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

D Anderson1, M Fakiola2, B J Hales1

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

Genes and Immunity
|May 1, 2015
PubMed

Insights

Human leucocyte antigen (HLA) genetic variations significantly influence antibody responses to pneumococcal surface protein C (PspC). These findings have implications for developing more effective pneumococcal vaccines, particularly for preventing invasive pneumococcal disease.

Area of Science:

  • Immunology
  • Genetics
  • Vaccinology

Background:

  • Streptococcus pneumoniae causes invasive pneumococcal disease, and delayed antibody development in infancy is linked to atopy and asthma.
  • Pneumococcal surface protein C (PspC) is a key vaccine candidate, with variations in its choline-binding region associated with disease invasiveness.

Purpose of the Study:

  • To identify genetic loci influencing immunoglobulin G1 (IgG1) responses to PspC in adolescents.
  • To investigate the association between single-nucleotide polymorphisms (SNPs) and PspC-specific IgG1 levels.

Main Methods:

  • Analysis of 523,060 SNPs in 1152 participants from The Western Australian Pregnancy Cohort (Raine) Study.
  • Genome-wide association study (GWAS) and imputation of human leucocyte antigen (HLA) amino-acid polymorphisms.
  • In silico analysis of HLA-PspC epitope binding.

Main Results:

  • Genome-wide significance was observed only at the HLA locus, with top SNP rs9275596 (P=3.1 × 10(-14)).
  • Strongest associations were with HLA amino-acid polymorphisms at positions DRB1 47, DQA1 34, DQB1 167R, and HLA-B 95W.
  • Conditional analyses revealed independent contributions from DRB1 47 and DQB1 167R, with a strong haplotype signal (DRB1_47_DQB1_167; P=9.02 × 10(-15)).
  • In silico analysis indicated differential binding of HLA variants to PspC epitopes, potentially affecting CD4 T-cell help for IgG1 responses.

Conclusions:

  • HLA genetic variations are major determinants of IgG1 responses to PspC.
  • Specific HLA amino-acid polymorphisms and haplotypes are strongly associated with PspC-specific antibody levels.
  • These findings suggest that HLA-based vaccine design strategies could enhance PspC-specific IgG1 responses and improve protection against invasive pneumococcal disease.

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