title: Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis.
abstract: BACKGROUND
  Tuberculosis remains a major cause of morbidity and mortality in the developing world. A better understanding of the mechanisms of disease protection could allow novel strategies to disease management and control.
  
  
  OBJECTIVE
  To identify human genomic loci with evidence of linkage to tuberculosis susceptibility and, within these loci, to identify individual genes influencing tuberculosis susceptibility.
  
  
  METHODS
  Affected sibling pair analysis in South African and Malawian populations. Independent case-control study in West Africa.
  
  
  RESULTS
  Two novel putative loci for tuberculosis susceptibility are identified: chromosome 6p21-q23 and chromosome 20q13.31-33--the latter with the strongest evidence for any locus reported to date in human tuberculosis (single point LOD score of 3.1, P = 10(-4), with a maximum likelihood score [MLS] of 2.8). An independent, multistage genetic association study in West African populations mapped this latter region in detail, finding evidence that variation in the melanocortin 3 receptor (MC3R) and cathepsin Z (CTSZ) genes play a role in the pathogenesis of tuberculosis.
  
  
  CONCLUSIONS
  These results demonstrate how a genomewide approach to the complex phenotype of human tuberculosis can identify novel targets for further research.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom. gcooke@africacentre.ac.za
authors.forename: Graham S
authors.initials: GS
authors.lastname: Cooke
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Campbell
authors.forename: Steve
authors.initials: S
authors.lastname: Bennett
authors.forename: Christian
authors.initials: C
authors.lastname: Lienhardt
authors.forename: Keith P W J
authors.initials: KP
authors.lastname: McAdam
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sirugo
authors.forename: Oumou
authors.initials: O
authors.lastname: Sow
authors.forename: Per
authors.initials: P
authors.lastname: Gustafson
authors.forename: Frank
authors.initials: F
authors.lastname: Mwangulu
authors.forename: Paul
authors.initials: P
authors.lastname: van Helden
authors.forename: Paul
authors.initials: P
authors.lastname: Fine
authors.forename: Eileen G
authors.initials: EG
authors.lastname: Hoal
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000354:Africa, Western / Q000453:epidemiology; D044383:Black People / Q000235:genetics; D016022:Case-Control Studies; D056657:Cathepsin K; D056663:Cathepsin Z; D002403:Cathepsins / Q000235:genetics*; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D006801:Humans; D016013:Likelihood Functions; D008295:Malawi / Q000453:epidemiology; D018895:Microsatellite Repeats; D010375:Pedigree; D011110:Polymorphism, Genetic; D044104:Receptor, Melanocortin, Type 3 / Q000235:genetics*; D012044:Regression Analysis; D035781:Siblings; D013019:South Africa / Q000453:epidemiology; D014397:Tuberculosis, Pulmonary / Q000208:ethnology* / Q000235:genetics*
chemical_list: C505392:MC3R protein, human; D044104:Receptor, Melanocortin, Type 3; D002403:Cathepsins; C534182:CTSZ protein, human; D056663:Cathepsin Z; C534130:CTSK protein, human; D056657:Cathepsin K