Helga Westerlind1,2, Marie-Rose Mellander3,4, Francesca Bresso2,3,4, Andreas Munch5, Ferdinando Bonfiglio2, Ghazaleh Assadi2, Joseph Rafter2, Matthias Hübenthal6, Wolfgang Lieb7, Henrik Källberg1, Boel Brynedal1, Leonid Padyukov3, Jonas Halfvarson8, Leif Törkvist4, Jan Bjork4, Anna Andreasson9, Lars Agreus9, Sven Almer3,4, Stephan Miehlke10, Ahmed Madisch11, Bodil Ohlsson12, Robert Löfberg3,13, Rolf Hultcrantz14, Andre Franke6, Mauro D'Amato2,15. 1. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. 2. Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden. 3. Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. 4. Gastrocentrum, Karolinska University Hospital, Stockholm, Sweden. 5. Department of Clinical and Experimental Medicine, Faculty of Health Science, Linköpings University, Linköping, Sweden. 6. Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany. 7. Institute of Epidemiology and Biobank POPGEN, Christian-Albrechts-University of Kiel, Kiel, Germany. 8. Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden. 9. Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden. 10. Center for Digestive Diseases, Internal Medicine Center Eppendorf, Hamburg, Germany. 11. Clinic for Gastroenterology, Endoscopy and Interventional Diabetology, Siloah Hospital, Hannover, Germany. 12. Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden. 13. Sophiahemmet Hospital, Stockholm, Sweden. 14. Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden. 15. BioCruces Health Research Institute and IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
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=4.2×10-10 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. 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/.
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. 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/.
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