title: HLA Risk Haplotype: Insulin Deficiency in Pediatric Type 1 Diabetes.
abstract: BACKGROUND
  Certain HLA class II haplotypes have long been related with the risk of developing type 1 diabetes. The presence of the HLA haplotype DRB1*04/DQA1*03/DQB1*03:02, together with specific β-cell autoantibodies, contributes to the development and/or severity of insulin deficiency in type 1 diabetes.
  
  
  OBJECTIVE
  To evaluate the association of HLA risk haplotype HLA-DRB1/-DQA1/-DQB1 with β-cell function and antibody markers in recent-onset type 1 diabetes patients, their siblings, and controls.
  
  
  METHODS
  We studied recently diagnosed type 1 diabetes pediatric patients, their siblings, and healthy controls, analyzing autoantibodies (anti-glutamic acid decarboxylase, anti-IA-2, and anti-insulin), HLA risk and protector haplotypes, and β-cell function (plasma proinsulin, insulin and C-peptide). X2, ANOVA or Kruskal-Wallis and multiple logistic regression were used to analyze data.
  
  
  RESULTS
  We included 46 patients, 72 siblings, and 160 controls. Prevalence of anti-tyrosine phosphatase-related islet antigen 2 and anti-glutamic acid decarboxylase antibodies was higher in patients than siblings and controls. We found risk haplotype DRB1*04/DQA1*03/DQB1*03:02 in 95.7% of patients vs. 51.87% of controls; DRB1*03:01/DQA1*05/DQB1*02 in 47.8% of patients vs. 8.12% of controls; and DRB1*14/DQA1*05/DQB1*03:01 in 2.2% of patients vs. 20.0% of controls. With DRB1*04/DQA1*03/DQB1*03:02, the prevalence of antibodies was significantly higher in patients, although not within any single group. In regression model based on insulin secretion, only anti-tyrosine phosphatase-related islet antigen 2 antibodies and age were associated with the risk haplotype.
  
  
  CONCLUSIONS
  The DRB1*04/DQA1*03/DQB1*03:02 haplotype increased the risk for lower insulin, proinsulin, and C-peptide concentrations, suggesting an association with the severity of insulin deficiency in type 1 diabetes patients. This haplotype, added to antibody positivity, is a predictor of deficient insulin secretion in a Mexican pediatric population.
authors.affiliation: Department of Medical Investigation in Clinical Epidemiology, UMAE Hospital de Especialidades, Mexico City, Mexico.|School of Medicine, Instituto Politécnico Nacional, Mexico City, Mexico.
authors.forename: Rita A
authors.initials: RA
authors.lastname: Gómez-Díaz
authors.affiliation: Department of Endocrinology, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nishimura-Meguro
authors.affiliation: Department of Endocrinology, UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, IMSS, Mexico City, Mexico.
authors.forename: Eulalia
authors.initials: E
authors.lastname: Garrido-Magaña
authors.affiliation: Department of Pediatric Endocrinology, UMAE Hospital General Dr. Gaudencio González Garza, Mexico City, Mexico.
authors.forename: Lorena
authors.initials: L
authors.lastname: Lizárraga-Paulin
authors.affiliation: Department of Pediatric Endocrinology, UMAE Hospital General Dr. Gaudencio González Garza, Mexico City, Mexico.
authors.forename: Blanca E
authors.initials: BE
authors.lastname: Aguilar-Herrera
authors.affiliation: Department of Medical Investigation in Infectology and Immunology, Hospital de Infectología, Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico.
authors.forename: Carolina
authors.initials: C
authors.lastname: Bekker-Méndez
authors.affiliation: School of Medicine, Instituto Politécnico Nacional, Mexico City, Mexico.
authors.forename: Roberto
authors.initials: R
authors.lastname: Medina-Santillán
authors.affiliation: Laboratory of Physiology, Biochemistry and Genetics, Escuela Nacional de Antropología e Historia, Mexico City, Mexico.|Department of Immunogenetics and Human Identification, Laboratorios Diagnomol, Mexico City, Mexico.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Barquera
authors.affiliation: Department of Medical Investigation in Clinical Epidemiology, UMAE Hospital de Especialidades, Mexico City, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Mondragón-González
authors.affiliation: Department of Medical Investigation in Clinical Epidemiology, UMAE Hospital de Especialidades, Mexico City, Mexico.
authors.forename: Niels H
authors.initials: NH
authors.lastname: Wacher
mesh_terms: D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D006681:HLA-D Antigens / Q000235:genetics*; D059848:HLA-DQ alpha-Chains / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D007328:Insulin / Q000172:deficiency / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D016015:Logistic Models; D008297:Male; D008800:Mexico; D012306:Risk; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D006681:HLA-D Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; D007328:Insulin