Association Between Rheumatoid Arthritis and Osteoporosis in Japanese Populations: A Mendelian Randomization Study

Abstract

Objective The positive association between rheumatoid arthritis (RA) and osteoporosis has been reported in previous observational studies, but the causal relationship remains unclear. This study was undertaken to investigate whether RA was causally associated with osteoporosis in Japanese populations using Mendelian randomization (MR) analyses. Methods Publicly available summarized data from genome‐wide association studies (GWAS) on RA (4,199 cases and 208,254 controls) and osteoporosis (7,788 cases and 204,665 controls) were obtained from BioBank Japan. Eleven RA‐related single‐nucleotide polymorphisms (P < 5×10−8) were selected as instrumental variables. We used the inverse variance–weighted method as the primary method to calculate the odds ratios (ORs) and 95% confidence intervals (95% CIs). We also used the MR–Egger's method, weighted median, and weighted mode to determine the robustness of the main results. To partially test the horizontal pleiotropy, we used the MR–Egger's intercept test and the Mendelian randomization pleiotropy residual sum and outlier (MRPRESSO) test. Results Using the inverse variance–weighted method, we showed that genetically predicted RA was positively associated with osteoporosis (OR 1.10, 95% CI 1.06–1.14, P < 0.001). The positive association was robust when we tested the results using the MR–Egger's method (OR 1.09, 95% CI 1.03–1.16, P = 0.023), weighted median (OR 1.09, 95% CI 1.04–1.15, P < 0.001), and weighted mode (OR 1.08, 95% CI 1.03–1.13, P = 0.012). Horizontal pleiotropy was not detected (P = 0.737) by the MR–Egger's intercept test or the MRPRESSO test. Conclusion Our results show a potential causal association between genetically predicted RA and osteoporosis. The finding was consistent when we used different MR methods and the sensitivity analysis. Further MR studies are needed when GWAS with more details of RA and osteoporosis performed in other East Asian/Japanese populations are available.

Application of two-sample Mendelian randomization method to assess the causal relationship between rheumatoid arthritis and osteoporotic fracture

“…Similar findings were also observed by Song et al (34), which included European and Asian populations but failed to provide evidence for causation. Conversely, Deng et al (35) demonstrated positive support for a causal relationship between RA and osteoporosis specifically within the Japanese population.…”

Causal association between rheumatoid arthritis and pregnancy loss and intrauterine growth retardation: A bidirectional two-sample Mendelian randomization study

“…In this study, we assessed the causal relationship between RA and miscarriage as well as IUGR by 5 MR methods including inverse variance weighted (IVW) method, MR-Egger, Weighted median (WM), Simple mode, and Weighted mode. [ 18 ] Among these 5 MR methods, IVW is the most dominant MR analysis method, which can effectively assess the causal relationship. However, IVW has some limitations, so we used MR-Egger regression to compensate for the shortcomings of IVW in terms of the instability of multiplicity and to make the causality more stable.…”

“…[ 16 ] Therefore, it is a novel method of evaluating causality. [ 17 ] Many scholars have used MR to study the relationship between RA and a variety of diseases such as osteoporosis, [ 15 , 18 ] inflammatory bowel disease [ 19 ] and cancers, [ 20 ] but there is a gap in research on the relationship between RA and adverse pregnancy histories such as miscarriage and IUGR. In this study, for the first time, MR was used to investigate the causal relationship between RA and miscarriage and IUGR.…”

Causal association between rheumatoid arthritis and an increased risk of age-related macular degeneration: A Mendelian randomization study

“…[ 9 ] Rheumatoid arthritis is closely associated with many diseases. Some Mendelian randomization studies suggest a causal relationship between RA and osteoporosis, [ 10 ] another subset of studies showed that RA is not causally related to osteoporosis, and that osteoporosis in RA patients may be associated with side effects of antirheumatic therapy and reduced physical activity. [ 11 ] Previous studies have found the positive effects of rheumatoid arthritis on inflammatory bowel disease.…”