title: Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes.
abstract: The possible contribution of HLA-DRB3, -DRB4, and -DRB5 alleles to type 1 diabetes risk and to insulin autoantibody (IAA), GAD65 (GAD autoantibody [GADA]), IA-2 antigen (IA-2A), or ZnT8 against either of the three amino acid variants R, W, or Q at position 325 (ZnT8RA, ZnT8WA, and ZnT8QA, respectively) at clinical diagnosis is unclear. Next-generation sequencing (NGS) was used to determine all DRB alleles in consecutively diagnosed patients ages 1-18 years with islet autoantibody-positive type 1 diabetes (n = 970) and control subjects (n = 448). DRB3, DRB4, or DRB5 alleles were tested for an association with the risk of DRB1 for autoantibodies, type 1 diabetes, or both. The association between type 1 diabetes and DRB1*03:01:01 was affected by DRB3*01:01:02 and DRB3*02:02:01. These DRB3 alleles were associated positively with GADA but negatively with ZnT8WA, IA-2A, and IAA. The negative association between type 1 diabetes and DRB1*13:01:01 was affected by DRB3*01:01:02 to increase the risk and by DRB3*02:02:01 to maintain a negative association. DRB4*01:03:01 was strongly associated with type 1 diabetes (P = 10(-36)), yet its association was extensively affected by DRB1 alleles from protective (DRB1*04:03:01) to high (DRB1*04:01:01) risk, but its association with DRB1*04:05:01 decreased the risk. HLA-DRB3, -DRB4, and -DRB5 affect type 1 diabetes risk and islet autoantibodies. HLA typing with NGS should prove useful to select participants for prevention or intervention trials.
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Lue Ping
authors.initials: LP
authors.lastname: Zhao
authors.affiliation: Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
authors.forename: Shehab
authors.initials: S
authors.lastname: Alshiekh
authors.affiliation: Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Michael
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Lund University, Lund, Sweden.
authors.forename: Annelie
authors.initials: A
authors.lastname: Carlsson
authors.affiliation: Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
authors.forename: Helena Elding
authors.initials: HE
authors.lastname: Larsson
authors.affiliation: Department of Pediatrics, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Gun
authors.initials: G
authors.lastname: Forsander
authors.affiliation: Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden.
authors.forename: Sten A
authors.initials: SA
authors.lastname: Ivarsson
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Johnny
authors.initials: J
authors.lastname: Ludvigsson
authors.affiliation: Department of Clinical Neurosciences, Karolinska Institutet, Solna, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Kockum
authors.affiliation: Department of Clinical Science, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Claude
authors.initials: C
authors.lastname: Marcus
authors.affiliation: Department of Clinical Science, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Martina
authors.initials: M
authors.lastname: Persson
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Samuelsson
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Örtqvist
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Chul-Woo
authors.initials: CW
authors.lastname: Pyo
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Wyatt C
authors.initials: WC
authors.lastname: Nelson
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Geraghty
authors.affiliation: Department of Clinical Sciences, Lund University/Clinical Research Centre, Skåne University Hospital, Malmö, Sweden ake.lernmark@med.lu.se.
authors.forename: Åke
authors.initials: Å
authors.lastname: Lernmark
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology*; D016022:Case-Control Studies; D027682:Cation Transport Proteins / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics*; D059826:HLA-DRB3 Chains / Q000235:genetics*; D059845:HLA-DRB4 Chains / Q000235:genetics*; D059847:HLA-DRB5 Chains / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D007328:Insulin / Q000276:immunology; D008297:Male; D016017:Odds Ratio; D017422:Sequence Analysis, DNA; D000075703:Zinc Transporter 8
chemical_list: D001323:Autoantibodies; D027682:Cation Transport Proteins; D059811:HLA-DRB1 Chains; D059826:HLA-DRB3 Chains; D059845:HLA-DRB4 Chains; D059847:HLA-DRB5 Chains; C096322:ICA512 autoantibody; D007328:Insulin; C492522:SLC30A8 protein, human; D000075703:Zinc Transporter 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2