Human Molecular Genetics Advance Access originally published online on December 22, 2008
Human Molecular Genetics 2009 18(6):1148-1155; 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, Research Program for Molecular Medicine, Biomedicum Helsinki, University of Helsinki, PO Box 63, FIN-00014 Helsinki, Finland 2 Centre for Gastroenterology, Institute of Cell and Molecular Science, Queen Mary University of London, London E1 2AT, UK 3 Coeliac Disease Center, Heim Pal Children's Hospital, H-1089 Budapest, Hungary 4 Department of Pediatrics, University of Debrecen, Medical and Health Science Center, H-4032 Debrecen, Hungary 5 Paediatric Research Centre, University of Tampere Medical School and Tampere University Hospital, University of Tampere, FIN-33014 Tampere, Finland 6 Department of Reproductive and Development Sciences, University of Trieste and IRCCS ‘Burlo Garofolo’ Children Hospital, Trieste I-34100, Italy 7 Finnish Red Cross Blood Service, Kivihaantie 7, FIN-00310 Helsinki, Finland 8 Department of Preventive Medicine 9 Department of Epidemiology and Biostatistics, Faculty of Public Health, University of Debrecen, HUN-4028 Debrecen, Hungary 10 Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-14157 Huddinge, Sweden 11 Genetics Department, University Medical Center Groningen and University of Groningen, PO Box 30001, 9700 RR Groningen, Netherlands
* To whom correspondence should be addressed. Tel: +358 919125086; Fax: +358 919125624; Email: paivi.saavalainen{at}helsinki.fi
Received October 17, 2008; Revised December 12, 2008; Accepted December 18, 2008
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. 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. 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, odds ratio = 1.475, 95% confidence interval 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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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