03084nas a2200637   4500000000100000008004100001260001300042653001200055653001100067653002500078653001900103653001900122653001900141653003200160653002500192653001100217653001900228653002000247653003800267653002000305653001300325653001100338653001200349653003700361653000900398653000900407653001800416653002100434653001900455653001300474653003100487653002100518653001700539653003000556100001700586700001500603700001400618700001600632700001600648700001700664700001300681700001400694700000900708700001900717700001300736700001200749700001500761700001800776245013000794856005100924300001000975490000600985050001800991520142301009022001402432       2004                            d  c2004 Jan10aAnimals10aBrazil10aCase-Control Studies10aChemokine CCL310aChemokine CCL410aChemokines, CC10aChromosomes, Human, Pair 1710aDNA-Binding Proteins10aFemale10aGene Frequency10aGenetic Markers10aGenetic Predisposition to Disease10aGenetic Testing10agenotype10aHumans10aleprosy10aMacrophage Inflammatory Proteins10aMale10aMice10aMilk Proteins10aMultigene Family10aPoint Mutation10aProteins10aSTAT5 Transcription Factor10aTrans-Activators10aTuberculosis10aTumor Suppressor Proteins1 aJamieson S E1 aMiller E N1 aBlack G F1 aPeacock C S1 aCordell H J1 aHowson J M M1 aShaw M-A1 aBurgner D1 aXu W1 aLins-Lainson Z1 aShaw J J1 aRamos F1 aSilveira F1 aBlackwell J M00aEvidence for a cluster of genes on chromosome 17q11-q21 controlling susceptibility to tuberculosis and leprosy in Brazilians.  uEvidence for a cluster of genes on chromosome   a46-570 v5  aJAMIESON 20043 a<p>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.</p>  a1466-4879