Fatou Sisay-Joof

Publications (17)168.57 Total impact

• Article: Clinical features of severe malaria associated with death: a 13-year observational study in the gambia.

  Muminatou Jallow, Climent Casals-Pascual, Hans Ackerman, Brigitte Walther, Michael Walther, Margaret Pinder, Fatou Sisay-Joof, Stanley Usen, Mariatou Jallow, Ismaela Abubakar, Rasaq Olaosebikan, Aminata Jobarteh, David J Conway, Kalifa Bojang, Dominic Kwiatkowski
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  ABSTRACT: Severe malaria (SM) is a major cause of death in sub-Saharan Africa. Identification of both specific and sensitive clinical features to predict death is needed to improve clinical management. A 13-year observational study was conducted from 1997 through 2009 of 2,901 children with SM enrolled at the Royal Victoria Teaching Hospital in The Gambia to identify sensitive and specific predictors of poor outcome in Gambian children with severe malaria between the ages 4 months to 14 years. We have measured the sensitivity and specificity of clinical features that predict death or development of neurological sequelae. Impaired consciousness (odds ratio {OR} 4.4 [95% confidence interval {CI}, 2.7-7.3]), respiratory distress (OR 2.4 [95%CI, 1.7-3.2]), hypoglycemia (OR 1.7 [95%CI, 1.2-2.3]), jaundice (OR 1.9 [95%CI, 1.2-2.9]) and renal failure (OR 11.1 [95%CI, 3.3-36.5]) were independently associated with death in children with SM. The clinical features that showed the highest sensitivity and specificity to predict death were respiratory distress (area under the curve 0.63 [95%CI, 0.60-0.65]) and impaired consciousness (AUC 0.61[95%CI, 0.59-0.63]), which were comparable to the ability of hyperlactatemia (blood lactate>5 mM) to predict death (AUC 0.64 [95%CI, 0.55-0.72]). A Blantyre coma score (BCS) of 2 or less had a sensitivity of 74% and specificity of 67% to predict death (AUC 0.70 [95% C.I. 0.68-0.72]), and sensitivity and specificity of 74% and 69%, respectively to predict development of neurological sequelae (AUC 0.72 [95% CI, 0.67-0.76]).The specificity of this BCS threshold to identify children at risk of dying improved in children less than 3 years of age (AUC 0.74, [95% C.I 0.71-0.76]). The BCS is a quantitative predictor of death. A BCS of 2 or less is the most sensitive and specific clinical feature to predict death or development of neurological sequelae in children with SM.
  PLoS ONE 01/2012; 7(9):e45645. · 4.09 Impact Factor
• Article: Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2.

  Thorsten Thye, Fredrik O Vannberg, Sunny H Wong, Ellis Owusu-Dabo, Ivy Osei, John Gyapong, Giorgio Sirugo, Fatou Sisay-Joof, Anthony Enimil, Margaret A Chinbuah, [......], Philip C Hill, Melanie Newport, Christian Lienhardt, Richard A Adegbola, Tumani Corrah, Andreas Ziegler, Andrew P Morris, Christian G Meyer, Rolf D Horstmann, Adrian V S Hill
  Nature Genetics 01/2011; 43(10):1040. · 35.53 Impact Factor
• Source

  Available from: Cyrille Bisseye

  Article: Randomized trial of safety and effectiveness of chlorproguanil-dapsone and lumefantrine-artemether for uncomplicated malaria in children in the Gambia.

