Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis.

Helga Westerlind, Marie-Rose Mellander, Francesca Bresso, Andreas Munch, Ferdinando Bonfiglio, Ghazaleh Assadi, Joseph Rafter, Matthias Hübenthal, Wolfgang Lieb, Henrik Källberg, Boel Brynedal, Leonid Padyukov, Jonas Halfvarson, Leif Törkvist, Jan Bjork, Anna Andreasson, Lars Agreus, Sven Almer, Stephan Miehlke, Ahmed Madisch, Bodil Ohlsson, Robert Löfberg, Rolf Hultcrantz, Andre Franke, Mauro D'Amato

Journal: Gut 2017;66(3):421-428

PMID: 26525574

Full Text on HighWire View on PubMed

Abstract

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 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; 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.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Address: Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.; Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.; Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.; Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden.; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.; Institute of Epidemiology and Biobank POPGEN, Christian-Albrechts-University of Kiel, Kiel, Germany.; Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.; Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden.; Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden.; Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.; Center for Digestive Diseases, Internal Medicine Center Eppendorf, Hamburg, Germany.; Clinic for Gastroenterology, Endoscopy and Interventional Diabetology, Siloah Hospital, Hannover, Germany.; Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden.; Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.; Sophiahemmet Hospital, Stockholm, Sweden.; Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.; Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.; BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.

DOI: 10.1136/gutjnl-2015-309934

Link outs

Free resources

Research Materials:

https://antibodies.cancer.gov/detail/CPTC-HLA-DQA1...

Subscription / membership required

Full Text Sources:

https://gut.bmj.com/lookup/pmidlookup?view=long&pm...

MeSH Terms: Aged, Alleles, Case-Control Studies, Chromosomes, Human, Pair 6, Colitis, Collagenous, Female, Genetic Loci, Genetic Predisposition to Disease, Genotyping Techniques, HLA Antigens, Haplotypes, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors