Background/Purpose:  Two Apolipoprotein L1 (APOL1) risk variants (RV), G1 and G2, located on chromosome 22q12.3, have been associated with excess renal risk in African Americans (AA). The strongest correlations are in those with comorbid infectious or inflammatory diseases such as HIV or SLE collapsing glomerulonephropathy potentially owing to increased gene expression in the setting of chronic inflammation. APOL1 related cardiovascular disease (CVD) risk has been more controversial. Of four large, population-based studies, two reported 2-8 fold increased CVD in RV homozygotes while two others reported no increased risk. APOL1 associated CVD has never been assessed in a cohort with comorbid inflammatory disease. Accordingly, this retrospective cohort study evaluates prevalent CVD across APOL1 genotypes in SLE patients to test the hypothesis that the APOL1 cardiovascular phenotype is more penetrant in an SLE population.

Methods:  PCR/sequencing was completed in 92 AA SLE patients. Subjects were stratified by genotype: ancestral (G0/G0), RV heterozygotes (RV/G0), and RV homozygotes (RV/RV). Clinical CVD endpoints including both cardiac: congestive heart failure, arrhythmia, and left ventricular hypertrophy; and atherosclerotic: coronary artery disease, myocardial infarction, peripheral vascular disease, vascular calcifications, and carotid artery disease were assessed by chart review. Logistic regression was used to test associations between the genotypes and a composite CVD end point defined by meeting one or more of the above parameters. Secondary analysis of atherosclerotic vs cardiac end points was also completed.

Results:  The G0/G0, RV/G0, and RV/RV groups comprised 33%, 54%, and 13% of the cohort. Subjects were predominantly female (90%). There were no differences in history of SLE nephritis, diabetes, smoking, or age across the genotypes. Among patients with current or past nephritis, a larger percentage of the RV/RV group had progressed to ESRD at the time of study enrollment (G0/G0 or G0/RV: 8.3% vs RV/RV: 33%; OR: 3.8 p: 0.051). The RV associated with CVD; 21.2%, 41.7%, and 63.6% of the G0/G0, RV/G0, and RV/RV groups met the composite endpoint respectively (χ²: 7.3; p: 0.026). When adjusting for CVD risk factors including smoking, ESRD, obesity, and hypertension, carrying one or more RV conferred a 3.1 fold increased risk of CVD (p: 0.03). The RV associated most strongly with atherosclerotic endpoints (OR: 7.5 p: 0.01) compared to cardiac disease end points (OR: 2.5, p: 0.22). These trends were present despite a shorter duration of SLE in the RV groups (groups (G0/G0: 15.1yrs±8.6, G0/RV: 9.2±7.9, RV/RV: 12.9±10.5, p: 0.04).

Conclusion:  The undulating inflammation of SLE plays an important role in each step of atherogeneisis from endothelial dysfunction to plaque rupture. In RV carriers, it may also increase the toxic protein burden leading to an amplified propensity towards CVD. Taken together, the RV is associated with prevalent CVD in this AA SLE cohort suggesting that SLE may be an important “second hit” in the relationship between APOL1 RV and CVD.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/apolipoprotein-l1-risk-variants-associate-with-prevalent-cardiovascular-disease-in-african-american-systemic-lupus-erythematous-patients/