  Samuel Dunyo, Giorgio Sirugo, Sanie Sesay, Cyrille Bisseye, Fanta Njie, Majidah Adiamoh, Davis Nwakanma, Mathurin Diatta, Ramatoulie Janha, Fatou Sisay Joof, Beth Temple, Paul Snell, David Conway, Robert Walton, Yin Bun Cheung, Paul Milligan
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  ABSTRACT: Chlorproguanil-dapsone (Lapdap), developed as a low-cost antimalarial, was withdrawn in 2008 after concerns about safety in G6PD deficient patients. This trial was conducted in 2004 to evaluate the safety and effectiveness of CD and comparison with artemether-lumefantrine (AL) under conditions of routine use in G6PD normal and G6PD deficient patients with uncomplicated malaria in The Gambia. We also examined the effects of a common genetic variant that affects chlorproguanil metabolism on risk of treatment failure. 1238 children aged 6 months to 10 years with uncomplicated malaria were randomized to receive CD or artemether-lumefantrine (AL) and followed for 28 days. The first dose was supervised, subsequent doses given unsupervised at home. G6PD genotype was determined to assess the interaction between treatment and G6PD status in their effects on anaemia. The main endpoints were clinical treatment failure by day 28, incidence of severe anaemia (Hb<5 g/dL), and haemoglobin concentration on day 3. One third of patients treated with AL, and 6% of patients treated with CD, did not complete their course of medication. 18% (109/595) of children treated with CD and 6.1% (36/587) with AL required rescue medication within 4 weeks, risk difference 12% (95%CI 8.9%-16%). 23 children developed severe anaemia (17 (2.9%) treated with CD and 6 (1.0%) with AL, risk difference 1.8%, 95%CI 0.3%-3.4%, P = 0.02). Haemoglobin concentration on day 3 was lower among children treated with CD than AL (difference 0.43 g/dL, 95% CI 0.24 to 0.62), and within the CD group was lower among those children who had higher parasite density at enrollment. Only 17 out of 1069 children who were typed were G6PD A- deficient, of these 2/9 treated with CD and 1/8 treated with AL developed severe anaemia. 5/9 treated with CD had a fall of 2 g/dL or more in haemoglobin concentration by day 3. AL was well tolerated and highly effective and when given under operational conditions despite poor adherence to the six-dose regimen. There were more cases of severe malaria and anaemia after CD treatment although G6PD deficiency was uncommon. Clinicaltrials.gov NCT00118794.
  PLoS ONE 01/2011; 6(6):e17371. · 4.09 Impact Factor
• Article: Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2.

  Thorsten Thye, Fredrik O Vannberg, Sunny H Wong, Ellis Owusu-Dabo, Ivy Osei, John Gyapong, Giorgio Sirugo, Fatou Sisay-Joof, Anthony Enimil, Margaret A Chinbuah, [......], Philip C Hill, Melanie Newport, Christian Lienhardt, Richard A Adegbola, Tumani Corrah, Andreas Ziegler, Andrew P Morris, Christian G Meyer, Rolf D Horstmann, Adrian V S Hill
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  ABSTRACT: We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.8 x 10(-9), odds ratio = 1.19, 95% CI = 1.13-1.27). Our study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.
  Nature Genetics 09/2010; 42(9):739-41. · 35.53 Impact Factor
• Source

  Available from: Mahamadou Diakite

  Article: Further evidence supporting a role for gs signal transduction in severe malaria pathogenesis.

  Sarah Auburn, Andrew E Fry, Taane G Clark, Susana Campino, Mahamadou Diakite, Angela Green, Anna Richardson, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Malcolm E Molyneux, Terrie E Taylor, Kasturi Haldar, Kirk A Rockett, Dominic P Kwiatkowski
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  ABSTRACT: With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs) signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls) studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A) and 2B (ADORA2B), beta-adrenergic receptor kinase 1 (ADRBK1), adenylyl cyclase 9 (ADCY9), G protein beta subunit 3 (GNB3), and regulator of G protein signalling 2 (RGS2). Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (approximately 20% frequency) appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09-1.37); P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s). Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies.
  PLoS ONE 01/2010; 5(4):e10017. · 4.09 Impact Factor
• Source

  Available from: Davis C Nwakanma

  Article: Prevention of the recurrence of anaemia in Gambian children following discharge from hospital.

