Evidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians.
The region of conserved synteny on mouse chromosome 11/human 17q11-q21 is known to carry a susceptibility gene(s) for intramacrophage pathogens. The region is rich in candidates including NOS2A, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL5/RANTES, CCR7, STAT3 and STAT5A/5B. To examine the region in man, we studied 92 multicase tuberculosis (627 individuals) and 72 multicase leprosy (372 individuals) families from Brazil. Multipoint nonparametric analysis (ALLEGRO) using 16 microsatellites shows two peaks of linkage for leprosy at D17S250 (Z(lr) score 2.34; P=0.01) and D17S1795 (Z(lr) 2.67; P=0.004) and a single peak for tuberculosis at D17S250 (Z(lr) 2.04; P=0.02). Combined analysis shows significant linkage (peak Z(lr) 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 (P=0.0004). To determine whether one or multiple genes contribute, 49 informative single nucleotide polymorphisms were typed in candidate genes. Family-based allelic association testing that was robust to family clustering demonstrated significant associations with tuberculosis susceptibility at four loci separated by intervals (NOS2A-8.4 Mb-CCL18-32.3 kb-CCL4-6.04 Mb-STAT5B) up to several Mb. Stepwise conditional logistic regression analysis using a case/pseudo-control data set showed that the four genes contributed separate main effects, consistent with a cluster of susceptibility genes across 17q11.2.
Jamieson
S E
SE
Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, UK.
Miller
E N
EN
Black
G F
GF
Peacock
C S
CS
Cordell
H J
HJ
Howson
J M M
JM
Shaw
M-A
MA
Burgner
D
D
Xu
W
W
Lins-Lainson
Z
Z
Shaw
J J
JJ
Ramos
F
F
Silveira
F
F
Blackwell
J M
JM
D000818:Animals; D001938:Brazil; D016022:Case-Control Studies; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000706:statistics & numerical data; D005838:Genotype; D006801:Humans; D007918:Leprosy / Q000209:etiology / Q000235:genetics*; D019402:Macrophage Inflammatory Proteins; D008297:Male; D051379:Mice; D008894:Milk Proteins; D005810:Multigene Family; D017354:Point Mutation; D011506:Proteins / Q000235:genetics; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000235:genetics; D014376:Tuberculosis / Q000209:etiology / Q000235:genetics*; D025521:Tumor Suppressor Proteins
C111792:CCL18 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D019402:Macrophage Inflammatory Proteins; D008894:Milk Proteins; D011506:Proteins; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins