Human Molecular Genetics Advance Access published online on December 22, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn438
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ASSOCIATION STUDY OF THE IL18RAP LOCUS IN THREE EUROPEAN POPULATIONS WITH COELIAC DISEASE
1 Department of Medical Genetics and Research Program for Molecular Medicine, Biomedicum Helsinki, P.O. Box 63, FIN-00014 University of Helsinki, Finland 2 Centre for Gastroenterology, Institute of Cell and Molecular Science, |nQueen Mary University of London, London E1 2AT, UK 3 Heim Pal Children's Hospital, H-1089 Budapest and University of Debrecen, H-4032 Debrecen, Hungary 4 Paediatric Research Centre, University of Tampere Medical School and Tampere University Hospital, FIN-33014 University of Tampere, Finland 5 Department of Reproductive and Development Sciences, University of Trieste and IRCCS "Burlo Garofolo" Children Hospital, Trieste, I-34100 Italy 6 Finnish Red Cross Blood Service, Kivihaantie 7, FIN-00310 Helsinki, Finland 7 Faculty of Public Health, Department of Preventive Medicine, University of Debrecen, HUN-4028 Debrecen, Hungary 8 Faculty of Public Health, Department of Epidemiology and Biostatistics, University of Debrecen, HUN-4028 Debrecen, Hungary 9 Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-14157 Huddinge, Sweden 10 Genetics Department, University Medical Center Groningen and University of Groningen, P.O. Box 30001, 9700 RR Groningen, Netherlands
* Corresponding author: Päivi Saavalainen, Department of Medical Genetics, Haartman Institute, Biomedicum Helsinki 1, PO Box 63, FIN-00014 University of Helsinki, Tel: +358-9-19125086, Fax: +358-9-19125624, E-mail: paivi.saavalainen{at}helsinki.fi
Received October 17, 2008; Revised December 12, 2008; Accepted December 18, 2008
Background: Coeliac disease is caused by dietary gluten, triggering a chronic inflammation of the small intestine in genetically predisposed individuals. Recently, a risk locus on chromosome 2q11-q12, harbouring interleukin 18 receptor accessory protein (IL18RAP) and three other genes, was suggested for coeliac disease. IL18 has been shown to play an important role in T helper type 1 activity in coeliac disease, making this locus a highly interesting candidate.
Materials and methods: In this study, two previously indicated risk variants at the IL18RAP locus (rs13015714 and rs917997) were tested for genetic association in 1638 cases with coeliac disease and 1385 control individuals from the Finnish, Hungarian, and Italian populations. The protein expression level of IL18RAP was also compared between risk allele carriers and non-carriers by Western blotting. Furthermore, immunohistochemical analysis was performed to study IL18RAP protein expression in small intestinal biopsies of untreated and treated coeliac patients and controls.
Results and conclusions: We confirmed genetic association and dose effects of variants at the 2q12.1 locus with coeliac disease in the Hungarian population. The GA haplotype of the markers rs13015714 and rs917997 showed the strongest association (P=0.0001, OR=1.475, 95% CI 1.21-1.80). Two putative isoforms of IL18RAP were detected and the ratios and total levels of these isoforms may contribute to the aetiology of coeliac disease. Our study supports IL18RAP as a novel predisposing gene for coeliac disease and highlights the need for further functional studies on this relatively unknown gene in coeliac disease pathogenesis.
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