  Kalifa A Bojang, Paul J M Milligan, David J Conway, Fatou Sisay-Joof, Muminatou Jallow, Davis C Nwakanma, Ismaela Abubakr, Fanta Njie, Brian Greenwood
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  ABSTRACT: In malaria endemic countries, children who have experienced an episode of severe anaemia are at increased risk of a recurrence of anaemia. There is a need to find ways of protecting these at risk children from malaria and chemoprevention offers a potential way of achieving this objective. During the 2003 and 2004 malaria transmission seasons, 1200 Gambian children with moderate or severe anaemia (Hb concentration <7 g/dL) were randomised to receive either monthly sulfadoxine-pyrimethamine (SP) or placebo until the end of the malaria transmission season in which they were enrolled, in a double-blind trial. All study subjects were treated with oral iron for 28 days and morbidity was monitored through surveillance at health centres. The primary endpoint was the proportion of children with moderate or severe anaemia at the end of the transmission season. Secondary endpoints included the incidence of clinical episodes of malaria during the surveillance period, outpatient attendances, the prevalence of parasitaemia and splenomegaly, nutritional status at the end of the malaria transmission season and compliance with the treatment regimen. The proportions of children with a Hb concentration of <7 g/dL at the end of the malaria transmission season were similar in the two study groups, 14/464 (3.0%) in children who received at least one dose of SP and 16/471 (3.4%) in those who received placebo, prevalence ratio 0.89 (0.44,1.8) P = 0.742. The protective efficacy of SP against episodes of clinical malaria was 53% (95% CI 37%, 65%). Treatment with SP was safe and well tolerated; no serious adverse events related to SP administration were observed. Mortality following discharge from hospital was low among children who received SP or placebo (6 in the SP group and 9 in the placebo group respectively). Intermittent treatment with SP did not reduce the proportion of previously anaemic children with moderate or severe anaemia at the end of the malaria season, although it prevented malaria. The combination of appropriate antimalarial treatment plus one month of iron supplementation and good access to healthcare during follow-up proved effective in restoring haemoglobin to an acceptable level in the Gambian setting. ClinicalTrials.gov NCT00131716.
  PLoS ONE 01/2010; 5(6):e11227. · 4.09 Impact Factor
• Article: Genome-wide and fine-resolution association analysis of malaria in West Africa.

  Muminatou Jallow, Yik Ying Teo, Kerrin S Small, Kirk A Rockett, Panos Deloukas, Taane G Clark, Katja Kivinen, Kalifa A Bojang, David J Conway, Margaret Pinder, [......], Anavaj Sakuntabhai, Pratap Singhasivanon, Sodiomon Sirima, Adama Tall, Terrie E Taylor, Mahamadou Thera, Marita Troye-Blomberg, Thomas N Williams, Michael Wilson, Dominic P Kwiatkowski
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  ABSTRACT: We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.
  Nature Genetics 06/2009; 41(6):657-65. · 35.53 Impact Factor
• Source

  Available from: Mahamadou Diakite

  Article: Positive selection of a CD36 nonsense variant in sub-Saharan Africa, but no association with severe malaria phenotypes.

  Andrew E Fry, Anita Ghansa, Kerrin S Small, Alejandro Palma, Sarah Auburn, Mahamadou Diakite, Angela Green, Susana Campino, Yik Y Teo, Taane G Clark, [......], Charles R Newton, Kevin Marsh, Malcolm E Molyneux, Terrie E Taylor, Kwadwo A Koram, Abraham R Oduro, William O Rogers, Kirk A Rockett, Pardis C Sabeti, Dominic P Kwiatkowski
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  ABSTRACT: The prevalence of CD36 deficiency in East Asian and African populations suggests that the causal variants are under selection by severe malaria. Previous analysis of data from the International HapMap Project indicated that a CD36 haplotype bearing a nonsense mutation (T1264G; rs3211938) had undergone recent positive selection in the Yoruba of Nigeria. To investigate the global distribution of this putative selection event, we genotyped T1264G in 3420 individuals from 66 populations. We confirmed the high frequency of 1264G in the Yoruba (26%). However, the 1264G allele is less common in other African populations and absent from all non-African populations without recent African admixture. Using long-range linkage disequilibrium, we studied two West African groups in depth. Evidence for recent positive selection at the locus was demonstrable in the Yoruba, although not in Gambians. We screened 70 variants from across CD36 for an association with severe malaria phenotypes, employing a case-control study of 1350 subjects and a family study of 1288 parent-offspring trios. No marker was significantly associated with severe malaria. We focused on T1264G, genotyping 10,922 samples from four African populations. The nonsense allele was not associated with severe malaria (pooled allelic odds ratio 1.0; 95% confidence interval 0.89-1.12; P = 0.98). These results suggest a range of possible explanations including the existence of alternative selection pressures on CD36, co-evolution between host and parasite or confounding caused by allelic heterogeneity of CD36 deficiency.
  Human Molecular Genetics 05/2009; 18(14):2683-92. · 7.64 Impact Factor
• Article: Allelic heterogeneity of G6PD deficiency in West Africa and severe malaria susceptibility.

