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Genetic variations in the serotonin 5-HT2A receptor gene (HTR2A) are associated with rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
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2008 (English)In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 67, no 8, 1111-1115 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To analyse the association between the genetic polymorphisms within the HTR2A gene for the serotonin receptor and rheumatoid arthritis (RA).

METHODS: HTR2A gene polymorphisms were analysed in patients with RA and controls from two study populations using PCR based restriction endonuclease mapping or TaqMan allelic discrimination with more than 4000 individuals included in the current study.

RESULTS: At the discovery stage we detected significant differences in frequency of rs6313 (T102C polymorphism) between the patients with RA and controls (p = 0.006). Following validation with an extended set of single nucleotide polymorphisms (SNPs) and number of DNA samples, a trend in associations in allelic model for SNPs rs6314, rs1328674, rs6313 and rs6311 (p = 0.006, 0.002, 0.006, 0.009) was seen, although it was lost after correction for multi-comparison for all but rs1328674 (empirical p value = 0.021). However, haplotype frequency analysis based on these four SNPs showed significantly low representation of TCTT combination in patients with RA in comparison with controls (3.6% and 5.6%, p<0.001 on chi(2) test, empirical p = 0.004 after 100 000 permutations) and a significantly higher frequency of CTCC combination in patients with RA in comparison with controls (3.6% and 2.2%, p = 0.002 on chi(2) test, empirical p = 0.022 after 100 000 permutations).

CONCLUSIONS: In our study, genetic polymorphisms at the HTR2A gene are associated with susceptibility for RA, suggesting possible links between the serotonergic system and development of the disease.

Place, publisher, year, edition, pages
2008. Vol. 67, no 8, 1111-1115 p.
National Category
Social and Clinical Pharmacy
URN: urn:nbn:se:umu:diva-25995DOI: 10.1136/ard.2007.074948PubMedID: 18006541OAI: diva2:235663
Available from: 2009-09-17 Created: 2009-09-17 Last updated: 2013-01-14Bibliographically approved
In thesis
1. 5-HT2A: a serotonin receptor with a possible role in joint diseases
Open this publication in new window or tab >>5-HT2A: a serotonin receptor with a possible role in joint diseases
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]


Serotonin (5-HT), an amino acid derivative and neurotransmitter, has for long been studied in relation to inflammation. It is an endogenous ligand for several different types of serotonin receptors. The serotonin receptor 5-HT2A has been reported to have a role in the pathophysiology of arthritis in animal experiment models. However, no studies into this subject have been reported in man.


The objectives of this project were firstly, to examine possible associations for the 5-HT2A receptor and also for the gene (HTR2A) encoding for the receptor with arthritis in man and secondly, to explore possible mechanisms underlying such associations.


The density and affinity of platelet 5-HT2A receptors were determined in 43 patients with a common inflammatory joint disease, i. e., rheumatoid arthritis (RA), in comparison with matched controls using a radio-ligand assay. The effects of treatment with prednisolone on 5-HT2A density and affinity were also examined in 27 individuals diagnosed with polymyalgia rheumatica before and after start of treatment. In addition, possible candidate HTR2A genes were studied in relation to RA in two Swedish cohorts incorporating a total of 2450 RA patients. Furthermore, a register study using reports of joint symptoms as adverse drug reactions (ADRs) in the Swedish and the WHO ADR databases was undertaken. The proportion of reports concerning joint symptoms in relation to all ADR reports and to sales figures was analysed for 5-HT2A blocking atypical antidepressant substances compared with another group of antidepressants, i. e., selective serotonin re-uptake inhibitors (SSRIs), used for similar clinical indications.


The mean density of 5-HT2A receptors in RA patients was significantly lower than in controls, 45.3 versus 57.4 fmol/mg protein (p = 0.004). There was no significant difference in affinity. Variation of four single nucleotide polymorphisms (SNPs) (rs6314, rs1328674, rs6313 and rs6311) in the HTR2A gene was associated with RA, although not significantly so for all SNPs after testing for multiple comparisons. The proportion of joint symptoms reported as ADRs, relative to all ADRs was significantly higher for the 5-HT2A blocking antidepressants compared with the SSRIs in both databases (p< 0.001). In the Swedish material the comparison of ADRs was also related to sales figures, showing a considerable higher frequency of joint symptoms for the 5-HT2A antagonists (p< 0.001). The density of 5-HT2A receptors increased after treatment with prednisolone in 23 out of 27 individuals. The mean density at baseline was 45.2 versus 64.9 fmol/mg protein at the end of the study (p=0.001). There were no significant differences in affinity during the treatment period, although a low affinity at baseline was a predictor for higher density following treatment with prednisolone.


The density of 5-HT2A receptors, reflecting the number of receptors, was markedly reduced in a cohort of patients with RA from Northern Sweden. This may depend, at least in part, on an association between RA and certain HTR2A SNPs. Genetically determined or acquired low levels of accessible 5-HT2A receptors may contribute to susceptibility for development of joint symptoms, not only in RA but more generally, e. g., joint ADRs caused by 5-HT2A blocking atypical antidepressants. The benefits of treatment with glucocorticoids may, at least partially, be mediated by an effect on 5-HT2A receptors.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2013. 79 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1547
5-HT2A serotonin receptor, serotonin, rheumatoid arthritis, adverse drug reaction, HTR2A, glucocorticoids
National Category
Pharmacology and Toxicology
Research subject
Clinical Pharmacology
urn:nbn:se:umu:diva-64013 (URN)978-91-7459-549-9 (ISBN)
Public defence
2013-01-28, Vårdvetarhusets aula, Vårdvetarhuset, Umeå, 13:00 (Swedish)
Available from: 2013-01-14 Created: 2013-01-11 Last updated: 2013-01-14Bibliographically approved

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Kling, AndersArlestig, LisbethRantapää-Dahlqvist, Solbritt
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