title: Genetic variation in the serotonin receptor gene affects immune responses in rheumatoid arthritis.
abstract: Many genetic variants associate with the risk of developing rheumatoid arthritis (RA); however, their functional roles are largely unknown. Here, we aimed to investigate whether the RA-associated serotonin receptor 2A (HTR2A) haplotype affects T-cell and monocyte functions. Patients with established RA (n=379) were genotyped for two single-nucleotide polymorphisms (SNPs) in the HTR2A locus, rs6314 and rs1328674, to define presence of the risk haplotype for each individual. Patients with and without the RA-associated TC haplotype were selected and T-cell and monocyte function was monitored following in vitro stimulations with staphylococcal enterotoxin B and lipopolysaccharide (LPS) using multiparameter flow cytometry. Within the cohort, 44 patients were heterozygous for the TC haplotype (11.6%) while none were homozygous. Upon stimulation, T cells from TC-carrier patients produced more proinflammatory cytokines (tumor necrosis factor alpha (TNF-α), interleukin-17 (IL-17) and interferon gamma (IFN-γ)) and monocytes produced higher levels of TNF-α compared with patients carrying the non-TC haplotype (P<0.05 and 0.01, respectively). Such cytokine production could be inhibited in the presence of the selective 5-HT2 receptor agonist (2,5-Dimethoxy-4-iodoamphetamine, DOI); interestingly, this effect was more pronounced in TC carriers. Our data demonstrate that association of RA with a distinct serotonin receptor haplotype has functional impact by affecting the immunological phenotype of T cells and monocytes.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Snir
authors.forename: E
authors.initials: E
authors.lastname: Hesselberg
authors.forename: P
authors.initials: P
authors.lastname: Amoudruz
authors.forename: L
authors.initials: L
authors.lastname: Klareskog
authors.forename: I
authors.initials: I
authors.lastname: Zarea-Ganji
authors.forename: A I
authors.initials: AI
authors.lastname: Catrina
authors.forename: L
authors.initials: L
authors.lastname: Padyukov
authors.forename: V
authors.initials: V
authors.lastname: Malmström
authors.forename: M
authors.initials: M
authors.lastname: Seddighzadeh
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000662:Amphetamines / Q000494:pharmacology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000662:Amphetamines; D004768:Enterotoxins; D020381:Interleukin-17; D008070:Lipopolysaccharides; D044402:Receptor, Serotonin, 5-HT2A; D017366:Serotonin Receptor Agonists; D014409:Tumor Necrosis Factor-alpha; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine