Unraveling the genetic background of cachexia in COPD: a perspective overview

Abstract

Abstract. Chronic obstructive pulmonary disease (COPD) is a multifactorial disorder influenced not only by environmental exposure but also by genetic susceptibility. Recent advances in molecular genetics have enabled the identification of many candidate genes and genome-wide associations contributing to COPD development and its systemic manifestations. Cachexia in COPD is a syndrome that is associated with increased protein catabolism, severe weight loss, and reduction of muscle and adipose mass. The imbalance between protein synthesis and degradation, impaired skeletal muscle regeneration, and inflammatory activation are central mechanisms in its pathogenesis. The loss of muscle mass can be affected by mechanisms that participate in the balance between protein synthesis and protein breakdown. Thus, the impaired ability to regenerate skeletal muscle mass might contribute to the reduction of muscle mass in COPD and cachexia. Cachexia in these patients drastically increases treatment cost. Several genetic factors have demonstrated a significant association with both COPD and cachexia. Subjects with alpha1-antitrypsin deficiency (SERPINA1) are at increased risk of developing both conditions. Early candidate gene studies have implicated ACE, bradykinin receptor, vitamin D receptor, secretory phospholipase A2, and inflammatory cytokines (IL-1 β, IL-6, TNF) in muscle loss and systemic inflammation. More recent GWAS and transcriptomic analyses have identified associations with EFNA2, BAIAP2, FTO, NEB, TPM1, and TPM2, highlighting molecular pathways involved in muscle remodeling, regeneration, and hypoxia response. The aim of this review is to summarize current evidence on the genetic factors contributing to cachexia in COPD, integrating findings from candidate gene studies and genome-wide analyses, and to discuss their potential biological and clinical implications.