GENOME WIDE SEARCH FOR VISCERALLEISHMANIASIS SUSCEPTIBILITY GENESIN SUDANESE POPULATION

Abstract

ABSTRACT Sudan is one of the major foci of visceral leishinaniasis (VL) globally (the other two foci are Brazil and India). Familial clustering and ethnic differences suggest genetic factors may be involved in the infection. In this study a two stages genome-wide scan was employed using two independent sets of families from two villages: El-Rugab and Um—Salala. located 40 kilometers apart in the heart of the endemic area of eastem Sudan. These villages are inhabited by the Masalit ethnic group who migrated from westem Sudan in the 1980s. In the first stage (= scanl) we genotyped 400 highly polymorphic microsatellite markers (approximately 10 cM apart) in 220 individuals from 38 multicase pedigrees (= scanl families) comprising 48 nuclear families (1 18 affected sibs). Scan] was followed by grid tightening strategy in which 35 additional markers were added close to regions that gave suggestive evidence for linkage of VL susceptibility in scan 1. These markers were typed in scanl families. ln the second stage (scan2). 20 markers from positive regions of linkage and the 35 additional markers were all typed in family set 2 (=scan2 families: 21 nuclear families, 48 affected sibs). ln scan 1, the multipoint analysis performed provided evidence for linkage of VL susceptibility to 5 regions on chromosome lp22, ]q3l.3. 5q34-35.3, 6q27 and l3q 31.1 (0.0002<p< 0.05). Stratification of scanl families by village revealed village-specific peaks for linkage in Um Salala at lp22 (LOD=2.8. p=l.6xl04) and at 5q34 (LOD score: 0.61. p=0.047). in El Rugab at ]q3l.l (LOD=l .31, p=0.0()7). at 5q35.3 (LOD score: 1.8. p=0.002) & at 6q27 (LOD=3.05, p=8.95xI0'5). in addition four novel village-specific regions of positive linkage occurred on chromosomes Z. 7 and 18 for Um Salala. chromosomcl4 for El Rugab. Grid tightening analysis confirmed the result of scanl stratifying by village. However no evidence for Linkage was observed on chromosome 13q31.l. Analysis of seanl+2 families stratified by village demonstrated a major gene at D6S28l on 6q27 (LOD score 3.07; p=8.6x10'5) in El-Rugab only. Both villages contributed to the second peak at D6S396 (LOD score 1.35; p=()06) on 6q26-q27. A broad region of linkage on chromosome l also resolved into two clezu peaks upon stratification by village: at DIS2766 on 1p22 (LOD score 1.19; P=0.009) for Um-Salala and at DISZ38 on lq3l.l for El-Rugab (LOD score 1.25; p=0.008). Region on chromosome 22 ql2 being demonstrated by the previous study as VL susceptibility locus in Aringa ethnic group from Sudan (Bucheton er n/.. 2003b) was pursued with further analysis. however, neither village provided support for evidence for linkage in this region: neither in the grid tightening nor when analyzing scan1+2 families. Analysis of scan 2 families by themselves provided no evidence for linkage in either village. These results together indicate that VL susceptibility might be indeed complex or oligogenic inheritance and that population substructure could be vital in the implication of the disease in different populations.