title: A haplotype spanning P2X7R, P2X4R and CAMKK2 may mark susceptibility to pulmonary non-tuberculous mycobacterial disease.
abstract: Despite widespread exposure to potentially pathogenic mycobacteria present in the soil and in domestic water supplies, it is not clear why only a small proportion of individuals contract pulmonary nontuberculous mycobacterial (NTM) infections. Here, we explore the impact of polymorphisms within three genes: P2X ligand gated ion channel 7 (P2X7R), P2X ligand gated ion channel 4 (P2X4R) and calcium/calmodulin-dependent protein kinase kinase 2 beta (CAMKK2) on susceptibility. Thirty single nucleotide polymorphisms (SNPs) were genotyped in NTM patients (n = 124) and healthy controls (n = 229). Weak associations were found between individual alleles in P2X7R and disease but were not significant in multivariate analyses adjusted to account for gender. Haplotypes spanning the three genes were derived using the fastPHASE algorithm. This yielded 27 haplotypes with frequencies >1% and accounting for 63.3% of the combined cohort. In univariate analyses, seven of these haplotypes displayed associations with NTM disease above our preliminary cut-off (p ≤ 0.20). When these were carried forward in a logistic regression model, gender and one haplotype (SH95) were independently associated with the disease (model p < 0.0001; R2= 0.05). Examination of individual alleles within these haplotypes implicated P2X7R and CAMKK2 in pathways affecting pulmonary NTM disease.
authors.affiliation: School of Medicine and Biomedical Science, University of Queensland, QLD, Brisbane, Australia.|School of Biomedical Science, Curtin University, Perth, WA, Australia.|Gallipoli Medical Research Foundation, Greenslopes Private Hospital, QLD, Brisbane, Australia.
authors.forename: Samuel
authors.initials: S
authors.lastname: Halstrom
authors.affiliation: Centre for Biomedical Research, Burnet Institute, and Department of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, VIC, Australia.|School of Physiology, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Cherry
authors.affiliation: Centre for Comparative Genomics, Murdoch University, Perth, WA, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Black
authors.affiliation: School of Medicine and Biomedical Science, University of Queensland, QLD, Brisbane, Australia.|Gallipoli Medical Research Foundation, Greenslopes Private Hospital, QLD, Brisbane, Australia.
authors.forename: Rachel
authors.initials: R
authors.lastname: Thomson
authors.affiliation: Harry Perkins Institute of Medical Research, Perth, WA, Australia.
authors.forename: Hayley
authors.initials: H
authors.lastname: Goullee
authors.affiliation: Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Baltic
authors.affiliation: Translational Cancer Pathology Laboratory, PathWest Laboratory Medicine W.A, Nedlands, WA, Australia.|School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, WA, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Allcock
authors.affiliation: Institute for Respiratory Health, University of Western Australia, Nedlands, WA, Australia.
authors.forename: Suzanna E L
authors.initials: SEL
authors.lastname: Temple
authors.affiliation: School of Biomedical Science, Curtin University, Perth, WA, Australia. patricia.price@curtin.edu.au.|School of Physiology, University of the Witwatersrand, Johannesburg, South Africa. patricia.price@curtin.edu.au.
authors.forename: Patricia
authors.initials: P
authors.lastname: Price
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008171:Lung Diseases / Q000453:epidemiology / Q000235:genetics* / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D009161:Mycobacterium / Q000472:pathogenicity; D009165:Mycobacterium Infections, Nontuberculous / Q000453:epidemiology / Q000235:genetics* / Q000382:microbiology; D020641:Polymorphism, Single Nucleotide; D058848:Receptors, Purinergic P2X4 / Q000235:genetics*; D058486:Receptors, Purinergic P2X7 / Q000235:genetics*
chemical_list: C546468:P2RX7 protein, human; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; C517698:CAMKK2 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase
keywords: Genetic polymorphism; Immunogenetics; Non-tuberculous mycobacteria; Pulmonary disease