Colon to Rectum
J Crohns Colitis. 2024;18(3):349–59
Human leukocyte antigen signatures as pathophysiological discriminants of microscopic colitis subtypes
Background and aims: Microscopic colitis (MC) is currently regarded as an inflammatory bowel disease that manifests as 2 subtypes: collagenous colitis (CC) and lymphocytic colitis (LC). Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies.
Methods: The authors conducted a genome-wide association study (GWAS) meta-analysis in 1498 CC patients, 373 LC patients, and 13,487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen (2599 MC cases and 552,343 controls in total). Human leukocyte antigen (HLA) alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied.
Results: The authors detected a strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 x 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia (rg = 0.77; p = 0.048) and oesophageal diseases (rg = 0.45, p = 0.023). An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 (rs35099084, p = 2.0 x 10-8, OR = 1.31). No significant association was detected for LC.
Conclusion: These results suggest collagenous colitis (CC) and lymphocytic colitis have distinct pathophysiological underpinnings, characterised by a human leukocyte antigen-predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of microscopic colitis umbrella definitions.