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Next-Generation Sequencing Reveals That HLA-DRB3, -DRB4, and -DRB5 May Be Associated With Islet Autoantibodies and Risk for Childhood Type 1 Diabetes
Fred Hutchinson Cancer Research Centre, WA 98104 USA.
Lund University, Sweden.
Fred Hutchinson Cancer Research Centre, WA 98104 USA.
Lund University, Sweden.
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2016 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 3, 710-718 p.Article in journal (Refereed) PublishedText
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER DIABETES ASSOC , 2016. Vol. 65, no 3, 710-718 p.
National Category
Clinical Medicine
URN: urn:nbn:se:liu:diva-126246DOI: 10.2337/db15-1115ISI: 000370961000024PubMedID: 26740600OAI: diva2:913456

Funding Agencies|European Foundation for the Study of Diabetes Clinical Research Grants Programme; Swedish Child Diabetes Foundation; National Institutes of Health [DK-63861, DK-26190]; Swedish Research Council; Linne grant; Skane County Council for Research and Development; Swedish Association of Local Authorities and Regions; Knut and Alice Wallenberg Foundation

Available from: 2016-03-21 Created: 2016-03-21 Last updated: 2016-03-21

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Ludvigsson, JohnnySamuelsson, Ulf
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Division of Clinical SciencesFaculty of Medicine and Health SciencesDepartment of Paediatrics in Linköping
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