Association study of the IL18RAP locus in three European populations with coeliac disease

Lotta L.E. Koskinen, Elisabet Einarsdottir, Emma Dukes, Graham A.R. Heap, Patrick Dubois, Ilma R. Korponay-Szabo, Katri Kaukinen, Kalle Kurppa, Fabiana Ziberna, Serena Vatta, Tarcisio Not, Alessandro Ventura, Pertti Sistonen, Róza Ádány, Zsuzsa Pocsai, György Széles, Markku Mäki, Juha Kere, Cisca Wijmenga, David A. Van HeelPäivi Saavalainen

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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.

Original languageEnglish
Pages (from-to)1148-1155
Number of pages8
JournalHuman molecular genetics
Issue number6
Publication statusPublished - Mar 13 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Koskinen, L. L. E., Einarsdottir, E., Dukes, E., Heap, G. A. R., Dubois, P., Korponay-Szabo, I. R., Kaukinen, K., Kurppa, K., Ziberna, F., Vatta, S., Not, T., Ventura, A., Sistonen, P., Ádány, R., Pocsai, Z., Széles, G., Mäki, M., Kere, J., Wijmenga, C., ... Saavalainen, P. (2009). Association study of the IL18RAP locus in three European populations with coeliac disease. Human molecular genetics, 18(6), 1148-1155.