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Genome-wide association study of IgG1 responses to the choline-binding protein PspC of Streptococcus pneumoniae

Genes & Immunity volume 16, pages 289–296 (2015)Cite this article

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Abstract

Streptococcus pneumoniae causes invasive pneumococcal disease. Delayed development of antibodies to S. pneumoniae in infancy is associated with the development of atopy and asthma. Pneumococcal surface protein C (PspC) is a vaccine candidate and variation in its choline-binding region is associated with invasive disease. This study examined 523 060 single-nucleotide polymorphisms in The Western Australian Pregnancy Cohort (Raine) Study to find loci influencing immunoglobulin G1 (IgG1) responses to PspC measured at age 14 years (n=1152). Genome-wide significance (top SNP rs9275596; P=3.1 × 10−14) was only observed at human leucocyte antigen (HLA). Imputed HLA amino-acid polymorphisms showed the strongest associations at positions DRB1 47 (P=3.2 × 10−11), 13SRG (P=9.8 × 10–10) and 11SP (P=9.8 × 10−10), and at DQA1 34 (P=6.4 × 10–10), DQB1 167R (P=9.3 × 10−6) and HLA-B 95 W (P=1.2 × 10−9). Conditional analyses showed independent contributions from DRB1 47 and DQB1 167R to the signal at rs9275596, supported by an omnibus test showing a strong signal for the haplotype DRB1_47_DQB1_167 (P=9.02 × 10−15). In silico analysis showed that DRB1 four-digit allele groups defined by DRB1 47F bind to a greater complexity of core 9-mer epitopes compared with DRB1 47Y, especially across repeats in the C-term choline-binding region. Consequent differences in CD4 T-cell help for IgG1 to PspC could have implications for vaccine design. Further analysis in other cohorts is merited.

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Acknowledgements

We are extremely grateful to all the families who took part in this study and the whole Raine Study team, which includes data collectors, cohort managers, data managers, clerical staff, research scientists and volunteers. The Raine Study has been supported by the National Health and Medical Research Council over the last 20 years with additional funding for core management provided by The University of Western Australia (UWA), Raine Medical Research Foundation, Telethon Kids Institute, UWA Faculty of Medicine, Dentistry and Health Sciences, Women and Infants Research Foundation, Curtin University and Edith Cowan University. The 14-year follow-up was supported by the National Health and Medical Research Council (ID 211912 and ID 003209) and The Raine Foundation. Genome-wide SNP genotyping data generated from samples collected at either the 14- or 17-year follow-ups were supported by the National Health and Medical Research Council (ID 572613). IgG1 measurements in the 14-year follow-up samples were funded by the National Health and Medical Research Council (ID 458513). Web resources: BEAGLE Software: http://faculty.washington.edu/browning/beagle/beagle.html; BlockLogo tool: http://research4.dfci.harvard.edu/cvc/blocklogo/; The Raine Study: http://www.rainestudy.telethonkids.org.au/.

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  1. D Anderson and M Fakiola: These authors contributed equally to this work.

Authors and Affiliations

  1. Telethon Kids Institute, The University of Western Australia, Subiaco, Western Australia, Australia

    D Anderson, B J Hales, W R Thomas & J M Blackwell

  2. Department of Pathology, University of Cambridge, Cambridge, UK

    M Fakiola

  3. School of Women's and Infants' Health, University of Western Australia, Perth, Australia

    C E Pennell

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  1. D Anderson
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Correspondence to J M Blackwell.

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Anderson, D., Fakiola, M., Hales, B. et al. Genome-wide association study of IgG1 responses to the choline-binding protein PspC of Streptococcus pneumoniae. Genes Immun 16, 289–296 (2015). https://doi.org/10.1038/gene.2015.12

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