This study demonstrated a significant relationship between LRP5 rs3736228 and the skeletal disorders of OA and osteoporosis in elderly community-dwelling female residents randomly sampled from a Japanese town resident registry. A statistically significant protective association of the common allele of MTHFR rs1801133 with knee OA prevalence was also observed. As the population sampling of our cohort minimized selection bias, our results might be considered reflective of the Japanese general population.
LRP5 and 6 (LRP5/6) are required as co-receptors for canonical Wnt signaling8,9 and play important roles in skeletal development and metabolism. A number of LRP5 gene variants have been reported. Of those, associations of the missense variants LRP5 rs3736228 (Ala1330Val) and rs4988321 (Val667Met) with decreased BMD and the risk of osteoporotic fracture are well described10,11. In particular, a relationship between LRP5 A1330V and diminished BMD has been identified in the Japanese population12,13. A loss of function in LRP5 increased cartilage degradation in a mouse model14 and was also suggested to be associated with OA. However, little is known on the precise connection between OA and LRP5 gene variants. Although associations of LRP5 rs41494349 (Gln89Arg) with spinal OA15 and LRP5 rs3736228 with knee OA16 have been reported, no information has been recorded in the GWAS catalog to date (https://www.ebi.ac.uk/gwas/)3. Therefore, the findings of this study demonstrating a relationship between the T allele of LRP5 rs3736228 and knee/hip OA prevalence in a randomly sampled population cohort will be of value for further understanding the relationship between OA development and the pathophysiological role of LRP5 dysfunction.
In the subgroup analysis for knee OA, there was a protective association for the common C allele of MTHFR rs1801133 (Ala222Val) rather than a risk association of the minor T allele with the prevalence rate of knee OA. MTHFR is known to act within the methionine cycle and play an essential role in homocysteine clearance. A functional deficiency of the MTHFR enzyme leads to mild elevation of circulating homocysteine levels17. The A222V missense variant is a common mutation in the MTHFR gene that causes dysfunctional enzymatic activity. Notably, the T allele of MTHFR rs1801133 has been implicated in decreased BMD and the occurrence of osteoporotic fractures18,19, and we very recently uncovered a relationship among homocysteine, MTHFR rs1801133, and spinal OA in Japanese postmenopausal women [under review]. The results of the present study imply a correlation between diminished homocysteine levels and a lower risk of knee OA prevalence. Since circulating homocysteine levels can be decreased by vitamin B group supplementation20, the significance of B-vitamins intervention in individuals bearing the T allele of MTHFR rs1801133 for preventing OA development may warrant further investigation.
An intron variant of LRP5 gene rs312009 as well as GDF5 rs143383 and SMAD3 rs12901499 showed no remarkable correlations with OA or osteoporosis prevalence in this study. The rs143383 is located in the 5′-untranslated region core promotor of GDF5, which encodes a chondrogenic protein. A relationship of rs143383 with OA has been demonstrated in various racial groups, including a Japanese cohort21,22. On the other hand, SMAD3 is a member of the SMAD family of proteins and plays an essential role in mediating the transforming growth factor-beta signaling pathway. A genetic variant, rs12901499, within the intron 1 of SMAD3 is reportedly associated with OA in Caucasian and Asian populations23,24. However, other studies have shown no relationship for either GDF5 rs143383 or SMAD3 rs12901499 with OA prevalence25,26. Relatively small number of samples limited to female subjects is a limitation of the current study. Besides, although the subjects were randomly sampled from a resident registry, there was a potential for selection bias due to the low participation rate (32.0%) as a result of the noncompulsory survey design. Furthermore, since it sampled from a single town in Japan, this study might contain local features that should be considered when interpreting the data. Future studies with larger sample sizes and male subjects that include multiple regions in Japan and/or other Asian countries will overcome the controversial issues.
In conclusion, we observed significant associations of LRP5 rs3736228 and MTHFR rs1801133 with knee/hip OA and osteoporosis prevalences and knee OA prevalence, respectively, in Japanese elderly women from the randomly sampled Obuse study cohort. The results of the present study will help further the understanding of OA pathogenesis and related genetic risk factors, which will contribute to improved disease prevention and therapeutic management.
Data availability statements
The data analyzed and/or generated during the current study are available from the corresponding author on reasonable request.