Causal Relationship Between Parathyroid Hormone and the Risk of Osteoarthritis: A Mendelian Randomization Study

Abstract

BackgroundPrevious studies have demonstrated an inverse association between parathyroid hormone (PTH) and the risk of osteoarthritis (OA). However, it remains unknown whether such association reflects causality. We aimed to apply a Mendelian randomization (MR) approach to investigate the causal association between PTH and OA.Materials and MethodsWe performed a two-sample MR analysis using summary statistics from 13 cohorts (PTH, N = 29,155) and a recent genome-wide association study meta-analysis (OA, N = 455,221) by the UK Biobank and Arthritis Research UK OA Genetics (arcOGEN). MR analyses were carried out mainly using the inverse-variance-weighted method. Sensitivity analyses were performed to test the robustness of the associations using the weighted median method, the MR–Egger method, and “leave-one-out” analysis. Analyses were performed again to test whether the associations remained statistically significant after excluding any outlier variants that were detected using the MR-PRESSO (Mendelian Randomization Pleiotropy RESidual Sum and Outlier) test.ResultsFive single-nucleotide polymorphisms (SNPs) were selected as instrumental variables at the genome-wide significance threshold (p < 5 × 10–8). The causal effect between PTH and OA was genetically predicted using the inverse-variance-weighted method (odds ratio = 0.67, 95% confidence interval: 0.50–0.90; p = 0.008). This result was borne out using the weighted median method (odds ratio = 0.73, 95% confidence interval: 0.60–0.90; p = 0.004). The causality remained robust after discarding the outlier variants as well as SNPs associated with confounding factors.ConclusionMR analysis supported a potential causative relationship between decreased serum circulating PTH and a higher risk of hip and knee OA.

Causal Factors for Osteoarthritis: A Scoping Review of Mendelian Randomization Studies

“…25 Higher genetically predicted levels of parathyroid hormone have been associated in two studies with lower OA risk (OR 0.67, 95% CI 0.50-0.90; OR 0.71, 95% CI 0.61-0.82), with sensitivity analyses in one of these studies also indicating the association unlikely to be due to pleiotropy. 26,27 There is modest support for a causal association of sex hormone-binding globulin with OA risk at the hip, but not the knee (OR 1.09, 95% CI 1.01-1.17), although again, further sensitivity analyses were unable to rule out the possibility of the association being secondary to horizontal pleiotropy. 28 There was little support for a causal association of OA risk with genetically predicted levels of testosterone, dehydroepiandrosterone sulfate, or dihydrotestosterone.…”

“…In contrast, genetically predicted levels of insulin‐like growth factor 1 (IGF‐1) were robustly associated with higher OA risk, with sensitivity analyses (OR 1.49, 95% CI 1.21–1.83), including adjustment for a BMI PRS suggesting that the IGF‐1 PRS association with OA was unlikely to be due to pleiotropy with BMI 25 . Higher genetically predicted levels of parathyroid hormone have been associated in two studies with lower OA risk (OR 0.67, 95% CI 0.50–0.90; OR 0.71, 95% CI 0.61–0.82), with sensitivity analyses in one of these studies also indicating the association unlikely to be due to pleiotropy 26,27 . There is modest support for a causal association of sex hormone–binding globulin with OA risk at the hip, but not the knee (OR 1.09, 95% CI 1.01–1.17), although again, further sensitivity analyses were unable to rule out the possibility of the association being secondary to horizontal pleiotropy 28 .…”

Effect of Osteoporosis Treatments on Osteoarthritis Progression in Postmenopausal Women: A Review of the Literature

“…Mendelian randomization is a method of using measured variations in genes of known function to examine the causal effect of a modifiable exposure. Two Mendelian randomization studies were identified in our review, and both found a causative relation between decreased circulating PTH level and increased risk of hip and knee OA [ 36 , 37 ].…”

Rheumatoid arthritis increases the risk of malignant neoplasm of bone and articular cartilage: a two-sample bidirectional mendelian randomization study

“…Efforts were made to exclude the influence of outliers on the causal assessment of exposure and outcome. Analyzing the impact of individual SNPs on the causal assessment, a “leave-one-out” analysis was performed for detection [ 29 ]. Furthermore, the normal distribution of the MR analyses was examined, and the MR robust adjusted profile score (MR-RAPs) method was employed.…”