title: Rare variants in MYD88, IRAK4 and IKBKG and susceptibility to invasive pneumococcal disease: a population-based case-control study.
abstract: Although rare variants within the Toll-like receptor signalling pathway genes have been found to underlie human primary immunodeficiencies associated with selective predisposition to invasive pneumococcal disease (IPD), the contribution of variants in these genes to IPD susceptibility at the population level remains unknown. Complete re-sequencing of IRAK4, MYD88 and IKBKG genes was undertaken in 164 IPD cases from the UK and 164 geographically-matched population-based controls. 233 single-nucleotide variants (SNVs) were identified, of which ten were in coding regions. Four rare coding variants were predicted to be deleterious, two variants in MYD88 and two in IRAK4. The predicted deleterious variants in MYD88 were observed as two heterozygote cases but not seen in controls. Frequencies of predicted deleterious IRAK4 SNVs were the same in cases and controls. Our findings suggest that rare, functional variants in MYD88, IRAK4 or IKBKG do not significantly contribute to IPD susceptibility in adults at the population level.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom; Queensland Institute of Medical Research, Brisbane, Australia; Centenary Institute and Sydney Medical School, University of Sydney, Sydney Australia.
authors.forename: Magda K
authors.initials: MK
authors.lastname: Ellis
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Elliott
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom.
authors.forename: Anna
authors.initials: A
authors.lastname: Rautanen
authors.affiliation: Department of Microbiology, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Derrick W
authors.initials: DW
authors.lastname: Crook
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom.
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, United Kingdom; Oxford Centre for Respiratory Medicine, Churchill Hospital Site, Oxford University Hospitals, Oxford, United Kingdom.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chapman
mesh_terms: D016022:Case-Control Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D020125:Mutation, Missense; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D011008:Pneumococcal Infections / Q000235:genetics*; D013296:Streptococcus pneumoniae / Q000472:pathogenicity*
chemical_list: C491731:IKBKG protein, human; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051550:I-kappa B Kinase