Mapping of a novel susceptibility locus suggests a role for MC3R and CTSZ in human tuberculosis.
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.
Cooke
Graham S
GS
Wellcome Trust Centre for Human Genetics, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom. gcooke@africacentre.ac.za
Campbell
Sarah J
SJ
Bennett
Steve
S
Lienhardt
Christian
C
McAdam
Keith P W J
KP
Sirugo
Giorgio
G
Sow
Oumou
O
Gustafson
Per
P
Mwangulu
Frank
F
van Helden
Paul
P
Fine
Paul
P
Hoal
Eileen G
EG
Hill
Adrian V S
AV
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*
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