Background/Purpose: Two Apolipoprotein L1 (APOL1) risk variants (RV), G1 and G2, are enriched in ancestrally African populations due to a conferred superior resistance to Trypanosoma brucei. This improved infectious evolutionary fitness comes at the cost of propensity toward progressive renal disease by multiple causes including SLE. In Ghana’s Ashanti people, Allelic frequencies for G0, G1, and G2 have been reported at 0.46, 0.49, and 0.13 respectively. Despite their high frequencies, and the established role in SLE nephritis, no study has examined outcomes in a Ghanaian SLE cohort. Accordingly, this prospective study evaluated APOL1 risk traits including renal, damage accrual, and mortality in 101 Ghanaian patients followed at Korle bu Teaching Hospital in Accra, Ghana.

Methods: From 05/2015-04/2018, 101 Ghanaian patients meeting at least 4 ACR criteria for SLE were followed prospectively with data evaluated every six months. DNA was extracted from saliva and patients were stratified by APOL1 genotype as follows: reference allele (G0/G0), RV heterozygote (RV/G0), and RV homozygotes (RV/RV). Sera were shipped to the NYU clinical lab for confirmation of anti-dsDNA. Clinical endpoints included demographics, ACR criteria, SLEDAI score, SLICC damage index, mortality, vital signs, and laboratory values as available.

Results: The frequencies of the G1, and G2 alleles were 0.24, and 0.12 respectively— lower than would be expected given the reported regional frequencies. Subjects were 100% female, with and average age of 32.1 years and disease duration of 2.9 years. There were no differences in demographics across the genotypes. The RV associated with higher BP: 108/71, 108/73, and 120/82 in the G0/G0, RV/G0, and RV/RV groups respectively (p=0.04 systolic; 0.009 diastolic). Among those with nephritis, RV/RV carriers presented with higher dipstick proteinuria than G0/G0 and RV/G0 carriers (2.6 vs 1.2 and 1.3 respectively; p=0.05; F=3.1). While proteinuria responded most robustly to therapy in RV/RVs, it remained higher at each time point compared to the other genotypes (p=0.002; F=5.4). SLEDAI scores were comparable across the genotypes, however RV/RV carriers had lower dsDNA titers (10.7 IU/mL) than G0/G0 (57.1 IU/mL) and RV/G0 (95.6 IU/mL) carriers (p: 0.03). RV homozygosity associated with elevated SLICC damage index: G0/G0 or RV/G0: 0.95 vs RV/RV: 1.7; driven by renal, CVD, and neurologic manifestations G0/G0: 0.46, RV/G0: 0.39, RV/RV: 1.25; (p=0.03). There were 5 deaths during the study period: 1 death in the G0/G0 group (ESRD), 1 in the RV/G0 group (post-partum sepsis plus renal), and 3 in the RV/RV group (myocarditis/heart failure; ESRD; unknown). RV carrier status associated with mortality with 25% of the RV/RV group succumbing to disease vs 2% in the G0/G0 and RV/G0 groups (p=0.003; F=6.3).

Conclusion: Taken together, APOL1 RV associates with renal progression, organ damage accrual, and mortality in this Ghanaian SLE cohort. Despite having poorer outcomes, RV homozygotes exhibited lower dsDNA titers and similar SLEDAI scores compared to G0/G0 or RV/G0 patients suggesting a genetic effect independent of SLE activity. APOL1 genotyping could have important prognostic implications in ancestrally African SLE patients.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/apolipoprotein-l1-risk-variants-associate-with-poor-renal-outcomes-damage-accrual-and-death-a-prospective-ghanaian-sle-cohort/