rs143383

This genome-wide association study (GWAS) of radiographic tibiofemoral knee osteoarthritis in 3,898 cases and 3,168 controls from four North American cohorts identified one novel locus near LSP1P3 (rs4867568, OR=0.84, P=3.02×10⁻⁶) and confirmed associations with previously reported loci GDF5 (rs143383, OR=1.12, P=2.13×10⁻³) and FTO (rs8044769, OR=1.10, P=6.13×10⁻³). Despite the large sample size and standardized radiographic phenotyping, no variants achieved genome-wide significance, highlighting the polygenic nature of knee OA.

A case-control study in 220 adults with severe hip osteoarthritis found associations between TGFB1 29T>C (rs1800470) and IL6 -572G>C (rs1800796) polymorphisms with developmental dysplasia of the hip (DDH). The TGFB1 C/C genotype was associated with increased DDH risk (OR=2.42, p=0.032), the IL6 C/C genotype with stronger association (OR=6.36, p<0.001), and combined risk genotypes at both loci showed the strongest association (OR=11.3, p<0.001), suggesting a potential interaction between these cytokines in DDH pathogenesis.

This comprehensive meta-analysis examined the association between GDF5 genetic variants and osteoarthritis (OA) across knee, hip, and hand joints. The study analyzed 16 independent samples from 11 research teams, investigating SNP rs143383 located in the 5'-UTR of GDF5. Results showed the T-allele of rs143383 is a significant risk factor for knee OA (OR=1.18, 95% CI=1.10-1.27, P=1.84×10⁻⁶) and hand OA, but not hip OA, providing further support for GDF5 in OA etiology.

This functional study investigates the molecular mechanism by which the osteoarthritis-associated SNP rs143383 in GDF5 regulates allelic expression through CpG methylation. The authors show that GDF5 is upregulated in osteoarthritic cartilage and demonstrate that methylation of the +37 CpG site modulates the binding of SP1, SP3, and DEAF1 transcriptional repressors to rs143383 in an allele-specific manner, with the effect particularly pronounced in knee cartilage, potentially explaining the knee-specific osteoarthritis association.

Candidate gene study of 4 SNPs in Russian population replicating GWAS-significant variants associated with stage 4 knee osteoarthritis. The A allele of rs6499244 in NFAT5 was identified as a risk factor for knee osteoarthritis in additive (OR=1.61, p=0.02) and recessive (OR=2.07, p=0.02) models. Functional analysis shows rs6499244 is located in DNase-hypersensitive regions and enhancers, associated with expression of 9 genes including NFAT5 itself.

A meta-analysis of five Northern European population cohorts (total N=5,259) found that the GDF5 SNP rs143383 is associated with lumbar disc degeneration (LDD) in women, with the T allele conferring increased risk (OR=1.72, 95% CI 1.15-2.57, P=0.008). This association was strongest for the combined phenotype of disc space narrowing and osteophytes, consistent with the previously established role of GDF5 in peripheral joint osteoarthritis.

This Japanese cohort study of 206 elderly women (mean age 69.7 years) from the Obuse registry investigated associations between genetic variants and osteoarthritis (OA) prevalence. LRP5 rs3736228 showed significant associations with knee/hip OA (OR 7.28, 95% CI 2.22-28.08) and osteoporosis (OR 5.24, 95% CI 0.95-26.98). MTHFR rs1801133 showed a protective association with knee OA prevalence (OR 0.58, 95% CI 0.35-0.97). Other variants (LRP5 rs312009, GDF5 rs143383, SMAD3 rs12901499) showed no significant associations.

Genome-wide association study identifying 14,938 osteoarthritis cases and approximately 39,000 controls found that the C-allele of rs3815148 on chromosome 7q22 (near GPR22 gene) is associated with 1.14-fold increased risk of knee/hand OA (p=8×10⁻⁸) and 30% increased risk for knee OA progression. The same study identified rs10248619 and rs6088813 with secondary associations to OA.

This functional study investigated the GDF5 SNP rs143383 (T-to-C), an established osteoarthritis susceptibility variant. Using differential allelic expression analysis in multiple joint tissues from OA patients, the authors demonstrated that the OA-risk T allele shows consistently reduced expression (mean T/C ratio 0.79) across all joint tissues tested, not just cartilage. They identified a second regulatory variant rs143384 in the GDF5 5'-UTR that modulates rs143383's effect, and a third variant (2250ct) in the 3'-UTR that acts independently to reduce expression. EMSA assays revealed that the transcription factor DEAF-1 binds preferentially to the T allele at rs143383.

Large-scale meta-analysis of 14 collaborative studies examining associations between GDF5 rs143383, FRZB rs7775, and FRZB rs288326 polymorphisms with osteoarthritis (OA) of the hip, knee, and hand. GDF5 rs143383 showed strong association with knee OA (OR=1.15, P=9.4×10⁻⁷) with consistent effects across populations, but effects were heterogeneous for hip and hand OA. FRZB variants showed no significant overall effects on OA phenotypes.

This case-control study of 519 Greek individuals (251 knee osteoarthritis patients, 268 controls) investigated whether the GDF5 +104T/C polymorphism (rs143383) is associated with knee OA susceptibility. The variant was previously reported to associate with OA in Japanese and Han Chinese populations. No significant differences in genotype or allele frequencies were found between cases and controls (all p > 0.05), with OR=1.061 (95% CI: 0.931-1.209) for the T allele, indicating this polymorphism is not a risk factor for OA in Greek Caucasians and highlighting ethnic heterogeneity in genetic susceptibility to osteoarthritis.