Graves’ Disease and Rheumatoid Arthritis: A Bidirectional Mendelian Randomization Study

Abstract

BackgroundThe frequent coexistence of Graves’ disease (GD) and rheumatoid arthritis (RA) has been cited and discussed in observational studies, but it remains a question as to whether there is a causal effect between the two diseases.MethodsWe retrieved genome-wide association study (GWAS) summary data of GD and RA from BioBank Japan (BBJ). Single nucleotide polymorphisms (SNPs) associated with diseases of interest were selected as instrumental variables (IVs) at a genome-wide significance level (P < 5.0 × 10−8). The random-effects inverse variance weighted method (IVW) was used to combine the causal effect of IVs. The horizontal pleiotropy effect was analyzed by MR-Egger and weighted median method sensitivity test. A leave-one-out analysis was conducted to avoid bias caused by a single SNP. The statistical power of our MR result was calculated according to Brion’s method.ResultsOur study discovered a bidirectional causal effect between GD and RA. The presence of RA may increase the risk of GD by 39% (OR 1.39, 95% CI 1.10–1.75, P = 0.007). Similarly, the existence of GD may increase the risk of RA by 30% (OR 1.30, 95% CI 0.94–1.80, P = 0.112). Our study provides 100% power to detect the causal effect of RA on GD risk, and vice versa.ConclusionsWe found a bidirectional causal effect between GD and RA in an Asian population. Our study supported the clinical need for screening GD in RA patients, and vice versa. The potential benefit of sound management of RA in GD patients (or GD in RA patients) merits excellent attention. Moreover, novel satisfactory medicine for RA may be applicable to GD and such potential is worthy of further investigation.

Association between rheumatoid arthritis and thyroid dysfunction: A meta-analysis and systematic review

“…It is reasonable to speculate that thyroid dysfunction shares a common pathogenesis with RA (59). Exploring the co-pathogenesis pathway of these two diseases and appropriate application of drugs that can act on the co-pathogenesis targets may be an ideal way to prevent and treat co-diseases in the future (58,60). In addition, a study by Raterman et al also emphasized the need for careful drug selection in patients with RA complicated by autoimmune thyroiditis.…”

“…The vast majority of hypothyroidism is caused by autoimmune diseases, such as Hashimoto’s thyroiditis, whereas autoimmune diseases lead to hyperthyroidism in relatively few cases and are influenced by age and environmental factors ( 57 ). A study using Mendelian randomization found a bidirectional causal relationship between RA and Graves’ disease, and good treatment and management of one may benefit the other ( 58 ). It is reasonable to speculate that thyroid dysfunction shares a common pathogenesis with RA ( 59 ).…”

Genetic association of leukocyte telomere length with Graves’ disease in Biobank Japan: A two-sample Mendelian randomization study

“…To date, no studies, to our knowledge, have been conducted to investigate the role of TL in Graves’ disease. A recent study showed that the relationship between Graves’ disease and rheumatoid arthritis, implying that these two autoimmune diseases were likely to share similar underlying mechanisms ( 42 ). Inflammation and oxidative stress are recognized as parts of the process for most of these diseases, but their molecular mechanisms have not fully been understood.…”

No genetic causal association between Alzheimer’s disease and osteoporosis: A bidirectional two-sample Mendelian randomization study

“…MR–Egger has low statistical power, so the focus is more on direction and effect ( Luo et al, 2020 ; Cai et al, 2021 ). The weighted median provided a reliable Mendelian evaluation when 50% of the instrumental variables (instrument variables) were not valid ( Wu et al, 2021 ). The odds ratio (OR) and 95% confidence interval (CI) were used to assess the relative risk due to the presence of the disease of interest.…”