Higher educational attainment leads to lower relative odds of rheumatoid arthritis (RA), and this effect is mediated with smoking and body mass index (BMI), according to findings published in a study in Rheumatology.

Researchers aimed to investigate the effect of educational attainment on the risk for RA and quantify the roles of smoking and BMI as mediators with use of 2-sample Mendelian randomization (MR).

The study authors obtained summary single nucleotide polymorphism–phenotype association data from genome-wide association studies (GWAS) for each phenotype. Educational attainment was based on the Social Science Genetic Association Consortium GWAS meta-analysis regarding years of education of 766,345 participants of European ancestry. RA genetic associations were obtained from a GWAS meta-analysis of 14,361 RA cases and 43,923 control participants.

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A GWAS meta-analysis of 681,275 individuals of European ancestry was used to obtain BMI data, and smoking data were based on a GWAS of 462,690 participants of European ancestry in the UK Biobank.

The relative odds of RA were 63% lower (odds ratio [OR] 0.37; 95% CI, 0.31, 0.44) for each standard deviation (4.2 years) increase in educational attainment. Higher educational attainment was associated with lower smoking exposure (β= –0.25; 95% CI, –0.26, –0.23) and lower BMI (β= –0.27; 95% CI, –0.31, –0.24).

Univariable MR demonstrated that each standard deviation increase in smoking exposure (OR 2.13; 1.25, 3.62) or in BMI (OR 1.14; 0.95, 1.36) was associated with an increased relative odds of RA. Bidirectional positive effects were observed between smoking and BMI, as smoking exposure increased BMI (β = 0.59; 0.34, 0.84) and BMI increased smoking exposure (β = 0.11; 0.10, 0.13).

The combined effect of BMI and smoking mediated 47% (95% CI, 11%, 82%) of the effect of education on RA.

The investigators noted that they were not able to assess for a potential exposure-mediator interaction. In addition, MR may not capture the time-varying nature of the exposures, and a snapshot BMI measurement may not be representative of BMI for an entire life course.

“Broader efforts to improve socioeconomic inequalities and access to education are required, as well as further research into other environmental risk factors that act as potentially modifiable mediators of socioeconomic deprivation,” the researchers commented.


Zhao SS, Holmes MV, Zheng J, et al. The impact of education inequality on rheumatoid arthritis risk is mediated by smoking and body mass index: Mendelian randomization study. Rheumatology (Oxford). Published online August 26, 2021. doi:10.1093/rheumatology/keab654