The impact of education inequality on rheumatoid arthritis risk is mediated by smoking and body mass index: Mendelian randomization study

Objective To estimate the causal relationship between educational attainment-as a proxy for socioeconomic inequality-and risk of RA, and quantify the roles of smoking and BMI as potential mediators. Methods Using the largest genome-wide association studies (GWAS), we performed a two-sample Mendelian randomization (MR) study of genetically predicted educational attainment (instrumented using 1265 variants from 766 345 individuals) and RA (14 361 cases, 43 923 controls). We used two-step MR to quantify the proportion of education's effect on RA mediated by smoking exposure (as a composite index capturing duration, heaviness and cessation, using 124 variants from 462 690 individuals) and BMI (517 variants, 681 275 individuals), and multivariable MR to estimate proportion mediated by both factors combined. Results Each s.d. increase in educational attainment (4.2 years of schooling) was protective of RA (odds ratio 0.37; 95% CI: 0.31, 0.44). Higher educational attainment was also protective for smoking exposure (beta = -0.25 s.d.; 95% CI: -0.26, -0.23) and BMI [beta = -0.27 s.d. (similar to 1.3 kg/m(2)); 95% CI: -0.31, -0.24]. Smoking mediated 24% (95% CI: 13%, 35%) and BMI 17% (95% CI: 11%, 23%) of the total effect of education on RA. Combined, the two risk factors explained 47% (95% CI: 11%, 82%) of the total effect. Conclusion Higher educational attainment has a protective effect on RA risk. Interventions to reduce smoking and excess adiposity at a population level may reduce this risk, but a large proportion of education's effect on RA remains unexplained. Further research into other risk factors that act as potentially modifiable mediators are required.