Cited by 256Diabetes and associated disordersGenetic Associations and EpidemiologyMultiple Sclerosis Research Studies

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HLA Class I and Genetic Susceptibility to Type 1 Diabetes

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Noble, Janelle A., Valdes, Ana Maria, Varney, Michael D., Carlson, Joyce A., Moonsamy, Priscilla, Fear, Anna Lisa, Lane, Julie A., Lavant, Eva, Rappner, Rebecca, Louey, Anthony, Concannon, Patrick, Mychaleckyj, Josyf C., Erlich, Henry A., for the Type 1 Diabetes Genetics Consortium·2010·Diabetes

DOI 10.2337/db10-0699PMC PMC2963558

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Abstract

OBJECTIVE: We report here genotyping data and type 1 diabetes association analyses for HLA class I loci (A, B, and C) on 1,753 multiplex pedigrees from the Type 1 Diabetes Genetics Consortium (T1DGC), a large international collaborative study. RESEARCH DESIGN AND METHODS: Complete eight-locus HLA genotyping data were generated. Expected patient class I (HLA-A, -B, and -C) allele frequencies were calculated, based on linkage disequilibrium (LD) patterns with observed HLA class II DRB1-DQA1-DQB1 haplotype frequencies. Expected frequencies were compared to observed allele frequencies in patients. RESULTS: Significant type 1 diabetes associations were observed at all class I HLA loci. After accounting for LD with HLA class II, the most significantly type 1 diabetes–associated alleles were B*5701 (odds ratio 0.19; P = 4 × 10−11) and B*3906 (10.31; P = 4 × 10−10). Other significantly type 1 diabetes–associated alleles included A*2402, A*0201, B*1801, and C*0501 (predisposing) and A*1101, A*3201, A*6601, B*0702, B*4403, B*3502, C*1601, and C*0401 (protective). Some alleles, notably B*3906, appear to modulate the risk of all DRB1-DQA1-DQB1 haplotypes on which they reside, suggesting a class I effect that is independent of class II. Other class I type 1 diabetes associations appear to be specific to individual class II haplotypes. Some apparent associations (e.g., C*1601) could be attributed to strong LD to another class I susceptibility locus (B*4403). CONCLUSIONS: These data indicate that HLA class I alleles, in addition to and independently from HLA class II alleles, are associated with type 1 diabetes.

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Authors: Noble, J. A., Valdes, A. M., Varney, M. D., Carlson, J. A., Moonsamy, P., Fear, A. L., Lane, J. A., Lavant, E., Rappner, R., Louey, A., Concannon, P., Mychaleckyj, J. C., Erlich, H. A., & for the Type 1 Diabetes Genetics Consortium
Affiliations: Children's Hospital Oakland Research Institute, Oakland, California;
King's College London (GB)
Australian Red Cross Lifeblood (AU)
Skåne University Hospital (SE)
Roche Molecular Systems, Pleasanton, California;
University of Virginia (US)
Corresponding author: Noble, Janelle A.
ORCID: Noble, Janelle A.
Valdes, Ana Maria
Concannon, Patrick
Mychaleckyj, Josyf C.
Venue: Diabetes
Publisher: American Diabetes Association
Published: 2010-08-26
Volume: 59
Issue: 11
Pages: 2972-2979
ISSN: 0012-1797 (ISSN-L)
1939-327X
DOI: 10.2337/db10-0699
PMC: PMC2963558
OpenAlex: W2110458118
Cited by: 254
References: 21
Citations by year: 2026: 4 · 2025: 8 · 2024: 31 · 2023: 12 · 2022: 9 · 2021: 30 · 2020: 22 · 2019: 17 · 2018: 25 · 2017: 11 · 2016: 14 · 2015: 17 · 2014: 8 · 2013: 20 · 2012: 14
FWCI: 8.28
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by-nc-nd
creativecommons.org/licenses/by-nc-nd/3.0/ (vor, 4019 d)
Locations: Diabetes (publishedVersion, cc-by-nc-nd)
PubMed Central (publishedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Lund University Publications (Lund University) (submittedVersion)
Funders: Juvenile Diabetes Research Foundation International (U01 DK062418)
National Human Genome Research Institute
National Institute of Allergy and Infectious Diseases
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK061722, R01 DK-61722, DK062418, U01DK062418)
National Institute of Child Health and Human Development
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Health Sciences › Medicine › Clinical Neurology › Multiple Sclerosis Research Studies
Keywords: type 1 diabetes, HLA class I, HLA-A, HLA-B, HLA-C, genetic susceptibility, HLA class II, linkage disequilibrium, HLA-B*57:01, multiplex pedigrees, allele frequency
MeSH terms: Diabetes Mellitus, Type 1, Exons, Female, Gene Frequency, Humans, Male, Polymorphism, Genetic, T-Lymphocytes, HLA-A Antigens, HLA-B Antigens, HLA-C Antigens, Histocompatibility Antigens Class I, Linkage Disequilibrium, Genetic Predisposition to Disease, Insulin-Secreting Cells

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