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Evidence for a Cluster of Genes on Chromosome 17Q11–Q21 Controlling Susceptibility to Tuberculosis and Leprosy in Brazilians

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Evidence for a Cluster of Genes on Chromosome 17Q11–Q21 Controlling Susceptibility to Tuberculosis and Leprosy in Brazilians Genes and Immunity (2004) 5, 46–57 & 2004 Nature Publishing Group All rights reserved 1466-4879/04 $25.00 www.nature.com/gene Evidence for a cluster of genes on chromosome 17q11–q21 controlling susceptibility to tuberculosis and leprosy in Brazilians SE Jamieson1, EN Miller1, GF Black1, CS Peacock1, HJ Cordell1, JMM Howson1, M-A Shaw2, D Burgner3,6,WXu4, Z Lins-Lainson5, JJ Shaw5,7, F Ramos5, F Silveira5 and JM Blackwell1 1Cambridge Institute for Medical Research, University of Cambridge School of Clinical Medicine, Addenbrookes Hospital, Cambridge, UK; 2Department of Biology, University of Leeds, Leeds, UK; 3The Wellcome Trust Centre for Human Genetics, Oxford, UK; 4Wolfson Institute for Biomedical Research, Rayne Institute, University College, London, UK; 5Instituto Evandro Chagas, Belem, Brazil 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-1a, CCL4/MIP-1b, 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 (Zlr score 2.34; P¼0.01) and D17S1795 (Zlr 2.67; P¼0.004) and a single peak for tuberculosis at D17S250 (Zlr 2.04; P¼0.02). Combined analysis shows significant linkage (peak Zlr 3.38) at D17S250, equivalent to an allele sharing LOD score 2.48 (P¼0.0004). 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. Genes and Immunity (2004) 5, 46–57. doi:10.1038/sj.gene.6364029 Keywords: chromosome 17q11-q22; tuberculosis; leprosy; genetic susceptibility Introduction (eg CCL2/SCYA2/MCP-1, CCL3/SCYA3/MIP-1a, CCL4/ SCYA4/MIP-1b, CCL5/SCYA5/RANTES), the gene Many studies support the hypothesis that susceptibility (CCR7) encoding the receptor for CCL19/CCL21 and to Mycobacterium tuberculosis and M. leprae is genetically genes for signal transducers and activators of transcrip- regulated in humans.1,2 One approach to identifying tion STAT3, STAT5A and STAT5B. candidate genes is to study genetic susceptibility in mice The shared intramacrophage niche of leishmanial and and examine the regions of conserved synteny in man. mycobacterial (M. tuberculosis and M. leprae) pathogens, We took this approach to analyse susceptibility to and the similar spectra of disease caused by the two leishmanial infections.3,4 This led to identification of a groups of organisms, means that any gene identified as a region on mouse chromosome 11, syntenic with human susceptibility gene for one group of pathogens becomes a chromosome 17q11.1–q12, which carries susceptibility candidate for the others. A well-characterized example of genes to cutaneous leishmaniasis.5,6 This region is rich in this is the gene (Nramp1/NRAMP1) located on mouse candidate susceptibility genes. These include the gene chromosome 1/human 2q35 that encodes the natural (NOS2A) encoding the inducible form of nitric oxide resistance associated macrophage protein 1, now rede- synthase (iNOS), genes encoding members of the family signated as solute carrier family 11a member 1 (Slc11a1 in of small inducible chemokine gene (designated, for mice; SLC11A1 in man). This gene controls innate example, chemokine, CC motif, ligand 1 or CCL1) cluster resistance to Leishmania donovani,7–10 M. bovis BCG,11 M. lepraemurium12,13 and M. intracellulare14 in the mouse, 15–22 Correspondence: Dr JM Blackwell, Cambridge Institute for Medical and contributes to susceptibility to M. tuberculosis, Research, Wellcome Trust/MRC Building, University of Cambridge School M. leprae23 and L. donovani24,25 in man. of Clinical Medicine, Addenbrookes Hospital, Hills Road, Cambridge CB2 The successful mouse-to-man precedent set with 2XY, UK. E-mail: [email protected] Slc11a1/SLC11A1 encouraged us to take a similar 6Present address: Princess Margaret Hospital, Subiaco, Western approach in studying the region of human chromosome Australia, Australia. 