Background/Purpose: Many genetic variants are associated with lupus nephritis (LN). Yet, the majority of associated variants have a small effect size; hence, they convey small risk. Polygenic risk scores (PRS) provide a unique opportunity to aggregate an individual’s genetic risks. PRS are a weighted sum of genome-wide genetic risk load for an individual such that multiple variants, including variants that do not meet genome-wide cutoff, are included. We hypothesize that PRS constructed using multiple variants, along with demographic and clinical variables, are predictive of LN outcomes such as the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) estimated glomerular filtration rate (eGFR) and end-stage kidney disease (ESKD).

Methods: Subjects with LN were genotyped using Illumina Global Screening Array V3. Ancestry was determined using principal component analysis of the genotyped data. PRS for systemic lupus erythematosus (SLE) and CKD were constructed using multi-ancestry SLE and CKD base GWAS using the clumping and thresholding (C+T) approach. The base SLE Immunochip study included 11,590 SLE cases and 15,984 controls, and the base CKD GWAS study used eGFR as outcome and included 1,201,909 individuals. Relationships between SLE and CKD PRS with CKD-EPI eGFR and ESKD were assessed using multivariable linear and logistic regression models, adjusting for ancestry, sex, age at SLE diagnosis and history (yes/no) of hypertension, diabetes, and smoking.

Results: 653 individuals (87.3% female, 19.4% smokers, 9.8% diabetic and 55.2% hypertensive) were considered in the study. Genotyping PCA identified 46.6% African American, 27.9% European American, 13.1% Argentinian, 9.6% Mexican, and 2.9% Asian individuals. Mean (SD) age at SLE diagnosis was 26.7 (11.9) years. Mean (SD) CKD-EPI eGFR at last visit was 71.0 (41.4) mL/min/1.73m²; 86 (16.3%) individuals developed ESKD. 529 individuals were included in the final analyses following quality control and exclusion of individuals of Asian ancestry due to small sample size. Following C+T, approximately 23K SNPs were retained for both eGFR and ESKD PRS computation using SLE base data, and 482K SNPs were retained using CKD base data.

Lower eGFR was associated with higher SLE PRS (β = -8.45; 95% CI: -12.9, -3.97), older age (β = -0.44; 95% CI: -0.77, -0.12) and history of hypertension (β = -18.9; 95% CI: -27.6, -10.1); CKD PRS and ancestry were not associated with eGFR. Similarly, increased odds of ESKD were associated with higher SLE PRS (OR: 1.59; 95% CI: 1.08, 2.38), higher CKD PRS (OR: 2.61; 95% CI: 1.39, 5.01), and history of hypertension (OR: 3.01, 95% CI: 1.37, 7.12). Additionally, African American ancestry had higher odds of ESKD relative to European American (OR: 11.3; 95% CI: 2.51, 56.0) or Argentinian ancestry (OR: 9.54; 95% CI:1.92, 55.1).

Conclusion: SLE and CKD PRS are associated with LN outcomes like eGFR and ESKD and can potentially be used to identify those at risk for kidney deterioration and eventual damage. Adding assessment of genetic risk score for disease monitoring can allow physicians to focus on patients expected to do poorly and employ targeted as well as kidney-protective therapies earlier.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-risk-profiles-of-patients-with-lupus-nephritis-to-identify-those-at-risk-for-kidney-deterioration-and-eventual-damage/