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Seddighzadeh, M.; Korotkova, M.; Kallberg, H.; Ding, B.; Daha, N.; Kurreeman, F.A.S.; ... ; Padyukov, L. (2010)

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

Article / Letter to editor
It has repeatedly been suggested that the development of complex diseases can be elucidated by gene-gene interactions. Recently, we found that HTR2A, a member of the serotonin receptor family, is associated with rheumatoid arthritis (RA). This study was aimed to investigate the possibility of a gene-gene interaction between 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 from Sweden, the United States 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 biopsy samples 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 HTR2A and HLA...Show moreIt has repeatedly been suggested that the development of complex diseases can be elucidated by gene-gene interactions. Recently, we found that HTR2A, a member of the serotonin receptor family, is associated with rheumatoid arthritis (RA). This study was aimed to investigate the possibility of a gene-gene interaction between 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 from Sweden, the United States 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 biopsy samples 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 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 and colocalization of the product of these two genes in inflamed synovial tissue, which suggest a possible biological relationship between these two proteins. This finding may lead to the development of treatment based on enhancing the protective features of 5-HT2A in individuals with a certain HLA genotype. European Journal of Human Genetics (2010) 18, 821-826; doi: 10.1038/ejhg.2010.12; published online 24 February 2010Show less
serotonin receptor MHC class II RA gene-gene interaction hla-drb1 shared epitope gene association schizophrenia expression smoking ptpn22 cells risk identification
All authors
Seddighzadeh, M.; Korotkova, M.; Kallberg, H.; Ding, B.; Daha, N.; Kurreeman, F.A.S.; Toes, R.E.M.; Huizinga, T.W.; Catrina, A.I.; Alfredsson, L.; Klareskog, L.; Padyukov, L.
Date
2010-07-31
Journal
European Journal of Human Genetics
Volume
18
Issue
7
Pages
821 - 826
DOI
doi:10.1038/ejhg.2010.12