Physical activity and the risk of rheumatoid arthritis: evidence from meta-analysis and Mendelian randomization

Abstract

Background There is very little information about the association between physical activity (PA) and the risk of rheumatoid arthritis (RA). The purpose of this study is to understand the effect of PA on subsequent risk of developing RA. Methods A literature search was performed in PubMed and Web of Science up to 19 September 2020. Observational studies examining associations between PA and the RA development were identified. Categorical and dose–response meta-analyses were both performed. Then two-sample Mendelian randomization (MR) analysis was conducted to interrogate the causal relationship by utilizing genetic instruments identified from a genome-wide association study of self-reported and accelerometer-based PA traits. Results Four eligible studies were included in the meta-analyses, involving 4213 RA cases among 255 365 participants. The summary relative risk (RR) of RA risk was 0.79 [95% confidence interval (CI): 0.72, 0.87] for the highest vs the lowest PA, and 0.85 (95% CI: 0.79, 0.92) for PA vs inactivity/occasional PA. However, we found no convincing evidence supporting a causal role of genetically predicted accelerometer-measured PA [odds ratio (OR): 0.97; 95% CI: 0.88, 1.08 per 1-SD unit increment], genetically predicted moderate-to-vigorous PA (OR: 1.08; 95% CI: 0.49, 2.39 per 1-SD unit increment) or genetically predicted vigorous PA ≥3 days/week (OR: 2.63; 95% CI: 0.05, 130.96) with RA risk. Conclusions The meta-analyses of the observational studies indicated that higher PA levels correlate with reduced risk of RA. In contrast to meta-analyses, the MR analyses reported here suggested PA may not help to prevent RA.

Causal Relationships Between Total Physical Activity and Ankylosing Spondylitis: A Mendelian Randomization Study

“…Initially, the current study extracted SNPs associated with PA at the genome-wide significance threshold [P < 5 × 10 −8 for average acceleration and self-reported PA, P < 5 × 10 −7 for PA (acceleration fraction >425 mg)] ( 21 , 22 ). The present study clumped SNPs using the PLINK clumping algorithm (r 2 = 0.01 and clumping distance = 5,000 kb).…”

Causal risk and protective factors in rheumatoid arthritis: A genetic update

“…Again, HLA-DRB1 is retrieved as the main genetic factor to explain the direct association between chronic inflammation in RA with BMI. On the opposite a negative association appears with RA when using low level of sIL-6R as surrogate of anti-inflammatory and protective factor, this includes education factor with a higher education level (OR = 0.49; CI95: 0.34–0.69); and cognitive factors with intelligence (0R = 0.76; CI95: 0.63–0.91) [ 26 , 27 , 33 ]. For the education level and intelligence, the effect is independent and remains after adjusting with BMI and tobacco smoking.…”

“…Nutritional factors are suspected to increase RA risk [ 100 , 101 ] and the MR approaches can help to investigate the causality. A direct and protective association is reported with omega-3/6 polyunsaturated fatty acid (linoleic acid: OR = 0.97; CI95: 0.95–0.98) and monounsaturated fatty acids (oleic acid: OR = 0.24; IC95: 0.10–0.59; palmitoleic acid: OR = 0.98; IC95: 0.67–0.90), moderate alcohol consumption in some (OR = 0.75; CI95: 0.67–0.83) but not all studies (OR = 0.80; IC95: 0.54–1.19), and meat reduction (OR = 0.81; CI95: 0.76–0.90) [ 28 , 33 , 43 ]. Although RA and disease activity can influence dietary habits, no direct association is reported with the consumption of eggs, sweet, bread, rice, pasta, fruit, legumes, vegetable, coffee and tea [ 26 , 43 ].…”

“…Miscellaneous associations were further tested by MR in RA to highlight a negative association between life span and telomere length with RA [ 29 , 104 ], RA reduces the risk of Alzheimer's disease (S.-C. [ 26 ], and positive associations are retrieved between multisite chronic pain, magnesium supplementation and RA development [ 32 , 41 ]. Finally, no association is reported with coffee consumption, alcohol intake, attention-deficit/hyperactivity disorder (ADHD), physical activity, blood minerals (Ca2+, Zn+, Fe2+ and Cu+), the circulating level of growth differentiation factor (GDF)-15 and cellular capacity to glycosylate IgG [ 33 , 36 , 38 , 39 , 41 , 42 , 105 ].…”

Challenges and Opportunities of Targeted Behavioral Interventions for Groups at Risk for Developing Rheumatoid Arthritis

“…High physical activity may reduce RA risk by reducing production of inflammatory biomarkers including C-reactive protein [31] and via an overall anti-inflammatory effect [31,32]. A meta-analysis of physical activity demonstrated that high levels of physical activity reduce RA risk compared to low levels, and that physical activity decreases RA risk compared to inactivity/occasional physical activity [32].…”