ELUCIDATE – Epigenetics; lupus urine cells in decoding APOL1 transmutation effect

Ancestrally African (AA) patients suffer more from systemic lupus erythematosus-associated kidney inflammation known as lupus nephritis, compared to patients of European ancestry. AA patients with lupus nephritis are more likely to have genetic changes in a gene called APOL1. However, there is no non-invasive test to determine if lupus nephritis is progressing, which is a critical unmet need, for all lupus patients including the higher risk AA population.

Dr. Ashira Blazer will use LRA’s Career Development Award to build upon her preliminary research which successfully separated lupus nephritis patients from non-lupus nephritis patients based on the cells found in the lupus patient urine. Dr. Blazer’s research team will study systemic lupus erythematosus patient urinary sediment – the matter that settles to the bottom of the urine composed of immune cells and microbes. They aim to identify relationships between the cells and their unique genetic makeup, lupus nephritis, and treatment outcomes. A unique multi-national AA systemic lupus erythematosus patient group will be used in this study, which will provide a new opportunity to learn more about lupus nephritis in a high-risk and understudied patient group.

What this study means for people with lupus:

Study findings will allow physicians to better assess the progression of damage to kidney tissue related to lupus nephritis.

Ancestrally African (AA) SLE patients suffer disproportionately from lupus nephritis (LN) compared to Europeans. In AA individuals, end stage kidney disease (ESKD) risk is heightened in part due to two risk variants in the Apolipoprotein L1 (APOL1) gene, found commonly in African genomes. These variants confer an evolutionary advantage in resisting African Trypanosomiasis at the expense of progressive kidney disease. APOL1 high risk genotype (HRG) carriers with LN are twice as likely to progress to ESKD despite no differences in renal histopathology or serologic activity. The lack of non-invasive LN biomarkers that are able to provide granular prognostic information represents a critical unmet need in SLE—particularly in AA patients who are more vulnerable to LN and less likely to have consistent access to care. Urinary sediment epigenetic signatures are being developed to identify rare kidney diseases and are recognized as powerful diagnostic tools that can reflect both inherited and acquired pathologic processes.

In a recent Lupus Research Alliance-funded pilot study, we were able to leverage epigenetic profiling of SLE urine sediment to identify relative fractions of innate and adaptive immune cell types. Preliminary results in 14 patients differentiated LN patients from non-LN and healthy controls at an odds ratio of 12.5. We now propose testing this method as a biomarker of LN or APOL1 HRG nephropathy in a large cohort of AA SLE patients. We hypothesize that: A. Urinary epigenetic profile will vary across APOL1 genotype owing both to differential cell composition and gene regulation events occurring in the kidney. And B. That urinary sediment methylation profile will predict both incident LN and treatment response at 6 months. Methods: In order to understand the epigenetic underpinnings of urinary sediment in our cohort, we propose 2 aims to test associations between bulk urinary sediment DNA methylation across APOL1 genotype (SA1) and across LN status (SA2a). In incident LN, we will associate urinary epigenetic signature with 6-month treatment response in patients representing each APOL1 genotype (SA2b). We will identify both relative urinary cell fractions and differentially methylated genes using state of the art bioinformatics methods and cell-type deconvolution algorithms. We hypothesize that treatment non-response will associate with a persistence of invading immune cells in APOL1 low-risk but not HRG patients. Data will be controlled for patient country of origin, batching, and genetic ancestry using the robust Global Diversity Array, with dense representation of African ancestry SNPs. Impact: Our unique, large, multi-national AA SLE cohort offers unprecedented opportunity to disentangle LN pathogenesis in a high-risk and understudied patient group. Moreover, we are poised to deliver a non-invasive “liquid biopsy” biomarker of LN and APOL1 nephropathy with the power to assess both immunologic and kidney-intrinsic components.