title: Effects of Complement C4 Gene Copy Number Variations, Size Dichotomy, and C4A Deficiency on Genetic Risk and Clinical Presentation of Systemic Lupus Erythematosus in East Asian Populations.
abstract: Human complement C4 is complex, with multiple layers of diversity. The aims of this study were to elucidate the copy number variations (CNVs) of C4A and C4B in relation to disease risk in systemic lupus erythematosus (SLE), and to compare the basis of race-specific C4A deficiency between East Asians and individuals of European descent.
  
  
  
  The East Asian study population included 999 SLE patients and 1,347 healthy subjects. Variations in gene copy numbers (GCNs) of total C4, C4A, and C4B, as well as C4-Long and C4-Short genes, were determined and validated using independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein occurring concurrently with C4A deficiency.
  
  
  
  In East Asians, high GCNs of total C4 and C4A were strongly protective against SLE, whereas low and medium GCNs of total C4 and C4A, and the absence of C4-Short genes, were risk factors for SLE. Homozygous C4A deficiency was infrequent in East Asian subjects, but had an odds ratio (OR) of 12.4 (P = 0.0015) for SLE disease susceptibility. Low serum complement levels were strongly associated with low GCNs of total C4 (OR 3.19, P = 7.3 × 10(-7) ) and C4B (OR 2.53, P = 2.5 × 10(-5) ). Patients with low serum complement levels had high frequencies of anti-double-stranded DNA antibodies (OR 4.96, P = 9.7 × 10(-17) ), hemolytic anemia (OR 3.89, P = 3.6 × 10(-10) ), and renal disease (OR 2.18, P = 8.5 × 10(-6) ). The monomodular-Short haplotype found to be prevalent in European Americans with C4A deficiency, which was in linkage disequilibrium with HLA-DRB1*0301, was scarce in East Asians. Instead, most East Asian subjects with C4A deficiency were found to have a recombinant haplotype with bimodular C4-Long and C4-Short genes, encoding C4B1 and C4B96, which was linked to HLA-DRB1*1501. DNA sequencing revealed an E920K polymorphism in C4B96.
  
  
  
  C4 CNVs and deficiency of C4A both play an important role in the risk and manifestations of SLE in East Asian and European populations.
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan, Republic of China.
authors.forename: Ji Yih
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Yee Ling
authors.initials: YL
authors.lastname: Wu
authors.affiliation: Division of Rheumatology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Mo Yin
authors.initials: MY
authors.lastname: Mok
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan, Republic of China.
authors.forename: Yeong-Jian Jan
authors.initials: YJ
authors.lastname: Wu
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Lintner
authors.affiliation: Department of Rehabilitation, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan, Republic of China.
authors.forename: Chin-Man
authors.initials: CM
authors.lastname: Wang
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Erwin K
authors.initials: EK
authors.lastname: Chung
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Bi
authors.initials: B
authors.lastname: Zhou
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Yu
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Alaaedin
authors.initials: A
authors.lastname: Alhomosh
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Karla
authors.initials: K
authors.lastname: Jones
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Spencer
authors.affiliation: Division of Biostatistics, College of Public Health, The Ohio State University, Columbus, Ohio 43201, USA.
authors.forename: Haikady N
authors.initials: HN
authors.lastname: Nagaraja
authors.affiliation: Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Yu Lung
authors.initials: YL
authors.lastname: Lau
authors.affiliation: Division of Rheumatology, Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Chak-Sing
authors.initials: CS
authors.lastname: Lau
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute and Division of Pediatric Rheumatology, Nationwide Children's Hospital; and Department of Pediatrics, The Ohio State University, 700 Children's Drive, Columbus, Ohio 43205, USA.
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
mesh_terms: D000328:Adult; D044466:Asian People; D015934:Complement C4a / Q000172:deficiency* / Q000235:genetics*; D015935:Complement C4b / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D000081208:Hereditary Complement Deficiency Diseases; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics*; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D018570:Risk Assessment; D012307:Risk Factors; D044465:White People
chemical_list: D015934:Complement C4a; D015935:Complement C4b
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