Evidence for interaction between 5-hydroxytryptamine (serotonin) receptor 2A and MHC type II molecules in development of rheumatoid arthritis.

Leonid Padyukov (1) , Maria Seddighzadeh (1) , Marina Korotkova (1) , Henrik Källberg (1) , Bo Ding Ding (1) , Nina Daha (1) , Fina A. S. Kurreeman (1) , Rene Toes (1) , Tom Huizinga (1) , Anca I Catrina (1) , Lars Alfredsson (1) , Lars Klareskog (1)

1 Rheumatology Unit, Department of Medicine

It has repeatedly been suggested that the development of complex diseases can be elucidated by gene-gene interactions. Recently we found that HTR2A, the member of serotonin receptor family, is associated with RA. The current study was aimed to investigate the possibility of a gene-gene interaction between the HTR2A and the major genetic risk factor for RA, HLA-DRB1 shared epitope (SE) alleles. We studied 4095 RA cases and 3223 controls from three different populations; in Sweden, US and The Netherlands to test for interaction between the protective HTR2A haplotype and HLA-DRB1 SE alleles. Further, we analyzed mRNA and/or protein expression of HTR2A and HLA-DR in biopsies and in synovial fibroblasts from RA patients. The interaction was defined as departure from additivity of effects using attributable proportion due to interaction. First, we could demonstrate, and further replicate an interaction between a protective haplotype in the HTR2A and HLA-DRB1 SE alleles regarding risk of developing autoantibody positive RA. Second, we could show that both genes are constitutively expressed in fibroblasts from synovial tissue of RA patients and by double immunofluorescence staining we demonstrated that these two proteins are colocalized in these cells. In conclusion our data demonstrate a statistical interaction between HTR2A and HLA-DRB1 SE alleles as well as colocalization of the product of these two genes in inflamed synovial tissue, which suggest possible biological relationship between these two proteins. This finding may lead to the development of treatment based on enhancing protective features of 5-HT2A in individuals with a certain HLA genotype.

Mots clés: MHC class II; rheumatoid arthritis; gene-gene interaction

Leonid Padyukov, Maria Seddighzadeh, Marina Korotkova, Henrik Källberg, Bo Ding Ding, et al.. Evidence for interaction between 5-hydroxytryptamine (serotonin) receptor 2A and MHC type II molecules in development of rheumatoid arthritis.. European Journal of Human Genetics, 2010, n/a (n/a), pp.n/a-n/a. ⟨10.1038/ejhg.2010.12⟩. ⟨hal-00511181⟩