Kala-Azar, Susceptibility To, 1

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Retrieved

2019-09-22

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Omim

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Genes

TNF, IFNG, IL10, IL6, ARG1, IL18, CRP, TNFRSF18, MCL1, HSPA4, IL1B, SLC11A1, CXCL10, NLRP3, IL17A, TLR2, CCR5, TLR4, IL32, PRDX2, LEP, TGFB1, CD274, FCN2, CD163, MTOR, HM13, IL4, BCL2, BAX

TNF, IFNG, IL10, IL6, ARG1, IL18, CRP, TNFRSF18, MCL1, HSPA4, IL1B, SLC11A1, CXCL10, NLRP3, IL17A, TLR2, CCR5, TLR4, IL32, PRDX2, LEP, TGFB1, CD274, FCN2, CD163, MTOR, HM13, IL4, BCL2, BAX, LMLN, IGF1, HIF1A, ANXA1, VDR, UNG, TAM, NR0B2, EZR, ADA, TLR3, STAT1, MAPK3, MAPK4, EIF2AK2, PSG5, PSMD7, PTHLH, PTPN1, PTPN2, PTPN6, RPA1, RPS6, CCL2, CCL8, CXCL11, SLC1A5, SLC1A7, SNAP25, SOAT1, SPP1, TP63, EIF2S2, CDK5R1, GOPC, FOXP3, HSPA14, CD244, TOLLIP, FBLIM1, MSTO1, FBXW7, ACSS2, PDXP, SLC52A2, ALDH1A2, TMPRSS13, DCLK3, IL33, CDCA5, PWAR1, ARMH1, HNP1, CCR2, UPK3B, DLL1, SGSM3, NOX1, PABPC1, NR1I2, SPHK1, EIF2B4, EIF2B2, PRKAB1, HSPB3, SLC7A6, ARHGEF2, AIM2, H6PD, RABEPK, LANCL1, TNFSF13B, EBNA1BP2, CD160, GABARAPL2, GABARAPL1, PRDX5, POLR1A, MAPK1, NOS2, PRKAA2, PRKAA1, CST3, CTLA4, CTSB, CTSL, CYP51A1, DDT, DHFR, DPAGT1, DPP4, DSPP, DUSP4, EEF1B2, EEF2, EGFR, EIF2B1, F2R, FCGR2A, FECH, FLI1, CPB1, CCR7, LRBA, ATR, AKT1, ALDH1A1, APEX1, APRT, AQP1, ATM, ATP2A3, ATP2B4, PRDM1, CD69, BRCA1, CAPN1, CD1A, CD28, CD86, CD40, CD40LG, CD44, FPR2, G6PD, GAPDH, CYTB, MNAT1, CD200, MPG, MPL, MPST, MRC1, MSMB, MST1, AHR, MFAP1, PAEP, PHB, PIK3CA, PIK3CB, PIK3CD, PIK3CG, PLP1, PNOC, MAP3K10, MBL2, GCHFR, IFNB1, GCK, GTF3C1, HLA-C, HMOX1, HSPD1, IFN1@, IFNA1, IFNA13, IL1A, LTA, IL9, IL12A, IL12RB1, IL13, ITGA4, ITGAL, JAK2, RPSA, H3P28

Drugs

Enchochleate amphotericin B, Miltefosine ( IMPAVIDO ), Oleylphosphocholine

Enchochleate amphotericin B, Miltefosine ( IMPAVIDO ), Oleylphosphocholine, Paromomycin sulfate, Tretazicar

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Clinical Features

Kala-azar, also known as visceral leishmaniasis, is a life-threatening protozoal disease caused by Leishmania parasites (L. donovani, L. chagasi, and L. infantum). It is prevalent in Africa, South America, Asia, and the Mediterranean basin. Epidemics occur periodically, killing a large number of infected individuals. Bucheton et al. (2003) performed a longitudinal study in a population during an outbreak of kala-azar in a Sudanese village during 1995-2002. Sera epidemiologic surveys showed that almost all of the population had been exposed to infection and that 25% of inhabitants had been affected by kala-azar. Familial clustering of kala-azar cases and marked differences in disease prevalence between the ethnic groups in the village indicated that the population was suitable for studies aimed at identifying loci that might predispose to infection (Bucheton et al., 2002).

Mapping

Bucheton et al. (2003) performed a genomewide linkage study on 63 Sudanese families selected from the most affected ethnic group, including 169 children with kala-azar. Significant linkage was found to markers on chromosome 22q12; when the analysis included all patients, the lod score was 3.50, and when it was limited to patients who were affected early in the outbreak, the lod score was 3.90. Bucheton et al. (2003) also found modest support for the location of another kala-azar locus in the 2q35 region, which contains the NRAMP gene (SLC11A1; 600266). These results were said to provide the first evidence of a major genetic effect on the development of human kala-azar. Bucheton et al. (2003) suggested the interleukin-2 receptor beta-chain gene (IL2RB; 146710) as a candidate gene for susceptibility to kala-azar on chromosome 22q12.

By examining a northeastern Brazilian population with high rates of admixture from African, European, and native Brazilian groups and high rates of visceral leishmaniasis caused by L. chagasi, Ettinger et al. (2009) discerned no particular admixture proportion in the spectrum of clinical phenotypes. However, they detected excess European ancestry for D22S1169, a microsatellite marker on chromosome 22q12, in individuals with visceral leishmaniasis compared with asymptomatic individuals with type hypersensitivity to Leishmania antigen. Ettinger et al. (2009) noted that this region is the same as that identified by Bucheton et al. (2003) in a Sudanese population.

Heterogeneity

In addition to the KAZA1 locus on chromosome 22q12, kala-azar susceptibility loci have been identified on chromosomes 1p22 (KAZA2; 611381) and 6q27 (KAZA3; 611382).

Associations Pending Confirmation

Bucheton et al. (2003) performed a genomewide linkage study on 63 Sudanese families selected from the most affected ethnic group, including 169 children with kala-azar. In addition to significant linkage to chromosome 22q12, they found modest support for linkage to the 2q35 region, which contains the NRAMP gene (SLC11A1; 600266).

Mohamed et al. (2004) examined polymorphisms in the SLC11A1 gene in 59 multicase families with visceral leishmaniasis from the high-incidence Masalit tribe in Sudan. Multipoint nonparametric analysis showed significant linkage across SLC11A1 (Z(lr) scores, 2.38-2.55, p between 0.008 and 0.012). Mohamed et al. (2004) suggested that polymorphisms in the SLC11A1 gene may be associated with susceptibility to visceral leishmaniasis in the Masalit tribe in Sudan.

To identify susceptibility loci for visceral leishmaniasis in Indian and Brazilian populations, the LeishGEN Consortium and Wellcome Trust Case Control Consortium 2 (2013) used genomewide association studies and variance components methodology (i.e., a mixed model) to avoid confounding due to population structure and relatedness. They found that the HLA-DRB1 (142857)-HLA-DQA1 (146880) region on chromosome 6p21 was the only region to show strong evidence of association in both discovery populations and in a second Indian replication population. The SNP most significantly associated with visceral leishmaniasis that was common to all 3 populations was rs9271858, and combined analysis across the 3 cohorts for rs9271858 showed P-combined of 2.76 x 10(-17) and an odds ratio of 1.41. The LeishGEN Consortium and Wellcome Trust Case Control Consortium 2 (2013) concluded that the HLA-DRB1-HLA-DQA1 region contributes to susceptibility to visceral leishmaniasis, regardless of geographic region and parasite species.