title: Association study of the IL18RAP locus in three European populations with coeliac disease.
abstract: 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.
authors.affiliation: Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Lotta L E
authors.initials: LL
authors.lastname: Koskinen
authors.forename: Elisabet
authors.initials: E
authors.lastname: Einarsdottir
authors.forename: Emma
authors.initials: E
authors.lastname: Dukes
authors.forename: Graham A R
authors.initials: GA
authors.lastname: Heap
authors.forename: Patrick
authors.initials: P
authors.lastname: Dubois
authors.forename: Ilma R
authors.initials: IR
authors.lastname: Korponay-Szabo
authors.forename: Katri
authors.initials: K
authors.lastname: Kaukinen
authors.forename: Kalle
authors.initials: K
authors.lastname: Kurppa
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ziberna
authors.forename: Serena
authors.initials: S
authors.lastname: Vatta
authors.forename: Tarcisio
authors.initials: T
authors.lastname: Not
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ventura
authors.forename: Pertti
authors.initials: P
authors.lastname: Sistonen
authors.forename: Róza
authors.initials: R
authors.lastname: Adány
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Pocsai
authors.forename: György
authors.initials: G
authors.lastname: Széles
authors.forename: Markku
authors.initials: M
authors.lastname: Mäki
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Päivi
authors.initials: P
authors.lastname: Saavalainen
mesh_terms: D015153:Blotting, Western; D002446:Celiac Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053728:Interleukin-18 Receptor beta Subunit / Q000235:genetics*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D015201:Meta-Analysis as Topic; D044465:White People / Q000235:genetics*
chemical_list: C115629:IL18RAP protein, human; D053728:Interleukin-18 Receptor beta Subunit