Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease

Journal of Cachexia, Sarcopenia and Muscle

COPDGene, ECLIPSE and SPIROMICS investigators¹  Ruth Tal‐Singer²  Dawn L. DeMeo³  Brian D. Hobbs³  Edwin K. Silverman³  Craig P. Hersh³  Michael H. Cho³  Emily Wan³  Hemant K. Tiwari⁴  Anna Thalacker‐Mercer⁵  Victor E. Ortega⁶  Stephen I. Rennard⁷  Xingnan Li⁸  Deborah A. Meyers⁸  Russel P. Bowler⁹  Sharon M. Lutz^1,10  George R. Washko^1,11  Wassim W. Labaki^1,12  Surya P. Bhatt^1,13  Mark Dransfield^1,13  Preeti Lakshman Kumar^1,13  Merry‐Lynn N. McDonald^1,13  J. Michael Wells^1,13  Ava C. Wilson^1,13  Alison Rocco^1,13  Stephanie A. Christenson^1,14  Richard Casaburi^1,15  Harry Rossiter^1,15  David A. Lomas^1,16 

[1] ;COPD Foundation Miami FL USA;Channing Division of Network Medicine Brigham and Women's Hospital Boston MA USA;Department of Biostatistics University of Alabama at Birmingham Birmingham AL USA;Department of Cell Development and Integrative Biology University of Alabama at Birmingham Birmingham AL USA;Department of Internal Medicine, Section on Pulmonary, Critical Care, Allergy and Immunologic Diseases Wake Forest School of Medicine Winston‐Salem NC USA;Department of Medicine Nebraska Medical Center Omaha NE USA;Department of Medicine University of Arizona College of Medicine Tucson AZ USA;Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine National Jewish Health Denver CO USA;Department of Population Medicine Harvard Medical School Boston MA USA;Division of Pulmonary and Critical Care Medicine Brigham and Women's Hospital Boston MA USA;Division of Pulmonary and Critical Care Medicine University of Michigan Ann Arbor MI USA;Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine University of Alabama at Birmingham Birmingham AL USA;Division of Pulmonary, Critical Care, Allergy, & Sleep Medicine, Department of Medicine University of California San Francisco San Francisco CA USA;Rehabilitation Clinical Trials Center Los Angeles Biomedical Research Institute at Harbor Harbor‐UCLA Medical Center Torrance CA USA;UCL Respiratory University College London London UK;

关键词: GWAS;    Cachexia;    Weight loss;    COPD;    Genetics;    Biomarkers;   

DOI  :  10.1002/jcsm.12782

来源: DOAJ

【 摘 要 】

Abstract Background Chronic obstructive pulmonary disease (COPD) is the third leading cause of death globally. COPD patients with cachexia or weight loss have increased risk of death independent of body mass index (BMI) and lung function. We tested the hypothesis genetic variation is associated with weight loss in COPD using a genome‐wide association study approach. Methods Participants with COPD (N = 4308) from three studies (COPDGene, ECLIPSE, and SPIROMICS) were analysed. Discovery analyses were performed in COPDGene with replication in SPIROMICS and ECLIPSE. In COPDGene, weight loss was defined as self‐reported unintentional weight loss > 5% in the past year or low BMI (BMI < 20 kg/m2). In ECLIPSE and SPIROMICS, weight loss was calculated using available longitudinal visits. Stratified analyses were performed among African American (AA) and Non‐Hispanic White (NHW) participants with COPD. Single variant and gene‐based analyses were performed adjusting for confounders. Fine mapping was performed using a Bayesian approach integrating genetic association results with linkage disequilibrium and functional annotation. Significant gene networks were identified by integrating genetic regions associated with weight loss with skeletal muscle protein–protein interaction (PPI) data. Results At the single variant level, only the rs35368512 variant, intergenic to GRXCR1 and LINC02383, was associated with weight loss (odds ratio = 3.6, 95% confidence interval = 2.3–5.6, P = 3.2 × 10−8) among AA COPD participants in COPDGene. At the gene level in COPDGene, EFNA2 and BAIAP2 were significantly associated with weight loss in AA and NHW COPD participants, respectively. The EFNA2 association replicated among AA from SPIROMICS (P = 0.0014), whereas the BAIAP2 association replicated in NHW from ECLIPSE (P = 0.025). The EFNA2 gene encodes the membrane‐bound protein ephrin‐A2 involved in the regulation of developmental processes and adult tissue homeostasis such as skeletal muscle. The BAIAP2 gene encodes the insulin‐responsive protein of mass 53 kD (IRSp53), a negative regulator of myogenic differentiation. Integration of the gene‐based findings participants with PPI data revealed networks of genes involved in pathways such as Rho and synapse signalling. Conclusions The EFNA2 and BAIAP2 genes were significantly associated with weight loss in COPD participants. Collectively, the integrative network analyses indicated genetic variation associated with weight loss in COPD may influence skeletal muscle regeneration and tissue remodelling.

【 授权许可】

Unknown