  Taane G Clark, Andrew E Fry, Sarah Auburn, Susana Campino, Mahamadou Diakite, Angela Green, Anna Richardson, Yik Y Teo, Kerrin Small, Jonathan Wilson, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Pardis Sabeti, Dominic P Kwiatkowski, Kirk A Rockett
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  ABSTRACT: Several lines of evidence link glucose-6-phosphate dehydrogenase (G6PD) deficiency to protection from severe malaria. Early reports suggested most G6PD deficiency in sub-Saharan Africa was because of the 202A/376G G6PD A- allele, and recent association studies of G6PD deficiency have employed genotyping as a convenient way to determine enzyme status. However, further work has suggested that other G6PD deficiency alleles are relatively common in some regions of West Africa. To investigate the consequences of unrecognized allelic heterogeneity on association studies, in particular studies of G6PD deficiency and malaria, we carried out a case-control analysis of 2488 Gambian children with severe malaria and 3875 controls. No significant association was found between severe malaria and the 202A/376G G6PD A- allele when analyzed alone, but pooling 202A/376G with other deficiency alleles revealed the signal of protection (male odds ratio (OR) 0.77, 95% CI 0.62-0.95, P=0.016; female OR 0.71, 95% CI 0.56-0.89, P=0.004). We have identified the 968C mutation as the most common G6PD A- allele in The Gambia. Our results highlight some of the consequences of allelic heterogeneity, particularly the increased type I error. They also suggest that G6PD-deficient male hemizygotes and female heterozygotes are protected from severe malaria.
  European journal of human genetics: EJHG 03/2009; 17(8):1080-5. · 3.56 Impact Factor
• Source

  Available from: Mahamadou Diakite

  Article: TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis-variants acting on gene expression.

  Susana Campino, Julian Forton, Sarah Auburn, Andrew Fry, Mahamadou Diakite, Anna Richardson, Jeremy Hull, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Malcolm E Molyneux, Terrie E Taylor, Kirk Rockett, Taane G Clark, Dominic P Kwiatkowski
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  ABSTRACT: During malaria infection the Toll-like receptor 9 (TLR9) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis-acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out. No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis-acting variants, these results were replicated in a second experiment using biological replicates. By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis-regulatory variants, which may lead to differential inflammatory responses to infection between individuals.
  Malaria Journal 02/2009; 8:44. · 3.19 Impact Factor
• Article: Tumor necrosis factor and lymphotoxin-alpha polymorphisms and severe malaria in African populations.

  Taane G Clark, Mahamadou Diakite, Sarah Auburn, Susana Campino, Andrew E Fry, Angela Green, Anna Richardson, Kerrin Small, Yik Y Teo, Jonathan Wilson, [......], Fatou Sisay-Joof, Margaret Pinder, Michael J Griffiths, Norbert Peshu, Thomas N Williams, Kevin Marsh, Malcolm E Molyneux, Terrie E Taylor, Kirk A Rockett, Dominic P Kwiatkowski
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  ABSTRACT: The tumor necrosis factor gene (TNF) and lymphotoxin-alpha gene (LTA) have long attracted attention as candidate genes for susceptibility traits for malaria, and several of their polymorphisms have been found to be associated with severe malaria (SM) phenotypes. In a large study involving >10,000 individuals and encompassing 3 African populations, we found evidence to support the reported associations between the TNF -238 polymorphism and SM in The Gambia. However, no TNF/LTA polymorphisms were found to be associated with SM in cohorts in Kenya and Malawi. It has been suggested that the causal polymorphisms regulating the TNF and LTA responses may be located some distance from the genes. Therefore, more-detailed mapping of variants across TNF/LTA genes and their flanking regions in the Gambian and allied populations may need to be undertaken to find any causal polymorphisms.
  The Journal of Infectious Diseases 02/2009; 199(4):569-75. · 6.41 Impact Factor
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  Available from: Mahamadou Diakite

  Article: Lack of association of interferon regulatory factor 1 with severe malaria in affected child-parental trio studies across three African populations.

