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Structure of tumor necrosis factor-alpha haploblocks in European populations

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Abstract

DNA variants in the tumor necrosis factor-α (TNF) and linked lymphotoxin-α genes, and specific alleles of the highly polymorphic human leukocyte antigen B (HLA-B) gene have been implicated in a plethora of immune and infectious diseases. However, the tight linkage disequilibrium characterizing the central region of the human major histocompatibility complex (MHC) containing these gene loci has made difficult the unequivocal interpretation of genetic association data. To alleviate these difficulties and facilitate the design of more focused follow-up studies, we investigated the structure and distribution of HLA-B-specific MHC haplotypes reconstructed in a European population from unphased genotypes at a set of 25 single nucleotide polymorphism sites spanning a 66-kilobase long region across TNF. Consistent with the published data, we found limited genetic diversity across the so-called TNF block, with the emergence of seven common MHC haplotypes, termed TNF block super-haplotypes. We also found that the ancestral haplotype 8.1 shares a TNF block haplotype with HLA-B*4402. HLA-B*5701, a known protective allele in HIV-1 pathogenesis, occurred in a unique TNF block haplotype.

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Acknowledgments

Data in this manuscript were collected by the Multicenter AIDS Cohort Study (MACS) with centers (Principal Investigators) at the Johns Hopkins University Bloomberg School of Public Health (Joseph B. Margolick, Lisa Jacobson), Howard Brown Health Center and Northwestern University Medical School (John Phair), University of California, Los Angeles (Roger Detels), and University of Pittsburgh (Charles Rinaldo). Website located at http://www.statepi.jhsph.edu/macs/macs.html.

Funding was provided by R01-CA106168 (RAK) and partially by the Department of Epidemiology (BA). The Multicenter AIDS Cohort Study (MACS) is funded by the National Institute of Allergy and Infectious Diseases, with additional supplemental funding from the National Cancer Institute and the National Heart, Lung and Blood Institute. UO1-AI-35042, 5-MO1-RR-00722 (GCRC), UO1-AI-35043, UO1-AI-37984, UO1-AI-35039, UO1-AI-35040, UO1-AI-37613, UO1-AI-35041

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  1. Department of Epidemiology, R217J, School of Public Health, University of Alabama at Birmingham, 1665 University Blvd, Birmingham, AL, 35294-0022, USA

    Richard A. Kaslow & Brahim Aissani

  2. Department of Biostatistics, University of Alabama, Birmingham, AL, USA

    Kui Zhang

  3. Department of Medicine, University of Alabama, Birmingham, AL, USA

    Aimee M. Merino & Richard A. Kaslow

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  1. Aimee M. Merino
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  2. Kui Zhang
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  3. Richard A. Kaslow
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  4. Brahim Aissani
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Correspondence to Brahim Aissani.

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Merino, A.M., Zhang, K., Kaslow, R.A. et al. Structure of tumor necrosis factor-alpha haploblocks in European populations. Immunogenetics 65, 543–552 (2013). https://doi.org/10.1007/s00251-013-0700-2

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