Background/Purpose The apolipoprotein1 (APOL1) gene encodes a 3 domain protein found both in serum and intracellularly in endothelial cells among other cell types. Variant APOL1 has undergone positive selection as the serum protein offers heterozygous advantage by promoting lysis of Trypanosoma Brucei conferring resistance to African Trypanosomiasis.  Populations native to endemic regions carry this variant at high frequencies with 30% of African Americans (AA) heterozygous for the gene and 12% homozygous.  The intracellular form of APOL1 is a cytokine mediated apoptosis factor. Recently homozygous status for APOL1 risk allele (RA) has been associated with non-diabetic end stage renal disease by multiple causes including Lupus Nephritis (LN). While the mechanism of disease progression has not yet been described, we postulate that aberrant apoptosis in the renal vasculature may lead to arterial dysfunction and renal injury.This study was undertaken to establish a relationship between carrying at least one APOL1 RA and known clinical indicators of renal vascular dysfunction in a sample of 34 AA lupus patients with average eGFR above 60 (calculated by the CKD Epi formula). 

Methods APOL1 G1 and G2 risk alleles were genotyped by PCR/DNA sequencing. All patients satisfied ACR criteria for SLE. The patients were distributed into 2 groups: those carrying 2 wild type (WT) alleles (WT/WT) and those with at least 1 RA (G1/WT, G2/WT, G1/G1, G2/G2, G1/G2).  Charts were reviewed to assess clinical parameters including demographics, medical comorbidities, medications, vital signs, and laboratory values. 

Results There were 18 patients in the WT group and 16 in the risk variant (RV) group (G1/WT= 10pt; G2/WT=3pt; G2/G2= 1 pt; G1/G2= 2pt; G1/G1= 0pt).  Subjects were AA (100%) and predominantly female (WT: 100%; RV: 81%). Hypertension was defined as diagnosis of HTN on chart review, taking at least 1 antihypertensive drug, or having BP over 140 systolic and/or 90 diastolic on at least 2 clinic visits. The APOL1 RA was strongly associated with HTN with 69% of the RV group meeting criteria for HTN compared to 22% of the WT group (odds ratio: 7.7; p value: 0.009). Subgroup analysis of 15 patients with biopsy proven LN showed a higher effect size (odds: ratio of 16; p value: 0.04). There was no significant difference in age, disease duration, disease activity, eGFR, proteinuria, or history of LN between the groups. Next the relationship between inflammation and APOL1 regulation was assessed. As a surrogate of  mononuclear cells residing at patient blood vessels and renal tissue and to evaluate the capacity of macrophages to serve as a source of APOL1, THP1 macrophages were stimulated with hY3 ssRNA and we found that  APOL1 was a strongly upregulated transcript.

Conclusion AA SLE patients carrying at least 1 APOL1 RA have an increased risk of HTN before onset of clinically significant renal disease potentially suggesting vascular dysfunction associated with this gene. Increased APOL1 transcription in the setting of inflammation may increase the gene effect in heterozygous carriers.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-between-carrying-at-least-one-apolipoprotein1-variant-allele-and-hypertension-in-lupus-patients-with-normal-renal-function/