Two loci control tuberculin skin test reactivity in an area hyperendemic for tuberculosis.
Approximately 20% of persons living in areas hyperendemic for tuberculosis (TB) display persistent lack of tuberculin skin test (TST) reactivity and appear to be naturally resistant to infection by Mycobacterium tuberculosis. Among those with a positive response, the intensity of TST reactivity varies greatly. The genetic basis of TST reactivity is not known. We report on a genome-wide linkage search for loci that have an impact on TST reactivity, which is defined either as zero versus nonzero (TST-BINa) or as extent of TST in millimeters (TST-quantitative trait locus [QTL]) in a panel of 128 families, including 350 siblings, from an area of South Africa hyperendemic for TB. We detected a major locus (TST1) on chromosomal region 11p14 (P = 1.4 x 10(-5)), which controls TST-BINa, with a lack of responsiveness indicating T cell-independent resistance to M. tuberculosis. We also detected a second major locus (TST2) on chromosomal region 5p15 (P < 10(-5)), which controls TST-QTL or the intensity of T cell-mediated delayed type hypersensitivity (DTH) to tuberculin. Fine mapping of this region identified SLC6A3, encoding the dopamine transporter DAT1, as a promising gene for further studies. Our results pave the way for the understanding of the molecular mechanisms involved in resistance to M. tuberculosis infection in endemic areas (TST1) and for the identification of critical regulators of T cell-dependent DTH to tuberculin (TST2).
Cobat
Aurelie
A
Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de Santé et de Recherche Médicale, Paris 75015, France.
Gallant
Caroline J
CJ
Simkin
Leah
L
Black
Gillian F
GF
Stanley
Kim
K
Hughes
Jane
J
Doherty
T Mark
TM
Hanekom
Willem A
WA
Eley
Brian
B
Jaïs
Jean-Philippe
JP
Boland-Auge
Anne
A
van Helden
Paul
P
Casanova
Jean-Laurent
JL
Abel
Laurent
L
Hoal
Eileen G
EG
Schurr
Erwin
E
Alcaïs
Alexandre
A
D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics* / Q000276:immunology; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics* / Q000276:immunology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000276:immunology; D019353:Endemic Diseases; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000235:genetics* / Q000276:immunology; D008297:Male; D009169:Mycobacterium tuberculosis; D040641:Quantitative Trait Loci / Q000235:genetics* / Q000276:immunology; D035781:Siblings; D013019:South Africa / Q000453:epidemiology; D014373:Tuberculin / Q000276:immunology / Q000494:pharmacology; D014374:Tuberculin Test; D014376:Tuberculosis / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology
D050483:Dopamine Plasma Membrane Transport Proteins; C493214:SLC6A3 protein, human; D014373:Tuberculin