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Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes

Zheng, Tenghao ; Roda, Giulia ; Zabana, Yamile ; Escudero-Hernández, Celia ; Liu, Xingrong ; Chen, Ye ; Tavares, Leticia Camargo ; Bonfiglio, Ferdinando ; Mellander, Marie Rose and Janczewska, Izabella , et al. (2024) In Journal of Crohn's and Colitis 18(3). p.349-359
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
collagenous colitis, genetics, GWAS, HLA, Microscopic colitis
in
Journal of Crohn's and Colitis
volume
18
issue
3
pages
11 pages
publisher
Oxford University Press
external identifiers
  • pmid:37768647
  • scopus:85185695727
ISSN
1873-9946
DOI
10.1093/ecco-jcc/jjad165
language
English
LU publication?
yes
id
8ee4455e-30c9-4ed5-b985-fd248c7f5cbb
date added to LUP
2024-03-20 11:05:48
date last changed
2024-05-15 12:58:25
@article{8ee4455e-30c9-4ed5-b985-fd248c7f5cbb,
  abstract     = {{<p>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<sup>-23</sup>, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [r<sub>g</sub> = 0.77; p = 0.048] and oesophageal diseases [r<sub>g</sub> = 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<sup>-8</sup>, 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.</p>}},
  author       = {{Zheng, Tenghao and Roda, Giulia and Zabana, Yamile and Escudero-Hernández, Celia and Liu, Xingrong and Chen, Ye and Tavares, Leticia Camargo and Bonfiglio, Ferdinando and Mellander, Marie Rose and Janczewska, Izabella and Vigren, Lina and Sjöberg, Klas and Ohlsson, Bodil and Almer, Sven and Halfvarson, Jonas and Miehlke, Stephan and Madisch, Ahmed and Lieb, Wolfgang and Kupčinskas, Juozas and Weersma, Rinse K. and Bujanda, Luis and Julià, Antonio and Marsal, Sara and Esteve, Maria and Guagnozzi, Danila and Fernández-Bañares, Fernando and Ferrer, Carmen and Peter, Inga and Ludvigsson, Jonas F. and Pardi, Darrell and Verhaegh, Bas and Jonkers, Daisy and Pierik, Marieke and Münch, Andreas and Franke, Andre and Bresso, Francesca and Khalili, Hamed and Colombel, Jean Frederic and D’Amato, Mauro and Presser, Lance and Teirlinck, Anne and Knol, Mirjam and Piqueras, Marta and Busquets, David and Iglesias, Eva and Lucendo, Alfredo J.}},
  issn         = {{1873-9946}},
  keywords     = {{collagenous colitis; genetics; GWAS; HLA; Microscopic colitis}},
  language     = {{eng}},
  month        = {{03}},
  number       = {{3}},
  pages        = {{349--359}},
  publisher    = {{Oxford University Press}},
  series       = {{Journal of Crohn's and Colitis}},
  title        = {{Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes}},
  url          = {{http://dx.doi.org/10.1093/ecco-jcc/jjad165}},
  doi          = {{10.1093/ecco-jcc/jjad165}},
  volume       = {{18}},
  year         = {{2024}},
}