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Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis
  1. Helga Westerlind1,2,
  2. Marie-Rose Mellander3,4,
  3. Francesca Bresso2,3,4,
  4. Andreas Munch5,
  5. Ferdinando Bonfiglio2,
  6. Ghazaleh Assadi2,
  7. Joseph Rafter2,
  8. Matthias Hübenthal6,
  9. Wolfgang Lieb7,
  10. Henrik Källberg1,
  11. Boel Brynedal1,
  12. Leonid Padyukov3,
  13. Jonas Halfvarson8,
  14. Leif Törkvist4,
  15. Jan Bjork4,
  16. Anna Andreasson9,
  17. Lars Agreus9,
  18. Sven Almer3,4,
  19. Stephan Miehlke10,
  20. Ahmed Madisch11,
  21. Bodil Ohlsson12,
  22. Robert Löfberg3,13,
  23. Rolf Hultcrantz14,
  24. Andre Franke6,
  25. Mauro D'Amato2,15
  1. 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  2. 2Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
  3. 3Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  4. 4Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden
  5. 5Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden
  6. 6Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany
  7. 7Institute of Epidemiology and Biobank POPGEN, Christian-Albrechts-University of Kiel, Kiel, Germany
  8. 8Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden
  9. 9Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
  10. 10Center for Digestive Diseases, Internal Medicine Center Eppendorf, Hamburg, Germany
  11. 11Clinic for Gastroenterology, Endoscopy and Interventional Diabetology, Siloah Hospital, Hannover, Germany
  12. 12Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
  13. 13Sophiahemmet Hospital, Stockholm, Sweden
  14. 14Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
  15. 15BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
  1. Correspondence to Dr Mauro D'Amato, BioCruces Health Research Institute, Cruces University Hospital, Barakaldo 48903, Spain; mauro.damato{at}


Objective Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role.

Design Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin.

Results Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10−10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3×10−11; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis).

Conclusions HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.


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