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Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma

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Abstract

Although genome-wide association studies have identified several susceptibility loci for adult glioma, little is known regarding the potential contribution of genetic variation in the human leukocyte antigen (HLA) region to glioma risk. HLA associations have been reported for various malignancies, with many studies investigating selected candidate HLA polymorphisms. However, no systematic analysis has been conducted in glioma patients, and no investigation into potential non-additive effects has been described. We conducted comprehensive genetic analyses of HLA variants among 1746 adult glioma patients and 2312 controls of European-ancestry from the GliomaScan Consortium. Genotype data were generated with the Illumina 660-Quad array, and we imputed HLA alleles using a reference panel of 5225 individuals in the Type 1 Diabetes Genetics Consortium who underwent high-resolution HLA typing via next-generation sequencing. Case-control comparisons were adjusted for population stratification using ancestry-informative principal components. Because alleles in different loci across the HLA region are linked, we created multigene haplotypes consisting of the genes DRB1, DQA1, and DQB1. Although none of the haplotypes were associated with glioma in additive models, inclusion of a dominance term significantly improved the model for multigene haplotype HLA-DRB1*1501-DQA1*0102-DQB1*0602 (P = 0.002). Heterozygous carriers of the haplotype had an increased risk of glioma [odds ratio (OR) 1.23; 95% confidence interval (CI) 1.01–1.49], while homozygous carriers were at decreased risk compared with non-carriers (OR 0.64; 95% CI 0.40–1.01). Our results suggest that the DRB1*1501-DQA1*0102-DQB1*0602 haplotype may contribute to the risk of glioma in a non-additive manner, with the positive dominance effect partly explained by an epistatic interaction with HLA-DRB1*0401-DQA1*0301-DQB1*0301.

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Acknowledgements

The results published here are, in part, based upon data obtained from dbGaP Study Accession phs000652.v1.p1: “Cohort-based Genome-Wide Association Study of Glioma (GliomaScan)” which was supported by intramural funds from the NCI and federal funds from the NCI under Contract N01-CO-12400. The authors additionally acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council Grant G0000934 and the Wellcome Trust Grant 068545/Z/02. This research uses resources provided by the Type 1 Diabetes Genetics Consortium (T1DGC); 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; Juvenile Diabetes Research Foundation International (JDRF), supported by U01 DK062418.

Funding

This work was supported by the National Institutes of Health T32CA151022-06 (C.Z.), R25T CA112355 (J.S.W.), and The Sontag Foundation (K.M.W.)

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  1. Kyle M. Walsh

    Present address: Division of Neuro-epidemiology, Department of Neurosurgery, Duke University, Durham, NC, 27710, USA

Authors and Affiliations

  1. Division of Neuroepidemiology, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, 94158, USA

    Chenan Zhang, Ivan V. Smirnov, John K. Wiencke, Joseph L. Wiemels & Kyle M. Walsh

  2. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA

    Chenan Zhang, Adam J. de Smith, Joseph L. Wiemels, John S. Witte & Kyle M. Walsh

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Correspondence to Chenan Zhang.

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Zhang, C., de Smith, A.J., Smirnov, I.V. et al. Non-additive and epistatic effects of HLA polymorphisms contributing to risk of adult glioma. J Neurooncol 135, 237–244 (2017). https://doi.org/10.1007/s11060-017-2569-7

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