Association of Human Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study.

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the and core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on / transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. and 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 ( = 298), knee-OA ( = 277), and NC ( = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: = 72, NC: = 548). Initially, two SNPs were detected in the promoter and two additional SNPs in the promoter in perfect linkage disequilibrium (LD). promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the promoter SNPs. The homozygous genotype of promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2⁻3.7, = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2⁻2.5, = 0.006). Promoter variants may represent relevant susceptibility markers for knee-OA.