期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 20, 期 6, 页码 -出版社
MDPI
DOI: 10.3390/ijms20061382
关键词
AP-1; JUN; FOS; promoter; knee osteoarthritis
资金
- German Federal Ministry of Education and Research [FKZ 010405, 01KN0702, BMBF PtJ-Bio 0315883]
- Jena Centre for Bioinformatics [FKZ 0313652B, FKZ 01GS0413, NGFN-2]
- Sachsische Aufbaubank [7692/1187]
- European Fund for Regional Development [EFRE 4212/04-04]
- LIFE - Leipzig Research Center for Civilization Diseases, Universitat Leipzig
- European Union
- European Regional Development Fund (ERDF)
- Free State of Saxony
- Emil Aaltonen Foundation
Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2-3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2-2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA.
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