Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes

Tenghao Zheng, Giulia Roda, Yamile Zabana, Celia Escudero-Hernández, Xingrong Liu, Ye Chen, Leticia Camargo Tavares, Ferdinando Bonfiglio, Marie Rose Mellander, Izabella Janczewska, Lina Vigren, Klas Sjöberg, Bodil Ohlsson, Sven Almer, Jonas Halfvarson, Stephan Miehlke, Ahmed Madisch, Wolfgang Lieb, Juozas Kupčinskas, Rinse K. WeersmaLuis Bujanda, Antonio Julià, Sara Marsal, Maria Esteve, Danila Guagnozzi, Fernando Fernández-Bañares, Carmen Ferrer, Inga Peter, Jonas F. Ludvigsson, Darrell Pardi, Bas Verhaegh, Daisy Jonkers, Marieke Pierik, Andreas Münch, Andre Franke, Francesca Bresso, Hamed Khalili, Jean Frederic Colombel, Mauro D’Amato, Lance Presser, Anne Teirlinck, Mirjam Knol, Marta Piqueras, David Busquets, Eva Iglesias, Alfredo J. Lucendo, MC-Europe GETECCU GWAS group

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two 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: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 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: We detected 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 × 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 × 10-8, OR = 1.31]. No significant association was detected for LC. Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.

Originalspråkengelska
Sidor (från-till)349-359
Antal sidor11
TidskriftJournal of Crohn's and Colitis
Volym18
Nummer3
DOI
StatusPublished - 2024 mars 1

Ämnesklassifikation (UKÄ)

  • Medicinsk genetik

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