title: HLA genotyping in the international Type 1 Diabetes Genetics Consortium.
abstract: BACKGROUND
  Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers.
  
  
  OBJECTIVE
  In this article, we present the operational strategy of training, classification, reporting, and quality control of HLA genotyping in four laboratories on three continents over nearly 5 years.
  
  
  METHODS
  Methods to standardize HLA genotyping at eight loci included: central training and initial certification testing; the use of uniform reagents, protocols, instrumentation, and software versions; an automated data transfer; and the use of standardized nomenclature and allele databases. We implemented a rigorous and consistent quality control process, reinforced by repeated workshops, yearly meetings, and telephone conferences.
  
  
  RESULTS
  A total of 15,246 samples have been HLA genotyped at eight loci to four-digit resolution; an additional 6797 samples have been HLA genotyped at two loci. The genotyping repeat rate decreased significantly over time, with an estimated unresolved Mendelian inconsistency rate of 0.21%. Annual quality control exercises tested 2192 genotypes (4384 alleles) and achieved 99.82% intra-laboratory and 99.68% inter-laboratory concordances.
  
  
  CONCLUSIONS
  The chosen genotyping platform was unable to distinguish many allele combinations, which would require further multiple stepwise testing to resolve. For these combinations, a standard allele assignment was agreed upon, allowing further analysis if required.
  
  
  CONCLUSIONS
  High-resolution HLA genotyping can be performed in multiple laboratories using standard equipment, reagents, protocols, software, and communication to produce consistent and reproducible data with minimal systematic error. Many of the strategies used in this study are generally applicable to other large multi-center studies.
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
authors.forename: Josyf C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: Janelle A
authors.initials: JA
authors.lastname: Noble
authors.forename: Priscilla V
authors.initials: PV
authors.lastname: Moonsamy
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Carlson
authors.forename: Michael D
authors.initials: MD
authors.lastname: Varney
authors.forename: Jeff
authors.initials: J
authors.lastname: Post
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Helmberg
authors.forename: June J
authors.initials: JJ
authors.lastname: Pierce
authors.forename: Persia
authors.initials: P
authors.lastname: Bonella
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Fear
authors.forename: Eva
authors.initials: E
authors.lastname: Lavant
authors.forename: Anthony
authors.initials: A
authors.lastname: Louey
authors.forename: Sean
authors.initials: S
authors.lastname: Boyle
authors.forename: Julie A
authors.initials: JA
authors.lastname: Lane
authors.forename: Paul
authors.initials: P
authors.lastname: Sali
authors.forename: Samuel
authors.initials: S
authors.lastname: Kim
authors.forename: Rebecca
authors.initials: R
authors.lastname: Rappner
authors.forename: Dustin T
authors.initials: DT
authors.lastname: Williams
authors.forename: Letitia H
authors.initials: LH
authors.lastname: Perdue
authors.forename: David M
authors.initials: DM
authors.lastname: Reboussin
authors.forename: Brian D
authors.initials: BD
authors.lastname: Tait
authors.forename: Beena
authors.initials: B
authors.lastname: Akolkar
authors.forename: Joan E
authors.initials: JE
authors.lastname: Hilner
authors.forename: Michael W
authors.initials: MW
authors.lastname: Steffes
authors.forename: Henry A
authors.initials: HA
authors.lastname: Erlich
mesh_terms: D000465:Algorithms; D001681:Biological Assay; D019411:Clinical Laboratory Techniques; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics*; D004493:Education; D005838:Genotype; D014943:Global Health; D006680:HLA Antigens / Q000032:analysis / Q000235:genetics*; D006801:Humans; D007391:International Cooperation; D010375:Pedigree; D011110:Polymorphism, Genetic; D011786:Quality Control; D018570:Risk Assessment
chemical_list: D006680:HLA Antigens