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)
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 a...
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BMJ Publishing Group
2019-12-01
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| Series: | Lupus Science and Medicine |
| Online Access: | https://lupus.bmj.com/content/6/1/e000333.full |
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| author | 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 |
| author_facet | 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 |
| author_sort | Evan Mulvihill |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8b1aa9864b06475c94b2d8ced0247665 |
| institution | OA Journals |
| issn | 2053-8790 |
| language | English |
| publishDate | 2019-12-01 |
| publisher | BMJ Publishing Group |
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| series | Lupus Science and Medicine |
| spelling | doaj-art-8b1aa9864b06475c94b2d8ced02476652025-08-20T02:35:53ZengBMJ Publishing GroupLupus Science and Medicine2053-87902019-12-016110.1136/lupus-2019-000333Elevated 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 Mulvihill0Stacy Ardoin1Susan D Thompson2Bi Zhou3Gakit Richard Yu4Emily King5Nora Singer6D M Levy7Hermine Brunner8Yee Ling Wu9Haikady N Nagaraja10Laura Eve Schanberg11Chack-Yung Yu12Division of Rheumatology, Nationwide Children`s Hospitatl, Columbus, OH, USADivision of Rheumatology, Nationwide Children`s Hospitatl, Columbus, OH, USACenter for Autoimmune Genomics and Etiology, Cincinnati Children`s Hospital Medical Centre, Cincinnati, Ohio, USACenter for Microbial Pathogenesis, Abigail Wexner Research Institute, Columbus, Ohio, USAAbigail Wexner Research Institute, Nationwide Children`s Hospital, Columbus, Ohio, USAAbigail Wexner Research Institute, Nationwide Children`s Hospital, Columbus, Ohio, USA1Case Western Reserve University School of Medicine at MetroHealth, Cleveland, United States of AmericaDepartment of Rheumatology, Hospital for Sick Children and Univeristy of Toronto, Toronto, Ontario, Canada6Pediatric Rheumatology Collaborative Study Group (PRCSG), Cincinnati Children’s Hospital Medical Center, Cincinnati, United States of America2 Division of Rheumatology, Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University, Columbus, Ohio, USADivision of Biostatistics, College of Public Health, The Ohio State University, Columbus, Ohio, USAPediatrics, Duke University, Durham, North Carolina, USA1 Center for Microbial Pathogenesis, Abigail Wexner Research Institute, Nationwide Children`s Hospital, Columbus, Ohio, USAObjective 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.https://lupus.bmj.com/content/6/1/e000333.full |
| spellingShingle | 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 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 Science and Medicine |
| title | 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) |
| title_full | 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) |
| title_fullStr | 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) |
| title_full_unstemmed | 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) |
| title_short | 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) |
| title_sort | 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 |
| url | https://lupus.bmj.com/content/6/1/e000333.full |
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