The study of interactions between genome and exposome in the development of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a systemic inflammatory autoimmune disease characterized by a broad spectrum of clinical and serological manifestations. This may reflect a complex and multifactorial etiology involving several identified genetic and environmental factors, though not explaining the full risk of SLE. Established SLE risk genotypes are either very rare or with modest effect sizes and twin studies indicate that other factors besides genetics must be operative in SLE etiology. The exposome comprises the cumulative environmental influences on an individual and associated biological responses through the lifespan. It has been demonstrated that exposure to silica, smoking and exogenous hormones candidate as environmental risk factors in SLE, while alcohol consumption seems to be protective. Very few studies have investigated potential gene-environment interactions to determine if some of the unexplained SLE risk is attributable hereto. Even less have focused on interactions between specific risk genotypes and environmental exposures relevant to SLE pathogenesis. Cohort and case-control studies may provide data to suggest such biological interactions and various statistical measures of interaction can indicate the magnitude of such. However, such studies do often have very large sample-size requirements and we suggest that the rarity of SLE to some extent can be compensated by increasing the ratio of controls. This review summarizes the current body of knowledge on gene-environment interactions in SLE. We argue for the prioritization of studies that comprise the increasing details available of the genome and exposome relevant to SLE as they have the potential to disclose new aspects of SLE pathogenesis including phenotype heterogeneity.

Concordance of autoimmune disease in a nationwide Danish systemic lupus erythematosus twin cohort.

OBJECTIVE: To determine the concordance of systemic lupus erythematosus (SLE) and co-aggregating autoimmune diseases among Danish twins. METHODS: SLE-affected twins were ascertained by record linkage between the National Patient Register (NPR) and the Danish Twin Registry (DTR). Registered SLE codes were validated through medical chart review and information from the treating physicians. Twin pairs with at least one chart-validated SLE proband were invited to participate in a personal interview and clinical validation of the SLE diagnoses. RESULTS: Twenty-two twins fulfilled the ACR criteria for SLE. The age- and sex-adjusted point SLE prevalence in the Danish twin cohort was 30.3 per 100,000 persons (95% CI: 19.2-46.5). Among seven monozygotic (MZ), eight same-sex dizygotic (DZss) and five opposite-sex dizygotic (DZos) twin pairs, one MZ and one DZss were concordant for SLE. This corresponded to probandwise concordance rates of 25.0% (95% CI: 7.15-59.1) and 7.7% (95% CI: 1.37-33.3), and pairwise concordance rates of 14.3% (95% CI: 2.57-51.3) and 7.7% (95% CI: 1.37-33.3) among MZ and DZ twins, respectively. An SLE diagnosis was clinically validated in 17 twins from 15 twin pairs. Another four co-twins had other autoimmune disease, corresponding to a probandwise concordance of any autoimmune disease of 50.0% in MZ (95% CI: 21.5-78.5) and 23.1% in DZ twins (95% CI: 8.18-50.3). CONCLUSION: Population-based Danish data suggest that SLE twin concordance is lower than previously reported, but still point to the importance of both genetic and environmental factors, and indicate a substantial co-aggregation of other autoimmune diseases in SLE twins.

Family history of systemic lupus erythematosus and risk of autoimmune disease: Nationwide Cohort Study in Denmark 1977-2013.

Objective: To provide population-based estimates of relative risk of SLE and other autoimmune diseases (ADs) in relatives of SLE patients. Methods: A cohort of 5 237 319 Danish residents identified through the Civil Registration System was coupled to their relatives through the parental link and followed for SLE and other ADs between 1977 and 2013 through linkage to the National Patient Register. Twin zygosity was established through the Danish Twin Registry. Hazard ratios (HRs) with 95% CIs were calculated using Cox proportional hazards regression analyses. Results: During 117.5 million person-years of follow-up, 3612 persons were hospitalized with SLE. HRs of SLE were high among first-degree (HR = 10.3; 95% CI: 8.25, 12.9; n = 80) and second- or third-degree relatives of SLE patients (HR = 3.60; 95% CI: 2.20, 5.90; n = 16). HRs for any AD were elevated in first-degree (HR = 1.51; 95% CI: 1.41, 1.62; n = 785) and second- or third-degree relatives of SLE patients (HR = 1.28; 95% CI: 1.18, 1.39; n = 582). Among individuals with SLE-affected first-degree relatives, the risk was significantly increased for RA (HR = 1.64; 95% CI: 1.35, 1.99; n = 103), IBD (HR = 1.21; 95% CI: 1.02, 1.43; n = 130) and type 1 diabetes mellitus (HR = 1.23; 95% CI: 1.01, 1.48; n = 106). Risk of other ADs was significantly increased both among SLE-affected first-degree (HR = 2.08; 95% CI: 1.88, 2.31; n = 371) and second- or third-degree relatives (HR = 1.38; 95% CI: 1.23, 1.54; n = 313). Conclusion: Family history of SLE is associated with a clearly elevated risk of SLE and, to a much lesser degree, of RA and other ADs.