Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE

Abstract

Objective LN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE). Methods Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed <18 years) and aSLE patients (diagnosed ⩾18 years). Patients met ACR and/or SLICC SLE criteria and were genotyped on the Illumina Multi-Ethnic Global Array or Omni1-Quad arrays. We identified those with and without biopsy-confirmed LN. HLA and non-HLA additive SLE risk-weighted genetic risk scores (GRSs) were tested for association with LN risk in logistic models, stratified by cSLE/aSLE and ancestry. Stratified effect estimates were meta-analysed. Results Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002). Conclusion We observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort.

High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

“…Genetic risk scores (GRSs) have been applied in several fields of medicine, and studies have demonstrated their ability to predict matters like cardiovascular disease, prostate cancer risk and body mass index scores 22–24. In SLE, few studies have assessed the relationship between the cumulative genetic risk and disease subphenotypes,25–28 and the association between the polygenic risk and disease severity is unknown. In this study, we examined the relationship between a high GRS and clinical manifestations associated with more severe SLE phenotypes, including organ damage, defined by the Systemic Lupus Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI),29 cardiovascular events (CVE) and end-stage renal disease (ESRD).…”

Abundance and nuclear antigen reactivity of intestinal and fecal Immunoglobulin A in lupus-prone mice at younger ages correlate with the onset of eventual systemic autoimmunity

“…Importantly, women are more predisposed to SLE than men, and the disease prevalence ratio of women is about 9:1 over men 2 . Autoantibody production and gender bias in SLE is caused by a combination of genetic and environmental factors [1][2][3][4] . Disproportionate functioning of genes as well as sex hormones, estrogen in particular, contribute to the onset and development of disease activities in SLE 2,[5][6][7][8] .…”

Gut microbiota differently contributes to intestinal immune phenotype and systemic autoimmune progression in female and male lupus-prone mice

“…Systemic lupus erythematosus (SLE), an autoimmune disease, arises when abnormally functioning B lymphocytes produce auto-antibodies to DNA and nuclear proteins, resulting in immune complexes that cause damage to the tissue [1]. While the triggers are not known, it is generally believed that SLE is caused by a combination of genetic and environmental factors [1][2][3]. Dietary factors can also have a profound impact on the gut and systemic immune responses [4][5][6][7][8].…”