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

TitleGenetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease
Publication TypePublication
Year2021
AuthorsKumar PLakshman, Wilson AC, Rocco A, Cho MH, Wan E, Hobbs BD, Washko GR, Ortega VE, Christenson SA, Li X, J Wells M, Bhatt SP, DeMeo DL, Lutz SM, Rossiter H, Casaburi R, Rennard SI, Lomas DA, Labaki WW, Tal-Singer R, Bowler RP, Hersh CP, Tiwari HK, Dransfield M, Thalacker-Mercer A, Meyers DA, Silverman EK, McDonald M-LN
Corporate AuthorsCOPDGene, ECLIPSE and SPIROMICS investigators
JournalJ Cachexia Sarcopenia Muscle
Volume12
Issue6
Pagination1803-1817
Date Published2021 Dec
ISSN2190-6009
KeywordsAdult, Bayes Theorem, Genetic Variation, Genome-Wide Association Study, Humans, Muscle, Skeletal, Nerve Tissue Proteins, Pulmonary Disease, Chronic Obstructive, Regeneration, Weight Loss
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/m ). 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 ) 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.

DOI10.1002/jcsm.12782
Alternate JournalJ Cachexia Sarcopenia Muscle
PubMed ID34523824
PubMed Central IDPMC8718068
Grant ListR56HL153460 / NH / NIH HHS / United States
/ DH_ / Department of Health / United Kingdom
HHSN268200900018C / HL / NHLBI NIH HHS / United States
HHSN268200900014C / HL / NHLBI NIH HHS / United States
P30 DK079626 / DK / NIDDK NIH HHS / United States
HHSN268200900016C / HL / NHLBI NIH HHS / United States
R01 HL137927 / NH / NIH HHS / United States
HHSN268200900019C / HL / NHLBI NIH HHS / United States
U01 HL089856 / HL / NHLBI NIH HHS / United States
K08 HL136928 / HL / NHLBI NIH HHS / United States
IK2 RX002165 / RX / RRD VA / United States
HHSN268200900013C / HL / NHLBI NIH HHS / United States
U01 HL137880 / HL / NHLBI NIH HHS / United States
R00HL121087 / NH / NIH HHS / United States
R01 HL153460 / HL / NHLBI NIH HHS / United States
HHSN268200900017C / HL / NHLBI NIH HHS / United States
R01HL153460 / NH / NIH HHS / United States
U24 HL141762 / HL / NHLBI NIH HHS / United States
K08 HL136928 / NH / NIH HHS / United States
U01 HL089897 / HL / NHLBI NIH HHS / United States
R01HL135142 / NH / NIH HHS / United States
R01 HL151452 / HL / NHLBI NIH HHS / United States
HHSN268200900020C / HL / NHLBI NIH HHS / United States
R56 HL153460 / HL / NHLBI NIH HHS / United States
R01 HL137927 / HL / NHLBI NIH HHS / United States
HHSN268200900015C / HL / NHLBI NIH HHS / United States
R01 HL14714 / NH / NIH HHS / United States
MS#: 
MS155
Manuscript Full Title: 
Genetic variation in genes regulating skeletal muscle regeneration and tissue remodelling associated with weight loss in chronic obstructive pulmonary disease
Manuscript Lead/Corresponding Author Affiliation: 
Clinical Center: Birmingham (University of Alabama at Birmingham)
ECI: 
Manuscript Status: 
Published and Public