title: Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.
abstract: 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.
  
  
  
  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.
  
  
  
  Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2×10-10for 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).
  
  
  
  HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helga
authors.initials: H
authors.lastname: Westerlind
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.|Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Marie-Rose
authors.initials: MR
authors.lastname: Mellander
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.|Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Francesca
authors.initials: F
authors.lastname: Bresso
authors.affiliation: Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Munch
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Bonfiglio
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Assadi
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rafter
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hübenthal
authors.affiliation: Institute of Epidemiology and Biobank POPGEN, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Lieb
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Henrik
authors.initials: H
authors.lastname: Källberg
authors.affiliation: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Boel
authors.initials: B
authors.lastname: Brynedal
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.affiliation: Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Halfvarson
authors.affiliation: Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Törkvist
authors.affiliation: Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Bjork
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Andreasson
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Agreus
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.|Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Almer
authors.affiliation: Center for Digestive Diseases, Internal Medicine Center Eppendorf, Hamburg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Miehlke
authors.affiliation: Clinic for Gastroenterology, Endoscopy and Interventional Diabetology, Siloah Hospital, Hannover, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Madisch
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: Bodil
authors.initials: B
authors.lastname: Ohlsson
authors.affiliation: Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.|Sophiahemmet Hospital, Stockholm, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Löfberg
authors.affiliation: Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Hultcrantz
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Andre
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.|BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
mesh_terms: D000368:Aged; D000483:Alleles; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6; D046729:Colitis, Collagenous / Q000235:genetics* / Q000276:immunology*; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D006680:HLA Antigens
keywords: COLLAGENOUS COLITIS; GENETICS; HLA GENES