Genetic and epigenetic determinants of relapse risk in lupus nephritis

Lupus nephritis (LN) is a potentially severe manifestation of SLE, often resulting in permanent kidney damage. We investigated whether polygenic and/or epigenetic risk is associated with time to LN relapse and whether this association differs by initial therapy.

Caucasian patients with biopsy-verified LN between 1974 and 2022 (n=149) were genotyped using the Illumina Global Screening Array, and DNA methylation was assessed with the Illumina HumanMethylation450k BeadChip. A weighted Polygenic Risk Score (PRS) based on 55 non-Human leukocyte antigen (HLA) SLE risk gene variants and a Methylation Risk Score (MRS) based on the 17 most differentially methylated cytosine-phosphate-guanine sites identified in SLE-control comparison were calculated. Time to LN relapse was analysed using Cox proportional hazards models, adjusted for centre, sex and year of the first LN.

Neither PRS nor MRS was associated with time to LN relapse in the overall cohort, irrespective of treatment (PRS: HR=1.00 (0.77-1.30); p=0.99; MRS: HR=1.01 (1.00-1.02); p=0.21). No associations were observed among cyclophosphamide (CYC)-treated patients (PRS: HR=0.81 (0.55-1.20); p=0.29; MRS: HR=1.00 (0.99-1.02); p=0.89). In non-CYC-treated patients, PRS showed a non-significant trend towards shorter time to LN relapse (HR=1.26 (0.88-1.81); p=0.21), with a similar trend for MRS (HR=1.02 (1.00-1.03); p=0.066). Adding MRS to the PRS model improved performance in this subgroup (likelihood ratio test, p=0.028), with significant associations for MRS (PRS: HR=1.56 (0.97-2.50); p=0.066; MRS: HR=1.02 (1.00-1.04); p=0.037).

Genetic and epigenetic susceptibility appears to influence LN relapse risk in a treatment-dependent manner. The absence of an association among patients receiving CYC suggests that initial treatment with CYC may attenuate the impact of genetic and epigenetic predisposition on relapse. These findings support the potential of genetic and epigenetic profiling at LN diagnosis to improve relapse risk stratification and individualise selection of treatment.