Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: Systemic lupus erythematosus (SLE) is a complex, chronic, autoimmune disease. Genome-wide association studies (GWAS) have identified multiple risk SNPs in HLA and non-HLA gene regions. There is evidence that genetics are also important in lupus nephritis (LN) risk. LN is one of the most common and severe manifestations of SLE. The purpose of this study was to determine the association of known SLE risk SNPs with LN in both childhood-onset (cSLE) and adult-onset SLE (aSLE) populations.
Methods: The study population included two tertiary care SLE cohorts; one with cSLE and the other with aSLE. Participants met American College of Rheumatology (ACR) and/or Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, with prospectively collected clinical and laboratory data. Participants were genotyped on the Illumina MEGA or Omni1 arrays. Principal components were calculated in reference to the 1000 genomes project, and ancestry was genetically inferred. Ungenotyped SNPs were imputed. HLA alleles were imputed in Europeans only. HLA and non-HLA additive SLE weighted genetic risk scores (GRSs) were computed using published SLE GWAS weights. LN was confirmed by renal biopsy as defined by the WHO or the International Society of Nephrology/Renal Pathology Society or diagnosed with renal casts, hematuria, proteinuria, and/or pyuria on two consecutive urinalyses. HLA and non-HLA GRSs were regressed individually and jointly, against LN risk in logistic regression models stratified by cSLE/aSLE cohort and ancestry, adjusted for sex, age of SLE diagnosis, and duration of follow-up. Effect estimates from stratified analyses were meta-analyzed using inverse-variance weighted fixed effects models.
Results: The cohorts included 421 with cSLE and 878 with aSLE. The mean age of diagnosis of patients with cSLE was 12.9 years (SD=3.2), 82% were female and 41% had LN. Among the aSLE patients, the mean age of diagnosis was 30.2 years (SD=13.1), 89% were female and 39% had LN. Genotyping and imputation resulted in 11.5M SNPs with minor allele frequency ≥0.01 and imputation quality ≥0.9. Meta-analyses demonstrated that increasing non-HLA GRS was significantly associated with increased LN risk (OR = 1.27; 95% CI: 1.11, 1.45, p = 0.0005). The strongest effect was observed among Europeans with cSLE (OR = 1.60; 95% CI: 1.08, 2.35, p = 0.018), whereas in those with aSLE the association was positive but not significant (OR=1.12; 95% CI: 0.91, 1.37, p = 0.291). HLA-GRS was not significantly associated with increased LN risk in meta-analysis of all Europeans, yet was significant in Europeans with cSLE (OR = 2.14; 95% CI: 1.00, 4.59; p = 0.0499). This association was insignificant in Europeans with aSLE (OR = 1.03; 95 % CI: 0.56, 1.90; p = 0.923).
Conclusion: We found a significant association between non-HLA SLE genetic risk SNPs and LN in our cohort of children and adults with SLE. We found that the effects were strongest among the childhood-onset SLE patients of European ancestry. The HLA risk alleles were also associated with LN risk, but did not reach statistical significance. Futures studies will include additional SLE cohorts.
To cite this abstract in AMA style:Webber D, Cao J, Dominguez D, Gladman DD, Levy DM, Ng L, Paterson A, Touma Z, Urowitz M, Wither JE, Silverman E, Hiraki L. Association of Systemic Lupus Erythematosus (SLE) Genetic Susceptibility Loci with Lupus Nephritis in Children and Adults with SLE [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/association-of-systemic-lupus-erythematosus-sle-genetic-susceptibility-loci-with-lupus-nephritis-in-children-and-adults-with-sle/. Accessed September 16, 2021.
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