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Objective Systemic lupus erythematosus (SLE) is associated with the premature development of cardiovascular disease. The platelet–endothelium interaction is important in the pathogenesis of cardiovascular disease. In this study, we investigated the platelet phenotype from patients with SLE and matched controls, and their effect on endothelial cells. Approach and Results Platelet aggregability was measured in 54 SLE subjects off antiplatelet therapy (mean age 40.1±12.8 years; 82% female; 37% white) with age- and sex-matched controls. Platelets were coincubated with human umbilical vein endothelial cells (HUVECs) and changes to gene expression assessed by an RNA array and quantitative reverse transcription polymerase chain reaction. SLE disease activity index ranged from 0 to 22 (mean 5.1±3.9). Compared with controls, patients with SLE had significantly increased monocyte and leukocyte–platelet aggregation and platelet aggregation in response to submaximal agonist stimulation. An agnostic microarray of HUVECs cocultured with SLE platelets found a platelet-mediated effect on endothelial gene pathways involved in cell activation. Sera from SLE versus control subjects significantly increased (1) activation of control platelets; (2) platelet adhesion to HUVECs; (3) platelet-induced HUVEC gene expression of interleukin-8, and intercellular adhesion molecule 1; and (4) proinflammatory gene expression in HUVECs, mediated by interleukin-1β–dependent pathway. Incubation of SLE-activated platelets with an interleukin-1β–neutralizing antibody or HUVECs pretreated with interleukin-1 receptor antibodies attenuated the platelet-mediated activation of endothelial cells. Conclusions Platelet activity measurements and subsequent interleukin-1β–dependent activation of the endothelium are increased in subjects with SLE. Platelet–endothelial interactions may play a role in the pathogenesis of cardiovascular disease in patients with SLE.

ObjectiveTwo apolipoprotein L1 (APOL1) risk variants (RV) are enriched in sub-Saharan African populations due to conferred resistance to Trypanosoma brucei. These variants associate with adverse renal outcomes by multiple causes including SLE. Despite emerging reports that SLE is common in Ghana, where APOL1 variant allelic frequencies are high, the regional contribution to SLE outcomes has not been described. Accordingly, this prospective longitudinal cohort study tested the associations between APOL1 high-risk genotypes and kidney outcomes, organ damage accrual and death in 100 Ghanaian patients with SLE.MethodsThis was a prospective cohort study of 100 SLE outpatients who sought care at Korle bu Teaching Hospital in Accra, Ghana. Adult patients who met 4 American College of Rheumatology criteria for SLE were genotyped for APOL1 and followed longitudinally for SLE activity as measured by the Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) hybrid and organ injury as measured by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at baseline and every 6 months for 1 year. Outcomes of interest were kidney function, SDI and case fatality.ResultsAssuming a recessive inheritance, the APOL1 high-risk genotype (2RV) associated with end-stage renal disease (ESRD) at an OR of 14 (p=0.008). These patients accrued more SDI points particularly in renal and neurological domains. The SDI was 81.3% higher in 2RV patients compared with 0RV or 1RV patients despite no difference in SLE activity (p=0.01). After a 12-month period of observation, 3/12 (25%) of the 2RV patients died compared with 2/88 (2.3%) of the 0RV or 1RV carriers (OR=13.6, p=0.01). Deaths were due to end-stage kidney disease and heart failure.ConclusionAPOL1 RVs were heritable risk factors for morbidity and mortality in this Ghanaian SLE cohort. Despite no appreciable differences in SLE activity, APOL1 high-risk patients exhibited progressive renal disease, organ damage accrual and a 13-fold higher case fatality.

Objective: Two Apolipoprotein L1 (APOL1) risk variants (RV) are enriched in sub-Saharan African populations due to a conferred resistance to Trypanosoma brucei. This comes at the cost of progressive renal disease by multiple causes including systemic lupus erythematosus (SLE). In African Americans, APOL1 high-risk genotypes have emerged as an important risk factor for progressive lupus nephritis. Despite emerging reports that SLE is common in Ghana, where APOL1 variant allelic frequencies are high, the regional contribution to SLE outcomes has not been described. Accordingly, this prospective longitudinal cohort study tested the associations between APOL1 high-risk genotypes and kidney outcomes, organ damage accrual, and death in 100 Ghanaian SLE patients.Methods: A prospective cohort of 100 SLE outpatients met four 1982 American College of Rheumatology SLE criteria. Patients were assessed for demographics, SLE activity, and organ injury as measured by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at baseline and every 6 months for 1 year. Serum, plasma, and saliva samples were taken for serologic testing and APOL1 genotyping. Outcomes of interest were kidney function, SDI, and case fatality. Results: Assuming a recessive model of inheritance, the APOL1 high-risk genotype (2RV) associated with developing end stage renal disease (ESRD) at an odds ratio of 14 (p=0.008). These patients accrued more SDI points particularly in renal, neurologic, and cardio/pulmonary domains. The SDI was 81.3% higher in 2RV patients compared to 0RV or 1RV patients despite no difference in SLE activity (p=0.02). After a 12 month period of observation, 3/12 (25%) of the 2RV patients died compared to 2/88 (2.3%) of the 0RV or 1RV carriers (odds ratio=13.6, p=0.01). Deaths were due to end stage kidney disease and heart failure. Conclusion: Our results suggest that in Ghanaian SLE patients, APOL1 risk variants are heritable risk factors for morbidity and mortality. Despite no appreciable differences in SLE severity, APOL1 high-risk patients exhibited progressive renal disease, organ damage accrual, and a 13-fold higher case fatality rate.