Mendelian Randomization Studies of Lifestyle-Related Risk Factors for Osteoarthritis: A PRISMA Review and Meta-Analysis

Abstract

Risk factors for osteoarthritis (OA) often exert effects over protracted time-courses. Mendelian randomization (MR) studies therefore have an advantage over conventional observational studies when studying the causal effect of long-term lifestyle-related risk factors on OA. However, given the heterogeneous design of existing MR studies on OA, the reported causal estimates of these effects remain inconsistent, thus obscuring the true extent of the biological effects of OA lifestyle-risk factors. We conducted a PRISMA systematic review and specifically included MR studies that investigated the causal effect between lifestyle-related risk factors and OA, where causal estimates for various lifestyle factors were pooled for meta-analysis. Quality of studies was assessed according to STROBE-MR guidelines. A total of 1576 studies were evaluated and 23 were included. Overall, the studies included were of high quality and had a low risk of bias. Our meta-analysis demonstrates the positive causal effect of BMI (OR_{IVW-random effects} 1.49 [1.23-1.80]) and negative causal effects of serum calcium (OR_{IVW-random effects} 0.69 [0.57-0.83]) and LDL levels (OR_{IVW-random effects} 0.93 [0.90-0.96]) on OA. Despite the heterogeneous designs and estimates of causal effects provided by various MR studies, our meta-analysis suggests that lifestyle-related risk factors in the form of BMI, serum calcium, and LDL have true biological effects on the development of OA.

Keywords: Mendelian randomization; arthritis; genetic epidemiology; lifestyle-related risk factors; osteoarthritis.

Figure A1

Funnel Plot for publication bias under fixed-effects sampling variance; inverse standard error and inverse sampling variance were used as predictor.

Figure A2

Funnel Plot for publication bias under mixed-effects sampling variance; inverse standard error and inverse sampling variance were used as predictor.

Figure 1

Preferred Reporting Items of Systematic Review and Meta-analyses (PRISMA) flow diagram.

Figure 2

Forest plot of studies that evaluated the causal effect between BMI and all OA outcomes using values obtained by the IVW MR method.

Figure 3

Forest plot of studies that evaluated the causal effect between BMI and all OA outcomes using values obtained by the MR-Egger methods.

Figure 4

Forest plot of studies that evaluated the causal effect between BMI and all OA outcomes using values obtained by methods other than IVW and MR-Egger.

Figure 5

Forest plot of studies that evaluated the causal effect between BMI and all OA outcomes using values relating to European individuals.

Figure 6

Forest plot of studies that evaluated the causal effect between BMI and all OA outcomes using values relating to White-British individuals.

Figure 7

Forest plot of studies that evaluated the causal effect between serum calcium and all OA outcomes using values obtained by the IVW method.

Figure 8

Forest plot of studies that evaluated the causal effect between LDL and all OA outcomes using values obtained by the IVW method.

Figure 9

Funnel plot of the included studies, suggesting limited publication bias under fixed effects meta-regression models when the standard error was used as predictor, p-value 0.159.

Figure 10

Funnel plot of the included studies, suggesting limited publication bias under mixed effects (restricted maximum likelihood) meta-regression models when the standard error was used as predictor, p-value 0.822.