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- Kling, Anders, et al.
(författare)
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Genetic variations in the serotonin 5-HT2A receptor gene (HTR2A) are associated with rheumatoid arthritis
- 2008
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 67:8, s. 1111-1115
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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- Saevarsdottir, S., et al.
(författare)
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Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 81:8
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. Methods We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and similar to 1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). Results We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1x10(-9)), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3x10(-160)). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6x10(-11)). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10(-9)-10(-27)) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. Conclusion Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.
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