Background/Purpose: Two Apolipoprotein L1 (APOL1) risk variants (RV), G1 and G2 are enriched in African populations due to a conferred resistance to Trypanosoma brucei. This comes with the cost of progressive renal disease by multiple causes including SLE. Despite the high regional allelic frequencies, APOL1 variant phenotypes have never been described in a Sub-Saharan African SLE cohort. Further, it is unclear if SLE nephritis progression in RV carriers is driven by inflammation or intrinsic nephropathy. Accordingly, this prospective longitudinal cohort study evaluated APOL1 genotype-phenotype traits in the context of SLE activity in 72 Ghanaian patients seeking care at Korle bu Teaching Hospital in Accra, Ghana.

Methods: All 72 patients met 4 ACR criteria for SLE and were stratified by APOL1 genotype using PCR/sequencing as follows: ancestral (G0/G0), RV heterozygotes (RV/G0), and RV homozygotes (RV/RV). DNA was extracted from saliva, and ancestry informative markers were performed on a subset of 20 patients to confirm heritage. ANAs were confirmed in the NYU clinical lab by multiplex analysis. Endpoints collected at three, 6 month intervals included demographics, ACR criteria, SLEDAI score, vital signs, and lab values as available. To measure SLE serologic activity, dsDNA titers were completed and in 15 subjects (5 per genotype), interferon (IFN) signature was measured by the WISH cell assay.

Results: The frequencies of the G0, G1, and G2 alleles were 60%, 25%, and 14.5% respectively (meeting Hardy Weinberg Equilibrium) and principal component analysis confirmed ancestry. Subjects were all female, average age of 32.1 years with SLE duration of 2.3 years. Data were collected on at least one, two, or three time points on 72, 56, and 30 subjects respectively. There were no differences in history of nephritis, diabetes, or age across the genotypes. The RV associated with higher average BPs; 109.9/75.7, 111.3/75.2, and 125.2/85.6 mmHg in the G0/G0, RV/G0, and RV/RV groups respectively (p: 0.04 systolic; 0.02 diastolic). Only 13% of the cohort took anti-hypertensives regardless of genotype. Among those with nephritis, RV/RV had increased creatinine: 0.9, 1.1, and 2.5 mg/dL in the G0/G0, RV/G0, and RV/RV groups respectively (p: 0.03). RV/RV carriers took higher doses of prednisolone (17.2mg) compared to G0/G0 or RV/G0 (11.2mg; 11.8mg respectively), however this did not reach statistical significance and there was no difference in SLEDAI scores. Despite higher creatinine, RV/RV carriers were less likely to ever have had anti-DNA positivity (11% positive) and had lower dsDNA titers (10.7 IU/mL) than G0/G0 (41% positive; 57.1 IU/mL) and RV/G0 (43% positive; 95.6 IU/mL) carriers (p: 0.03). IFN signatures in both G0/G0 and RV/G0 patients were higher than in RV/RV (245.7, 81.3, and 24.3 respectively). G0/G0 or RV/G0 carriers were more likely to have IFN scores above the average value of 109.9 (LR: 4.3; p: 0.04).

Conclusion:

Taken together, RVs associated with higher BP and creatinine in this Ghanaian SLE cohort. Despite having poorer renal function, RV homozygotes exhibited lower dsDNA titers and lower IFN signatures than G0/G0 or RV/G0 patients potentially suggesting intrinsic renal disease independent of SLE activity in RV homozygotes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/apolipoprotein-l1-risk-variants-associate-with-hypertension-and-nephritis-progression-despite-lower-dsdna-titers-in-ghanaian-systemic-lupus-erythematous-patients/