Purpose Environmental- and genetic factors’ influence in the pathogenesis of rheumatic disease including systemic lupus erythematosus (SLE) have individually been extensively researched. Moreover, a synergistic effect of smoking with anti-citrullinated protein has been established for the risk of developing rheumatoid arthritis. In SLE, however, studies on synergistic effect are few and of limited sample size. We aim to investigate if established genetic end environmental risk factors for SLE display additive or synergistic interactions on the risk of SLE.

Methods A case-control designed nationwide epidemiological study of Danish patients with SLE will be conducted. Patient data-/blood samples for genetic analysis will be stored in the DANBIO-database/Danish Reuma Biobank, in which, since 2000/2015 respectively, collection of information regarding e.g. demographics and disease activity-/tissue samples from patients with inflammatory- and connective tissue disease has taken place. Patients will be matched (gender/age) against participants in the Danish Blood Donor Study in a 1:10 ratio. Sample size to detect degree of synergy between environmental risk behaviour and minor allele frequency of susceptible genes was calculated. Lifestyle and environmental exposures will be collected by self-report and by pulling data from Danish registries. Genetic analysis will be conducted with Illumina sequencing instruments.

Results We identified 966 patients registered in DANBIO with SLE. 20 000 control patients from the Danish Blood Donor Study have completed a self-report questionnaire and genetic sequencing on collected blood samples has been performed. To exemplify the power of this study, we found from the literature risk ratios for developing SLE of about 1.5 for both current smokers and persons with polymorphisms in the signal transducer and activator of transcription 4-gene. By computer modelling we calculated the ability to detect a degree of synergy of 45% with a power of 80%.

Conclusion From this study we expect to provide new information on how certain lifestyle and environmental factors may push the development of SLE in genetically predisposed individuals. Hereby point at new candidate sites of intervention in both treatment and prophylaxis.

This project will have the potential to collaborate with similar upcoming projects in Europe allowing analysis of less prevalent genetic aberrations and/or environmental exposures.