Genetic variations in the serotonin 5-HT2A receptor gene (HTR2A) are associated with rheumatoid arthritis

Kling, Anders; Seddighzadeh, Maria; Ärlestig, Lisbeth; Alfredsson, Lars; Rantapää‐Dahlqvist, Solbritt; Padyukov, Leonid

doi:10.1136/ard.2007.074948

Cited by 35 publications

(28 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, because not all four SNPs were genotyped in the NARAC study, we decreased the number of SNPs to two. As could be seen from Table 2, the TC haplotype based on rs6314 and rs1328674, which is part of what was previously reported to be in association with RA, 16 demonstrates a protective effect in the EIRA study (P¼0.005 in w 2 -test). Further, we addressed the hypothesis for association in two other study populations that was replicated in the NARAC study (P¼0.006 in w 2 -test) but not in the Leiden EAC study (P¼0.8206 in w 2 -test), although the control group had a 0.2% higher frequency compared with the patients group ( Table 2).…”

Section: Resultsmentioning

confidence: 75%

“…35 Partition of RA into ACPA-positive and ACPA-negative subtypes is adequate, as more evidence points toward the fact that these two subtypes differ in etiology and pathophysiology. In this paper, we have shown that HTR2A, recently found to be in association with RA, 16 interacts with HLA-DRB1 SE alleles in the ACPA-positive group of patients. HLA-DRB1 SE alleles have no effect on the development of ACPAnegative RA and that could be the reason why this interaction is not observed in this subgroup of the disease.…”

Section: Discussionmentioning

confidence: 98%

“…16 Our previously found haplotype consisted of four tagging SNPs. However, because not all four SNPs were genotyped in the NARAC study, we decreased the number of SNPs to two.…”

Section: Resultsmentioning

confidence: 99%

“…The method used for genotyping in the Dutch cohort and the NARAC cohort has been reported elsewhere. 27 The method used for SNP genotyping of EIRA samples, which was previously performed, 16 and of Leiden EAC samples was TaqMan allelic discrimination (Applied Biosystems, Foster City, CA, USA). The call rates for rs6314 and rs1328674 in all three cohorts were 497 and 498%, respectively.…”

Section: Acpa Status and Genotypingmentioning

confidence: 99%

“…15 Previously we have demonstrated that genetic variations in HTR2A are in association with RA. 16 However, as the strength of the association was moderate, we hypothesized that the strongest genetic risk factor for RA, HLA-DRB1 SE alleles, may modulate it and we can colocalize both products in rheumatoid tissue or in related cells.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2010

View full text Add to dashboard Cite

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 populationsfrom 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.

show abstract

Section: Resultsmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 98%

“…16 Our previously found haplotype consisted of four tagging SNPs. However, because not all four SNPs were genotyped in the NARAC study, we decreased the number of SNPs to two.…”

Section: Resultsmentioning

confidence: 99%

Section: Acpa Status and Genotypingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2010

View full text Add to dashboard Cite

show abstract

Association between the use of serotonin receptor 2A–blocking antidepressants and joint disorders

Kling

Danell-Boman

Stenlund

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

Family‐Based Clinical Associations and Functional Characterization of the Serotonin 2AReceptor Gene (HTR2A) in Autism Spectrum Disorder

et al. 2014

View full text Add to dashboard Cite

The serotonin 2A receptor gene (HTR2A) harbors two functional single nucleotide polymorphisms (SNPs) that are frequent in populations of African and European descent; rs6311, which affects mRNA expression, and rs6314, which changes the amino acid sequence of the encoded protein and affects the signaling properties of the receptor. Multiple clinical associations support a role for these SNPs in cognitive and neuropsychiatric phenotypes, although studies in autism spectrum disorder (ASD) remain equivocal. Here, we tested transmission disequilibrium of rs6311 and rs6314 in a cohort of 158 ASD trios (simplex and multiplex), observing significant under-transmission of the minor “A” allele of rs6311 to offspring with ASD (permuted p=0.0004). Consistent with our previous findings in the dorsolateral prefrontal cortex of unaffected individuals, rs6311/A decreases expression of HTR2A mRNA with an extended 5′ untranslated region in the frontopolar cortex in brain samples from 54 ASD patients and controls. Interpreting the clinical results in the context of our mRNA expression analysis, we speculate that any risk associated with rs6311 is conferred by greater expression of the long 5′UTR mRNA isoform. The current study corroborates earlier associations between rs6311 and ASD in a family study, supporting the hypothesis that rs6311 plays a modulatory role in ASD risk.

show abstract

Genetic variations in the serotonin 5-HT2A receptor gene (HTR2A) are associated with rheumatoid arthritis

Abstract: 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.

Cited by 35 publications

References 18 publications

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

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

Association between the use of serotonin receptor 2A–blocking antidepressants and joint disorders

Family‐Based Clinical Associations and Functional Characterization of the Serotonin 2AReceptor Gene (HTR2A) in Autism Spectrum Disorder

Contact Info

Product

Resources

About