Elevated serum complement levels and higher gene copy number of complementC4Bare associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

Abstract

ObjectiveSystemic lupus erythematosus (SLE) features high frequency of cardiovascular disease (CVD) and fluctuating complement levels. The clinical trial Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) aimed to evaluate whether atorvastatin treatment reduced the progression of atherosclerosis in 221 patients with childhood-onset SLE (cSLE), using carotid intima media thickness (CIMT) as surrogates. We leveraged APPLE biorepository and trial data to investigate the relationship between complement and CVD in cSLE.MethodsGene copy numbers (GCNs) for total C4, C4A and C4B were measured by TaqMan-based real-time PCR and Southern blotting, and analysed with laboratory and clinical parameters through Student’s t-test and χ2 analyses. Effects of total C4, C4A and C4B GCNs on the response to placebo or atorvastatin treatment and progression of CIMT were examined by regression analyses.ResultsAt baseline, C4 protein levels strongly correlated with GCNs of total C4 (p=1.8×10−6). Each copy of C4 gene increased mean serum C4 by 3.28 mg/dL. Compared with those without hypertension (N=142), individuals with hypertension demonstrated significantly elevated serum levels for C4 and C3 at baseline and serially (C4: P=5.0×10−25; C3: P=5.84×10−20). Individuals with ≥2 C4B genes had 2.5 times the odds of having hypertension (p=0.016) and higher diastolic blood pressure (p=0.015) compared with those with C4B deficiency. At the study end, subjects with ≥2 C4B and atorvastatin treatment had significantly slower increase in CIMT compared with those treated with placebo (p=0.018).ConclusionscSLE with hypertension had elevated serum levels of C4 and C3 and higher GCN of C4B; cSLE with ≥2 C4B genes would benefit from statins therapy to prevent atherosclerosis.

Relationships of complement components C3 and C4 and their genetics to cardiometabolic risk in healthy, non-Hispanic white adolescents

“…Recent studies from our laboratory have revealed that in patients with lupus inflammation is more closely linked to C4 than C3 levels (11,12). The current study extends this finding to healthy adolescents.…”

“…Among human subjects with antiphospholipid antibodies, those who experienced thromboses had consistently higher C4 and C3 serum protein levels and higher C4B gene copy number than patients who did not experience thrombosis (11). Moreover, pediatric lupus patients who had hypertension have persistently higher serum C4 and C3 protein levels than normotensive patients (12).…”

Linc8986 and linc0597 in plasma are novel biomarkers for systemic lupus erythematosus

“…Furthermore, it was indicated that overexpression of RPAIN inhibits the expression of C1q and that C1q was the functional target of RPAIN (27). It was also previously reported that C3 and C4 have diagnostic value for SLE (6,7). In the present study, elevated levels of linc8986 and linc0597 in the plasma of patients with SLE were indicated to be negatively correlated with C3, suggesting that high expression of linc8986 and linc0597 may inhibit the expression of C3.…”

“…Lupus nephritis (LN), one of the most serious manifestations of SLE, is the major cause of a large number of SLE-related deaths ( 4 , 5 ). In the internationally recognized SLE classification standard, complement component 3 (C3) and C4 are among the immunological diagnostic items for SLE ( 6 , 7 ). Although plasma levels of C3 and C4 are of certain diagnostic value for SLE, they are not specific diagnostic indicators ( 8 ).…”

Effect of Hypertension on Childhood-onset Systemic Lupus Erythematous in a Tertiary Medical Center in Korea

“…There is another report that disease activity was associated with hypertension in SLE patients, which compared with those with and without hypertension. Individuals with hyper tension demonstrated significantly elevated serum levels for C4 and C3 at baseline and serially 24) . These results sug gest that high disease activity at diagnosis could be a pre dictor of hypertension in childhoodonset SLE patients.…”