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Y chromosome lineage- and village-specific genes on chromosomes 1p22 and 6q27 control visceral leishmaniasis in Sudan.

ABSTRACT: Familial clustering and ethnic differences suggest that visceral leishmaniasis caused by Leishmania donovani is under genetic control. A recent genome scan provided evidence for a major susceptibility gene on Chromosome 22q12 in the Aringa ethnic group in Sudan. We now report a genome-wide scan using 69 families with 173 affected relatives from two villages occupied by the related Masalit ethnic group. A primary ten-centimorgan scan followed by refined mapping provided evidence for major loci at 1p22 (LOD score 5.65; nominal p = 1.72 x 10(-7); empirical p < 1 x 10(-5); lambdaS = 5.1) and 6q27 (LOD score 3.74; nominal p = 1.68 x 10(-5); empirical p < 1 x 10(-4); lambdaS = 2.3) that were Y chromosome-lineage and village-specific. Neither village supported a visceral leishmaniasis susceptibility gene on 22q12. The results suggest strong lineage-specific genes due to founder effect and consanguinity in these recently immigrant populations. These chance events in ethnically uniform African populations provide a powerful resource in the search for genes and mechanisms that regulate this complex disease.

SUBMITTER: Miller EN

PROVIDER: S-EPMC1866354 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Y chromosome lineage- and village-specific genes on chromosomes 1p22 and 6q27 control visceral leishmaniasis in Sudan.

Miller E Nancy EN Fadl Manal M Mohamed Hiba S HS Elzein Abier A Jamieson Sarra E SE Cordell Heather J HJ Peacock Christopher S CS Fakiola Michaela M Raju Madhuri M Khalil Eltahir A EA Elhassan Ahmed A Musa Ahmed M AM Ibrahim Muntaser E ME Blackwell Jenefer M JM

PLoS genetics 20070319 5

Familial clustering and ethnic differences suggest that visceral leishmaniasis caused by Leishmania donovani is under genetic control. A recent genome scan provided evidence for a major susceptibility gene on Chromosome 22q12 in the Aringa ethnic group in Sudan. We now report a genome-wide scan using 69 families with 173 affected relatives from two villages occupied by the related Masalit ethnic group. A primary ten-centimorgan scan followed by refined mapping provided evidence for major loci at ...[more]

PMID: 17500593

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Project description:INTRODUCTION:Visceral leishmaniasis (VL) is endemic in South Sudan, where outbreaks occur frequently. Because of changes in the immune system during pregnancy, pregnant women are considered particularly vulnerable for developing complications of VL disease, including opportunistic infections. There is limited evidence available about clinical aspects and treatment outcomes of VL in pregnancy. We describe characteristics, maternal and pregnancy outcomes from a cohort of pregnant women with VL. METHODS:We conducted a retrospective analysis using routine programme data from a MSF health facility in Lankien, Jonglei State, South Sudan, between Oct 2014 and April 2018. Records were extracted of women diagnosed with VL while pregnant, and those symptomatic during pregnancy but diagnosed during the first two weeks postpartum. Records were matched with a random sample of non-pregnant women of reproductive age (15-45 years) with VL from the same period. RESULTS:We included 113 women with VL in pregnancy, and 223 non-pregnant women with VL. Women with VL in pregnancy presented with more severe anaemia, were more likely to need blood transfusion (OR 9.3; 95%CI 2.5-34.2) and were more often prescribed antibiotics (OR 6.0; 95%CI 3.4-10.6), as compared to non-pregnant women with VL. Adverse pregnancy outcomes, including miscarriage and premature delivery, were reported in 20% (16/81) where VL was diagnosed in pregnancy, and 50% 13/26) where VL was diagnosed postpartum. Postpartum haemorrhage was common. Pregnant women were more likely to require extension of treatment to achieve cure (OR 10.0; 95%CI 4.8-20.9), as compared to non-pregnant women with VL. Nevertheless, overall initial cure rates were high (96.5%) and mortality was low (1.8%) in this cohort of pregnant women with VL. CONCLUSION:This is the largest cohort in the literature of VL in pregnancy. Our data suggest that good maternal survival rates are possible in resource-limited settings, despite the high incidence of complications.

Project description:BackgroundSouth Sudan is one of the most endemic countries for visceral leishmaniasis (VL), and is frequently affected by large epidemics. In resource-limited settings, clinicians require a simple clinical tool to identify VL patients who are at increased risk of dying, and who need specialised treatment with liposomal amphotericin B and other supportive care. The aim of this study was to develop and validate a clinical severity scoring system based on risk factors for death in VL patients in South Sudan.MethodsA retrospective analysis was conducted of data from a cohort of 6,633 VL patients who were treated in the Médecins Sans Frontières (MSF) hospital in Lankien between July 2013 and June 2015. Risk factors for death during treatment were identified using multivariable logistic regression models, and the regression coefficients were used to develop a severity scoring system. Sensitivity and specificity of score cut-offs were assessed by receiver operating characteristic (ROC) analysis.ResultsIn multivariable models, risk factors for death in adult VL patients were: anaemia (odds ratio (OR) 4.46 (95% CI 1.58-12.6) for Hb <6g/dL compared with ≥9g/dL), nutritional status (OR 4.84 (2.09-11.2) for BMI <13 kg/m2 compared with ≥16 kg/m2), weakness (OR 4.20 (1.82-9.73) for collapsed compared with normal weakness), jaundice (OR 3.41 (1.17-9.95)), and oedema/ascites (OR 4.86 (1.67-14.1)). For children and adolescents the risk factors were: age (OR 10.7 (6.3-18.3) for age <2 years compared with 6-18 years), anaemia (OR 7.76 (4.15-14.5) for Hb <6g/dL compared with ≥9g/dL), weakness (OR 3.13 (22.8-105.2) for collapsed compared with normal weakness), and jaundice (OR 12.8 (4.06-40.2)). Severity scoring predictive ability was 74.4% in adults and 83.4% in children and adolescents.ConclusionOur evidenced-based severity scoring system demonstrated sufficient predictive ability to be operationalised as a clinical tool for rational allocation of treatment to VL patients at MSF centres in South Sudan.

Dataset Information

Y chromosome lineage- and village-specific genes on chromosomes 1p22 and 6q27 control visceral leishmaniasis in Sudan.

Publications

Y chromosome lineage- and village-specific genes on chromosomes 1p22 and 6q27 control visceral leishmaniasis in Sudan.

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