Investigating a modern era role for IRGM in chronic obstructive pulmonary disease (COPD)
Evolutionary mismatch – the idea that populations living in rapidly changing environments differ radically from their ancestral environments – has been proposed to explain declining infectious disease trends and concomitant rising non-infectious chronic disease trends over time. Genetic variants formerly evolutionarily selected for or against by infectious pressures may in the modern era modify risk for non-infectious chronic diseases such as Crohn’s disease and chronic obstructive pulmonary disease (COPD), potentially through the same mechanisms involved in host defense. In this project, we use a genetic association study to explore a potential modern era role in COPD for the gene Immune Related GTPase Family M (IRGM). IRGM encodes a protein that plays a key role in autophagy, a process that degrades pathogens that invade host cells as well as damaged components of the host cell itself.
Phylogenic studies suggest that IRGM was pseudogenized ~40 million years ago and recently “resurrected” with an alu retrotransposon insertion. IRGM is involved in autophagy-dependent suppression of M. tuberculosis in human cells and IRGM polymorphisms have been firmly linked to increased tuberculosis (TB) risk. Defective autophagy has also been implicated in the pathogenesis of chronic diseases including Crohn’s disease (CD) and COPD. IRGM single nucleotide polymorphisms (SNPs) have been associated with increased risk for CD,7 but have not to our knowledge been examined in relation to COPD. We hypothesize that minor (TB/CD-associated) IRGM alleles at rs10065172 and rs13361189 will associate with increased risk for COPD, as well with worsened disease severity (cough, dyspnea) in patients with COPD.