Elevated serum complement levels and higher gene copy number of complement C4B are associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

Evan Mulvihill; Stacy Ardoin; Susan D Thompson; Bi Zhou; Gakit Richard Yu; Emily King; Nora Singer; D M Levy; Hermine Brunner; Yee Ling Wu; Haikady N Nagaraja; Laura Eve Schanberg; Chack-Yung Yu

doi:10.1136/lupus-2019-000333

Elevated serum complement levels and higher gene copy number of complement C4B are associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)

Lupus Sci Med. 2019 Jul 31;6(1):e000333. doi: 10.1136/lupus-2019-000333. eCollection 2019.

Authors

Evan Mulvihill^{1

2}, Stacy Ardoin^{2

3}, Susan D Thompson⁴, Bi Zhou⁵, Gakit Richard Yu¹, Emily King¹, Nora Singer⁶, D M Levy⁷, Hermine Brunner⁸, Yee Ling Wu⁹, Haikady N Nagaraja¹⁰, Laura Eve Schanberg¹¹, Chack-Yung Yu^{2

3

12}

Affiliations

¹ Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.
² Division of Rheumatology, Nationwide Children's Hospitatl, Columbus, OH, USA.
³ Department of Pediatrics, The Ohio State University, Columbus, Ohio, USA.
⁴ Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Centre, Cincinnati, Ohio, USA.
⁵ Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Columbus, Ohio, USA.
⁶ Department of Medicine, University Hospitals/Case Medical Center, Cleveland, Ohio, USA.
⁷ Department of Rheumatology, Hospital for Sick Children and Univeristy of Toronto, Toronto, Ontario, Canada.
⁸ Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, PRCSG Coordinating Center, Cincinnati, Ohio, USA.
⁹ Department of Medical Microbiology and Immunology, Loyola University Chicago, Chicago, Illinois, USA.
¹⁰ Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, Ohio, USA.
¹¹ Department of Pediatrics, Duke University, Durham, North Carolina, USA.
¹² Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio, USA.

Abstract

Objective: Systemic 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.

Methods: Gene 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.

Results: At 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).

Conclusions: cSLE 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.

Keywords: atherosclerosis; atorvastatin; complement C4 and C3; gene copy number variation; hypertension.

Abstract

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