Center., Pace RG; Marsico Lung Institute/UNC CF Research Center, School of Medicine., Dang H; Marsico Lung Institute/UNC CF Research Center, School of Medicine., Aksit MA; McKusick-Nathans Department of Genetic Medicine., Blue EE; Brotman Baty Institute for Precision Medicine, Seattle, Washington.; Division of Medical Genetics, Department of Medicine., Buckingham KJ; Division of Genetic Medicine, Department of Pediatrics., Collaco JM; Eudowood Division of Pediatric Respiratory Sciences., Faino AV; Children's Core for Biostatistics, Epidemiology and Analytics in Research and., Gordon WW; Division of Genetic Medicine, Department of Pediatrics., Hetrick KN; Department of Genetic Medicine, Center for Inherited Disease Research, and., Ling H; Department of Genetic Medicine, Center for Inherited Disease Research, and., Liu W; Department of Biostatistics., Onchiri FM; Children's Core for Biostatistics, Epidemiology and Analytics in Research and., Pagel K; The Institute for Computational Medicine, The Johns Hopkins University, Baltimore, Maryland., Pugh EW; Department of Genetic Medicine, Center for Inherited Disease Research, and., Raraigh KS; McKusick-Nathans Department of Genetic Medicine., Rosenfeld M; Department of Pediatrics, and.; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, Washington., Sun Q; Department of Biostatistics., Wen J; Department of Genetics, and., Li Y; Department of Biostatistics.; Department of Genetics, and.; Department of Computer Science, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Corvol H; Pediatric Pulmonary Department, Assistance Publique-Hôpitaux de Paris, Hôpital Trousseau, Paris, France.; Centre de Recherche Saint Antoine, Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Paris, France., Strug LJ; Division of Biostatistics, Dalla Lana School of Public Health.; Department of Statistical Sciences, and.; Department of Computer Science, University of Toronto, Toronto, Ontario, Canada; and.; Program in Genetics and Genome Biology and.; The Center for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada., Bamshad MJ; Brotman Baty Institute for Precision Medicine, Seattle, Washington.; Division of Genetic Medicine, Department of Pediatrics.; Department of Genome Sciences, University of Washington, Seattle, Washington., Blackman SM; McKusick-Nathans Department of Genetic Medicine.; Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, Baltimore, Maryland., Cutting GR; McKusick-Nathans Department of Genetic Medicine., Gibson RL; Department of Pediatrics, and.; Center for Clinical and Translational Research, Seattle Children's Research Institute, Seattle, Washington., O'Neal WK; Marsico Lung Institute/UNC CF Research Center, School of Medicine., Wright FA; Bioinformatics Research Center.; Department of Biological Sciences, and.; Department of Statistics, North Carolina State University, Raleigh, North Carolina., Knowles MR; Marsico Lung Institute/UNC CF Research Center, School of Medicine.
Jazyk:	angličtina
Zdroj:	American journal of respiratory and critical care medicine [Am J Respir Crit Care Med] 2023 May 15; Vol. 207 (10), pp. 1324-1333.
DOI:	10.1164/rccm.202209-1653OC
Abstrakt:	Rationale: Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR (CF transmembrane conductance regulator) genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance. Objectives: Identify genetic modifier loci and genes/pathways associated with pulmonary disease severity. Methods: Whole-genome sequencing data on 4,248 unique pwCF with pancreatic insufficiency and lung function measures were combined with imputed genotypes from an additional 3,592 patients with pancreatic insufficiency from the United States, Canada, and France. This report describes association of approximately 15.9 million SNPs using the quantitative Kulich normal residual mortality-adjusted (KNoRMA) lung disease phenotype in 7,840 pwCF using premodulator lung function data. Measurements and Main Results: Testing included common and rare SNPs, transcriptome-wide association, gene-level, and pathway analyses. Pathway analyses identified novel associations with genes that have key roles in organ development, and we hypothesize that these genes may relate to dysanapsis and/or variability in lung repair. Results confirmed and extended previous genome-wide association study findings. These whole-genome sequencing data provide finely mapped genetic information to support mechanistic studies. No novel primary associations with common single variants or rare variants were found. Multilocus effects at chr5p13 ( SLC9A3/CEP72 ) and chr11p13 ( EHF/APIP ) were identified. Variant effect size estimates at associated loci were consistently ordered across the cohorts, indicating possible age or birth cohort effects. Conclusions: This premodulator genomic, transcriptomic, and pathway association study of 7,840 pwCF will facilitate mechanistic and postmodulator genetic studies and the development of novel therapeutics for CF lung disease.
Databáze:	MEDLINE
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