Background/Purpose

Knee osteoarthritis (OA) is a heritable common joint disorder. In previously reported genetic studies, cases were usually defined with a radiographic Kellgren and Lawrence (K/L) grade ≥2. Since more severe knee OA is more likely to have greater medical and public health impact, we searched for genetic variations associated with severe radiographic knee OA (rKOA) of K/L grade 3 or 4.

Methods

Caucasian participants with knee radiographic grade from the Johnston County Osteoarthritis Project (JoCo) were included in this analysis. Cases were defined as the subjects with KL grade ≥3 in at least one knee, while the controls were defined as the subjects with KL grades = 0 in both knees.   Genome wide genotyping was completed using the Illumina Infinium 1M-Duo array and imputed into 2.5M using HapMap II Caucasian as the reference data.  Genome-wide association analysis was performed using logistic regression with adjustment for age and sex, with and without additional adjustment for BMI.

Results

Of 672 participants [64% women, mean age = 64.2 (SD=10.6), mean BMI = 30.3(SD=6.4)], 353 were cases and 319 were controls. Although no SNPs reached genome-wide significant p-values at 5E-8, we identified two SNPs with p-values less than E-06 in the model without BMI adjustment (table). After BMI adjustment, associations were attenuated but still statistically significant (table). Both SNPs, rs11196174 and rs11196175, are located in the TCF7L2 gene which encodes a T-cell specific transcription factor participating in the Wnt signaling pathway, which has been shown to be related to OA. 

Conclusion: Two SNPs, rs11196174 and rs11196175, located in the TCF7L2 gene were associated with severe rKOA, supporting the possibility that the pathogenesis of severe rKOA may be through the Wnt signaling pathway. Further studies will need to validate this finding in other populations.