OA02 High-risk apolipoprotein L1 genetic variants are associated with the occurrence of lupus nephritis: a case-control study in the United Kingdom

Abstract Background/Aims High-risk apolipoprotein L1 (APOL1) genetic variants are strongly associated with end-stage kidney disease in people of African ancestry with lupus nephritis (LN). However, previous studies have disputed a role for APOL1 high-risk genotypes (HRG) in the initial development of LN. We aimed to investigate the relationship of APOL1 HRG with LN occurrence and subsequent progression of kidney disease in patients of African ancestry with systemic lupus erythematosus (SLE) in the UK. Methods We conducted a case-control study of adults with SLE of self-reported African ancestry in a tertiary centre. Participants with biopsy-proven LN were defined as cases and individuals without LN (age and sex-matched 1:1) were recruited as controls. Conditional logistic regression was used to estimate the odds ratio (OR) of LN in individuals carrying APOL1 HRG versus low-risk genotypes (LRG; zero or one risk allele). For those within the LN cohort, we modelled trajectories of estimated glomerular filtration rates (eGFR) and urine protein:creatinine (uPCR) over time, by number of APOL1 risk alleles, using a mixed-effects model with restricted cubic splines. Results Between August 2022 and April 2025, 92 individuals were recruited (46 with LN and 46 control participants with SLE). APOL1 HRG frequency was 30% in cases and 15% in controls. APOL1 HRG were associated with increased odds of LN on multivariate analysis (OR 3.27, 95% CI 1.02-10.53). Among individuals with LN and relevant data (N = 40), longitudinal trends in the geometric means of eGFR and uPCR suggested worse outcomes for those with two APOL1 risk alleles compared to those with zero risk alleles. Those with no risk alleles displayed a fall in mean eGFR at LN diagnosis, which recovered over time (slope +8.2mLs/min/1.73m2/year, 95% CI -1.3 to 17.7, years 1-4 after LN diagnosis). In contrast, a steep and progressive decline was observed among those with one (slope -3.1, 95% CI -18.6 to 12.3) and two risk alleles (slope -7.0, 95% CI -21.7 to 7.7). Geometric mean uPCR was elevated at diagnosis across all risk allele groups and tended to be highest in the two-risk allele group, before falling in all groups four years after LN diagnosis. Conclusion This is the first report of APOL1 HRG and SLE in the UK. Our findings demonstrated an association between APOL1 HRG and the incidence of LN, with trends suggesting subsequent deterioration in renal function. Confidence intervals were wide for all groups, reflecting limited precision, yet trajectories still suggested distinct patterns across risk allele categories. These results may partly explain the high LN burden in people with SLE of recent African ancestry. APOL1 genotyping could help stratify the risk of developing LN and guide precision treatment strategies in people with SLE of African ancestry. Disclosure S. Patel: None. H. Rabee: None. A. Ramnarine: None. D. Kular: None. M. Russell: Honoraria; AbbVie, Lilly, Galapagos, Menarini, UCB and Viforpharma. Grants/research support; Sandoz UK. M. Al-Agil: None. M. Adas: None. C. Wincup: Honoraria; Astra Zeneca, AbbVie, Bristol Myers Squibb, Kyverna, Otsuka, UCB. Grants/research support; Astra Zeneca. E. Kougiouris: None. J. Dick: None. S. Norton: None. J. Galloway: Honoraria; Abbvie, Biovitrum, BMS, Celgene, Chugai, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, Roche, Sanofi, Sobi and UCB. Grants/research support; Sandoz UK. P. Gordon: None. K. Bramham: Honoraria; AstraZeneca, Vertex, GSK, Otsuka and Boehringer Ingelheim. Grants/research support; Astra Zeneca.