Background/Purpose:

With higher prevalence of renal and cardiovascular diseases (CVD), as well as HTN, African American (AA) SLE patients experience accelerated damage accrual and excess morbidity and mortality. Genome wide association studies have identified two Apolipoprotein L1 (APOL1) risk variants (RV) in individuals of African Ancestry which confer an evolutionary advantage in resisting African Trypanosomiasis, but an increased risk of renal failure and CVD in homozygous carriers across many disease states. As an innate immune factor, APOL1 expression is regulated by inflammatory conditions. This study focused on RV dependent clinical correlates in SLE, and the interaction between the SLE inflammatory milieu and APOL1 expression.  

Methods:

Genotyping was done by conventional PCR/sequencing in 93 AA SLE subjects. Chart review furnished clinical data including demographics, comorbidities, medications, and laboratory values. Serum sE-selectin (as a marker CVD risk) was measured by ELISA and mean concentrations stratified by carrier status (ancestral, RV heterozygous, RV homozygous). APOL1-genotyped primary human endothelial cells (ECs) isolated from healthy AA fetal cord tissue were used to address inflammation-dependent APOL1 expression.  Inflammatory conditions present in SLE were simulated using IFNα and supernatants from TLR stimulated macrophages. PCR products were genotyped to establish concordance with chromosomal DNA. 

Results:

The ancestral (WT/WT), RV heterozygous, and RV homozygous groups comprised 37.6%, 49.4%, and 13% of the cohort respectively.  Subjects were AA (100%) and predominantly female (90.3%). There were no significant differences in age, SLE duration or disease activity (SLEDAI scores), current proteinuria, or history of nephritis among the groups. However, a significantly increased risk of hypertension in heterozygous (OR: 3.6 p: 0.01) and homozygous (OR: 5.6 p: 0.04) RV subjects vs ancestral controls, supported an incomplete dominance model.  In the RV heterozygous and homozygous groups, increased sE-selectin concentration was associated with SLEDAI >8, increased dsDNA, and decreased C4 (p= 0.009, 0.003, 0.03 respectively). In contrast, there were no associations between the above parameters and sE-selectin in the ancestral group (p= 0.93, 0.53, 0.57 respectively).  Primary EC cultures from 5 healthy subjects (WT/WT= 1, RV/WT= 2, RV/RV= 2) were plated in serum free media, IFN-α, or supernatant from macrophages previously activated with ssRNA, hY3 (SLE-relevant TLR 7/8 agonist). Cells were ˃ 95% CD31 positive by FACS analysis. At 4 hours IFN-α alone, and macrophage supernatants increased APOL1 expression 9.21 fold (+/-1.8; p= 0.001) and 3.99 fold (+/-0.61; p= 0.0004) vs no treatment, respectively. RV heterozygous cells showed biallelic expression on genotyping of the qPCR product. Fold increase of sE-selectin was 2.24 (+/-0.2) (p=0.009) in response to IFNα.  

Conclusion:

Chronic inflammation in SLE may lead to RV over-expression in EC and resultant systemic endothelial dysfunction.  In AA SLE patients, tighter inflammatory control may be a step forward in preventing APOL1 RV-related damage in vascular beds.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/heritable-endotheliopathy-and-apolipoproteinl1-risk-traits-in-sle/