Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations

Elisabet Einarsdottir (1) , Marianna R Bevova (1) , A Zhernakova (1) , Alienke Monsuur (1) , Lotta L. E. Koskinen (1) , Ruben Vant Slot (1) , Chris J.J. Mulder (1) , M. Luisa Mearin (1) , Ilma Korponay-Szabo (1) , Katri Kaukinen (1) , Kalle Kurppa (1) , Juha Kere (1) , Markku Mäki (1) , Cisca Wijmenga (1) , Päivi Saavalainen (1)

1 Department of Medical Genetics

Celiac disease is an inflammatory enteropathy caused by intolerance to gluten. Previous linkage studies in the Dutch, Finnish and Hungarian populations have revealed a locus on chromosome 6q21-22 conferring susceptibility to celiac disease. This locus has previously been implicated in susceptibility to other autoimmune diseases such as Crohn's disease and type 1 diabetes. We performed finemapping on 446 independent individuals with celiac disease and 641 controls of Dutch origin, testing 872 tagging SNPs in a 22 Mb region of chromosome 6. The twelve most promising SNPs were followed up in 2071 individuals from 284 Finnish and 357 Hungarian celiac disease families to identify risk variants in this region. Multiple markers in the region were significantly associated with celiac disease in the Dutch material. Two SNPs, rs9391227 and rs4946111, were significantly associated with celiac disease in the Finnish population. The association to rs9391227 represents the strongest association signal found in the Finnish (p=0.0032, OR 0.66) as well as the combined Dutch, Finnish and Hungarian populations (p=3.6*10-5, OR 0.76). Rs9391227 is situated downstream of the HECT domain and ankyrin repeat containing, E3 ubiquitin protein ligase 1 (HACE1) gene and is contained within a region of strong linkage disequilibrium enclosing HACE1. Two additional, independent, susceptibility variants in the 6q21-22 region were also found in a meta-analysis of the three populations. The 6q21-22 region was confirmed as a celiac disease susceptibility locus and harbours multiple independent associations, some of which may implicate ubiquitin-pathways in celiac disease susceptibility.

Mots clés: celiac; association; linkage

Elisabet Einarsdottir, Marianna R Bevova, A Zhernakova, Alienke Monsuur, Lotta L. E. Koskinen, et al.. Multiple independent variants in 6q21-22 associated with susceptibility to celiac disease in the Dutch, Finnish and Hungarian populations. European Journal of Human Genetics, 2011, ⟨10.1038/ejhg.2011.2⟩. ⟨hal-00614742⟩