title: Gene CNVs and protein levels of complement C4A and C4B as novel biomarkers for partial disease remissions in new-onset type 1 diabetes patients.
abstract: OBJECTIVE
  To determine the roles of complement C4A and C4B gene copy-number variations and their plasma protein concentrations in residual insulin secretion and loss of pancreatic β-cell function in new-onset type 1 diabetes (T1D) patients.
  
  
  METHODS
  We studied 34 patients of European ancestry with new-onset T1D, aged between 3 and 17 yr (10.7 ± 3.45), at Nationwide Children's Hospital in Columbus, Ohio. Gene copy-number and size variations of complement C4A and C4B were determined by genomic Southern blot analyses. C4A and C4B protein phenotypes were elucidated by immunofixation and radial immunodiffusion. Two-digit human leukocyte antigen (HLA)-DRB1 genotypes were determined by sequence-specific polymerase chain reaction. At 1- and 9-month post diagnosis, stimulated C-peptide levels were measured after a standardized mixed-meal tolerance test.
  
  
  RESULTS
  The diploid gene copy-numbers of C4A varied from 0 to 4, and those of C4B from 0 to 3. Patients with higher copy-number of C4A or higher C4A plasma protein concentrations at diagnosis had higher C-peptide levels at 1-month post diagnosis (p = 0.008; p = 0.008). When controlled by the Z-score of body mass index, C4A copy-numbers, C4A protein concentrations, the age of disease onset, and the number of HLA-DR3 but not DR4 alleles were significant parameters in determining C-peptide levels. At 9-month post diagnosis, 42.3% of patients remained in partial remission, and these patients were characterized by lower total C4B copy-numbers or lower C4B protein concentrations (p = 0.02; p = 0.0004).
  
  
  CONCLUSIONS
  C4A appears to associate with the protection of residual β-cell function in new-onset T1D; C4B is correlated with the end of disease remission at 9-month post diagnosis.
authors.affiliation: Center for Molecular and Human Genetics, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Kingery
authors.forename: Yee Ling
authors.initials: YL
authors.lastname: Wu
authors.forename: Bi
authors.initials: B
authors.lastname: Zhou
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hoffman
authors.forename: C Yung
authors.initials: CY
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D015415:Biomarkers; D002096:C-Peptide / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015934:Complement C4a / Q000235:genetics*; D015935:Complement C4b / Q000235:genetics*; D056915:DNA Copy Number Variations; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D018628:Gene Dosage; D015803:HLA-DR3 Antigen / Q000235:genetics; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D020127:Recovery of Function; D044465:White People / Q000235:genetics
chemical_list: D015415:Biomarkers; D002096:C-Peptide; D015803:HLA-DR3 Antigen; D015934:Complement C4a; D015935:Complement C4b