Abstract
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-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.
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Acknowledgements
The EIRA study was supported by grants from the Swedish Medical Research Council, Swedish Council for Working life and Social Research, King Gustaf V's 80-year foundation, the Swedish Rheumatism Foundation, Stockholm County Council, the insurance company AFA and Combine (Vinnova). We thank the RA patients and controls for participating in the study; Eva Jemseby, Marie-Louise Serra, Lena Nise and Camilla Bengtsson for invaluable contributions to the collection of data and maintenance of the EIRA database; as well as Johan Rönnelid (Unit of Clinical Immunology Uppsala University/Akademiska Hospital) and Hiba Mahdi (Karolinska University Hospital) for performing the analysis of anti-CCP. The Leiden EAC study was supported by grants from the Duthch Arthritis foundation, the European program grant FP6 AutoCure and FP1 Masterswitch, as well as a grant from the center for Medical System Biology within the framework of the Netherlands Genomic Initiative. We thank Peter Gregersen and the NARAC investigators for providing continuing access to genotyping data on the NARAC cohort; the NARAC study is supported by grants from the National Institutes of Health RO1-AR44422 and NO1-AR-2-2263.
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Seddighzadeh, M., Korotkova, M., Källberg, H. et al. Evidence for interaction between 5-hydroxytryptamine (serotonin) receptor 2A and MHC type II molecules in the development of rheumatoid arthritis. Eur J Hum Genet 18, 821–826 (2010). https://doi.org/10.1038/ejhg.2010.12
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DOI: https://doi.org/10.1038/ejhg.2010.12
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