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Genetic variation within the HLA class III influences T1D susceptibility conferred by high-risk HLA haplotypes

Genes & Immunity volume 11, pages 209–218 (2010)Cite this article

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Abstract

Human leukocyte antigen (HLA) class II DRB1 and DQB1 represent the major type I diabetes (T1D) genetic susceptibility loci; however, other genes in the HLA region are also involved in T1D risk. We analyzed 1411 pedigrees (2865 affected individuals) from the type I diabetes genetics consortium genotyped for HLA classical loci and for 12 single-nucleotide polymorphisms (SNPs) in the class III region previously shown to be associated with T1D in a subset of 886 pedigrees. Using the transmission disequilibrium test, we compared the proportion of SNP alleles transmitted from within the high-risk DR3 and DR4 haplotypes to affected offspring. Markers rs4151659 (mapping to CFB) and rs7762619 (mapping 5′ of LTA) were the most strongly associated with T1D on DR3 (P=1.2 × 10−9 and P=2 × 10−12, respectively) and DR4 (P=4 × 10−15 and P=8 × 10−8, respectively) haplotypes. They remained significantly associated after stratifying individuals in analyses for B*1801, A*0101-B*0801, DPB1*0301, DPB1*0202, DPB1*0401 or DPB1*0402. Rs7762619 and rs4151659 are in strong linkage disequilibrium (LD) (r2=0.82) with each other, but a joint analysis showed that the association for each SNP was not solely because of LD. Our data support a role for more than one locus in the class III region contributing to risk of T1D.

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Acknowledgements

This research uses resources provided by the Type I Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD) and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418.This publication was also supported in part by NIH/NIAID contract number HHSN266200400076C, ABD N01-AI-40076 (GT and LFB). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. AMV is supported by the FP7 large program grant 200800 TREAT-OA. We thank Evangelis Evangelou for providing us with the excel spreadsheet to compute the credibility of the genetic associations.

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  1. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK

    A M Valdes

  2. Department of Integrative Biology, University of California at Berkeley, Berkeley, CA, USA

    G Thomson

  3. Division of Epidemiology, School of Public Health, University of California at Berkeley, Berkeley, CA, USA

    L F Barcellos

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Correspondence to A M Valdes.

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Valdes, A., Thomson, G., Barcellos, L. et al. Genetic variation within the HLA class III influences T1D susceptibility conferred by high-risk HLA haplotypes. Genes Immun 11, 209–218 (2010). https://doi.org/10.1038/gene.2009.104

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