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The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age\u2010related) sarcopenia. We tested if genetic contributors explain the variability in sarcopenic phenotype and accelerated senescence in COPD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To identify gene variants [single nucleotide polymorphisms (SNPs)] associated with sarcopenia in COPD, we performed a genome\u2010wide association study (GWAS) of fat free mass index (FFMI) in 32\u2009426 non\u2010Hispanic White (NHW) UK Biobank participants with COPD. Several SNPs within the fat mass and obesity\u2010associated (\n                      <jats:italic>FTO<\/jats:italic>\n                      ) gene were associated with sarcopenia that were validated in an independent COPDGene cohort (\n                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u00a03656). Leucocyte telomere length quantified in the UK Biobank cohort was used as a marker of senescence. Experimental validation was done by genetic depletion of FTO in murine skeletal myotubes exposed to prolonged intermittent hypoxia or chronic hypoxia because hypoxia contributes to sarcopenia in COPD. Molecular biomarkers for senescence were also quantified with FTO depletion in murine myotubes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Multiple SNPs located in the\n                      <jats:italic>FTO<\/jats:italic>\n                      gene were associated with sarcopenia in addition to novel SNPs both within and in proximity to the gene\n                      <jats:italic>AC090771.2,<\/jats:italic>\n                      which transcribes long non\u2010coding RNA (lncRNA). To replicate our findings, we performed a GWAS of FFMI in NHW subjects from COPDGene. The SNP most significantly associated with FFMI was on chromosome (chr) 16, rs1558902A\u00a0&gt;\u00a0T in the\n                      <jats:italic>FTO<\/jats:italic>\n                      gene (\u03b2\u00a0=\u00a00.151, SE\u00a0=\u00a00.021,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a01.40\u00a0\u00d7\u00a010\n                      <jats:sup>\u221212<\/jats:sup>\n                      for UK Biobank |\u03b2=\u00a00.220, SE\u00a0=\u00a00.041,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a09.99\u00a0\u00d7\u00a010\n                      <jats:sup>\u22128<\/jats:sup>\n                      for COPDGene) and chr 18 SNP rs11664369C\u00a0&gt;\u00a0T nearest to the\n                      <jats:italic>AC090771.2<\/jats:italic>\n                      gene (\u03b2\u00a0=\u00a00.129, SE\u00a0=\u00a00.024,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a04.64\u00a0\u00d7\u00a010\n                      <jats:sup>\u22128<\/jats:sup>\n                      for UK Biobank |\u03b2\u00a0=\u00a00.203, SE\u00a0=\u00a00.045,\n                      <jats:italic>P<\/jats:italic>\n                      \u00a0=\u00a06.38\u00a0\u00d7\u00a010\n                      <jats:sup>\u22126<\/jats:sup>\n                      for COPDGene). Lower handgrip strength, a measure of muscle strength, but not FFMI was associated with reduced telomere length in the UK Biobank. Experimentally, in vitro knockdown of\n                      <jats:italic>FTO<\/jats:italic>\n                      lowered myotube diameter and induced a senescence\u2010associated molecular phenotype, which was worsened by prolonged intermittent hypoxia and chronic hypoxia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Genetic polymorphisms of\n                      <jats:italic>FTO<\/jats:italic>\n                      and\n                      <jats:italic>AC090771<\/jats:italic>\n                      .\n                      <jats:italic>2<\/jats:italic>\n                      were associated with sarcopenia in COPD in independent cohorts. Knockdown of\n                      <jats:italic>FTO<\/jats:italic>\n                      in murine myotubes caused a molecular phenotype consistent with senescence that was exacerbated by hypoxia, a common condition in COPD. Genetic variation may interact with hypoxia and contribute to variable severity of sarcopenia and skeletal muscle molecular senescence phenotype in COPD.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jcsm.13198","type":"journal-article","created":{"date-parts":[[2023,3,1]],"date-time":"2023-03-01T06:25:54Z","timestamp":1677651954000},"page":"1083-1095","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Gene polymorphisms associated with heterogeneity and senescence characteristics of sarcopenia in chronic obstructive pulmonary disease"],"prefix":"10.1002","volume":"14","author":[{"given":"Amy H.","family":"Attaway","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annette","family":"Bellar","sequence":"additional","affiliation":[{"name":"Department of 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