17q syntenic with murine chromosome 11 in relation to 7Present address: Department of Parasitology, Institute of Bio- medical Sciences, Sao Paulo University, 05508-900, Brazil. genetic susceptibility to leprosy and tuberculosis in man. Received 17 April 2003; revised 14 August 2003; accepted 19 August Here we present linkage and allelic association data for 2003 polymorphic loci at 17q11–q21 from 92 multicase families Genetic susceptibility to tuberculosis and leprosy SE Jamieson et al 47 Table 1 Family structures for the 92 tuberculosis and 72 leprosy families collected from Belem, Brazil Number Families structure TB Leprosy per se Leprosy LL subtype Leprosy TT subtype No. of families 92 72 72 72 No. of nuclear families 118 87 56a 48a Nuclear families with 1 affected sib 58 19 27 22 Nuclear families with 2 affected sibs 37 50 25 17 Nuclear families with 3 affected sibs 17 7 3 7 Nuclear families with 4 affected sibs 4 5 1 1 Nuclear families with 5 affected sibs 2 5 0 0 Nuclear families with 6 affected sibs 0 0 0 1 Nuclear families with 7 affected sibs 0 1 0 0 No. of affected offspring 209 192 90 87 No. of affected parents 71 41 25 10 Total no. of affected individualsb 280 208c 109 93 Total no. of individuals 627 372 372 372 Nuclear families with a single affected offspring were always part of an extended multicase pedigree. aIn all, 17 nuclear families contain both LL and TT affected individuals; therefore, the numbers of LL+TT nuclear families do not add up to leprosy per se. bDue to pedigree structure, some individuals are classed as both sibs and parents in different nuclear families; therefore, the total number of affected is not the sibs+parents. cSix leprosy per se individuals not classified as LL or TT; therefore, the numbers of affected children and parents for LL+TT do not add up to leprosy per se. of tuberculosis and 72 multicase families of leprosy from D17S33 27.9Mb NOS2A CCL2 Belem, Brazil that support the hypothesis that a cluster of 5.7cM XulNOS 28.6Mb TNFAIP1 CCL7 4.2cM 31.0Mb CRLF3 CCL11 genes in this region regulate mycobacterial infections in man. CCL8 3.7cM D17S798 CCL13 CCL1 5.8cM D17S1293 34.6Mb CCL Cluster 8.0cM } D17S927 36.4Mb Results 4.8cM D17S250 40.1Mb CSF3 D17S1814 THRA1 MMP28 41.1Mb Genetic and physical maps for chromosome 5.8cM D17S1299 CCR7 CCL5 42.5Mb STAT5A & 5B CCL16 CCL14 17q11.1–q21.31 7.8cM STAT3 3.8cM D17S930 44.9Mb CCL15 1.4cM CCL23 A total of 627 individuals from 98 multicase tuberculosis 2.3cM CCL18 CCL3 families and 372 individuals from 72 multicase leprosy 3.9cM CCL4 D17S2015 48.5Mb SP2 families (Table 1) were initially genotyped for 16 2.6cM D17S1785 49.6 4.2cM D17S1868 D17S1795 microsatellite markers across the chromosome 17q11.1– D17S1869 q21.31 region. Marker–marker linkage data from the 6.8cM D17S1877 combined set of families were used to generate a genetic D17S787 55.7Mb 26 27 map (Figure 1) using CRI-Map and MAP-O-MAT. Figure 1 Line diagram comparing genetic map (Kosambi cM) This is compared (Figure 1) to the current physical map generated using CRI-Map and MAP-O-MAT with physical map order for the same markers obtained from the UCSC (Mb) based on information from the November 2002 freeze of the Human Genome Project Working Draft, November 2002 working draft of the human genome at (Electronic Database freeze (NCBI Build 31). The only inconsistency between Information 5). the genetic and physical map order is for the marker D17S2015. This discrepancy in position could be due contributed by the TT leprosy families (Zlr 2.58; P¼0.005), either to assembly errors in the physical map or to a lack whereas LL families appear to make some contribution to of informative meioses in the genetic mapping. Since the the leprosy per se peak at D17S1975. Combined linkage genetic map provides a more accurate representation of analysis for all leprosy and tuberculosis families gave a recombination events across the region, we used the peak multipoint Zlr¼3.38 (P¼0.0004). Again, the TT leprosy genetic map generated from the Brazilian families in subtype appeared to account for all of the combined multipoint linkage analyses presented below. linkage (multipoint Zlr 3.56; P¼0.0002). No evidence for linkage is observed for either leprosy or tuberculosis at Linking disease susceptibility to chromosome 17 NOS2A, which lies immediately proximal to the region of Results of multipoint nonparametric linkage analyses linkage. Multipoint information content remained constant carried out in ALLEGRO are presented in Figure 2. For (mean7s.d.) across the region (tuberculosis families: leprosy per se, a broad region of linkage was observed, 0.5370.05; leprosy families: 0.5170.05; LL subtype: 7 7 with an initial peak (Zlr 2.34; P¼0.01) at D17S250 and a 0.71 0.05; TT subtype: 0.81 0.09). second peak (Zlr 2.67; P¼0.004) at D17S1795. For tuberculosis, a single peak (Zlr 2.04; P¼0.02) suggestive Family-based transmission disequilibrium testing of linkage was observed at D17S250, with no linkage at (TDT) D17S1795.
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