Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes

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, respective...

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Veröffentlicht in:Diabetes (New York, N.Y.) Jg. 65; H. 3; S. 710
Hauptverfasser: Zhao, Lue Ping, Alshiekh, Shehab, Zhao, Michael, Carlsson, Annelie, Larsson, Helena Elding, Forsander, Gun, Ivarsson, Sten A, Ludvigsson, Johnny, Kockum, Ingrid, Marcus, Claude, Persson, Martina, Samuelsson, Ulf, Örtqvist, Eva, Pyo, Chul-Woo, Nelson, Wyatt C, Geraghty, Daniel E, Lernmark, Åke
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 01.03.2016
Schlagworte:
Adolescent
Autoantibodies - immunology
Case-Control Studies
Cation Transport Proteins - immunology
Child
Child, Preschool
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 1 - immunology
Female
Genetic Predisposition to Disease
Glutamate Decarboxylase - immunology
High-Throughput Nucleotide Sequencing
HLA-DRB1 Chains - genetics
HLA-DRB3 Chains - genetics
HLA-DRB4 Chains - genetics
HLA-DRB5 Chains - genetics
Humans
Infant
Insulin - immunology
Male
Odds Ratio
Sequence Analysis, DNA
Zinc Transporter 8
ISSN:1939-327X, 1939-327X
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1939-327X
1939-327X
DOI:10.2337/db15-1115