title: Alleles of the NRAMP1 gene are risk factors for pediatric tuberculosis disease.
abstract: Relatively little is known about the human genetics of susceptibility to common diseases caused by bacterial pathogens. Tuberculosis, caused by Mycobacterium tuberculosis, is a major cause of morbidity and mortality worldwide. So far, genetic studies of tuberculosis susceptibility have largely been focused on adult patients despite the fact that tuberculosis is highly prevalent among children. To study the host genetic component of pediatric tuberculosis susceptibility, we enrolled 184 ethnically diverse families from the Greater Houston area with at least one child affected by pediatric tuberculosis disease. Using a family-based control design, we found allelic variants of the natural resistance-associated macrophage protein gene 1 (NRAMP1) (alias SLC11A1) significantly associated with tuberculosis disease in this pediatric patient population [P = 0.01; odds ratio = 1.75 (95% confidence interval, 1.10-2.77)]. The association of NRAMP1 with pediatric tuberculosis disease was significantly heterogeneous (P = 0.01) between simplex [P <0.0008; odds ratio = 3.13 (1.54-6.25)] and multiplex families (P = 1), suggesting an interplay between mechanisms of genetic control and exposure intensities. In striking contrast to previous studies in the adult population, we observed that the common alleles of NRAMP1 polymorphisms were risk factors for pediatric tuberculosis disease. To explain the different direction of allelic association between adult and pediatric disease, we hypothesize that NRAMP1 influences the speed of progression from infection to tuberculosis disease.
authors.affiliation: McGill Centre for the Study of Host Resistance, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada H3G 1A4.
authors.forename: Suneil
authors.initials: S
authors.lastname: Malik
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Heather
authors.initials: H
authors.lastname: Tooker
authors.forename: Audrey
authors.initials: A
authors.lastname: Poon
authors.forename: Leah
authors.initials: L
authors.lastname: Simkin
authors.forename: Manon
authors.initials: M
authors.lastname: Girard
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Adams
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Starke
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Smith
authors.forename: Edward A
authors.initials: EA
authors.lastname: Graviss
authors.forename: James M
authors.initials: JM
authors.lastname: Musser
authors.forename: Erwin
authors.initials: E
authors.lastname: Schurr
mesh_terms: D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics*; D002648:Child; D017931:DNA Primers; D005190:Family; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D013781:Texas / Q000453:epidemiology; D014376:Tuberculosis / Q000453:epidemiology* / Q000235:genetics*; D000099173:Natural Resistance-associated Macrophage Protein 1
chemical_list: D027682:Cation Transport Proteins; D017931:DNA Primers; D000099173:Natural Resistance-associated Macrophage Protein 1