  Valentina D Mangano, Taane G Clark, Sarah Auburn, Susana Campino, Mahamadou Diakite, Andrew E Fry, Angela Green, Anna Richardson, Muminatou Jallow, Fatou Sisay-Joof, [......], Michael J Griffiths, Charles Newton, Norbert Peshu, Thomas N Williams, Kevin Marsh, Malcolm E Molyneux, Terrie E Taylor, David Modiano, Dominic P Kwiatkowski, Kirk A Rockett
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  ABSTRACT: Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.
  PLoS ONE 02/2009; 4(1):e4206. · 4.09 Impact Factor
• Article: TLR9 polymorphisms in African populations: no association with severe malaria, but evidence of cis -variants acting on gene expression

  Susana Campino, Julian Forton, Sarah Auburn, Andrew Fry, Mahamadou Diakite, Anna Richardson, Jeremy Hull, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Malcolm Molyneux, Terrie Taylor, Kirk Rockett, Taane Clark, Dominic Kwiatkowski
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  ABSTRACT: Abstract Background During malaria infection the Toll-like receptor 9 ( TLR9 ) is activated through induction with plasmodium DNA or another malaria motif not yet identified. Although TLR9 activation by malaria parasites is well reported, the implication to the susceptibility to severe malaria is not clear. The aim of this study was to assess the contribution of genetic variation at TLR9 to severe malaria. Methods This study explores the contribution of TLR9 genetic variants to severe malaria using two approaches. First, an association study of four common single nucleotide polymorphisms was performed on both family- and population-based studies from Malawian and Gambian populations (n>6000 individual). Subsequently, it was assessed whether TLR9 expression is affected by cis -acting variants and if these variants could be mapped. For this work, an allele specific expression (ASE) assay on a panel of HapMap cell lines was carried out. Results No convincing association was found with polymorphisms in TLR9 for malaria severity, in either Gambian or Malawian populations, using both case-control and family based study designs. Using an allele specific expression assay it was observed that TLR9 expression is affected by cis -acting variants, these results were replicated in a second experiment using biological replicates. Conclusion By using the largest cohorts analysed to date, as well as a standardized phenotype definition and study design, no association of TLR9 genetic variants with severe malaria was found. This analysis considered all common variants in the region, but it is remains possible that there are rare variants with association signals. This report also shows that TLR9 expression is potentially modulated through cis -regulatory variants, which may lead to differential inflammatory responses to infection between individuals.
  Malaria Journal. 01/2009;
• Article: A genetic association study in the Gambia using tagging polymorphisms in the major histocompatibility complex class III region implicates a HLA-B associated transcript 2 polymorphism in severe malaria susceptibility.

  Mahamadou Diakite, Taane G Clark, Sarah Auburn, Susana Campino, Andrew E Fry, Angela Green, Andrew P Morris, Anna Richardson, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Dominic P Kwiatkowski, Kirk A Rockett
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  ABSTRACT: The tumour necrosis factor (TNF) gene and other genes flanking it in the major histocompatibility complex (MHC) class III region are potentially important mediators of both immunity and pathogenesis of malaria. We investigated the association of severe malaria with 11 haplotype tagging-polymorphisms for 11 MHC class III candidate genes, including TNF, lymphotoxin alpha (LTA), allograft inflammatory factor 1 (AIF1), and HLA-B associated transcript 2 (BAT2). An analysis of 2,162 case-controls demonstrated the first evidence of association between a BAT2 polymorphism (rs1046089) and severe malaria.
  Human Genetics 12/2008; 125(1):105-9. · 5.07 Impact Factor
• Article: Association of the GNAS locus with severe malaria.

  Sarah Auburn, Mahamadou Diakite, Andrew E Fry, Anita Ghansah, Susana Campino, Anna Richardson, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Michael J Griffiths, [......], Thomas N Williams, Kevin Marsh, Malcolm E Molyneux, Terrie E Taylor, Kwadwo A Koram, Abraham R Oduro, William O Rogers, Kirk A Rockett, Kasturi Haldar, Dominic P Kwiatkowski
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  ABSTRACT: Functional studies have demonstrated an interaction between the stimulatory G protein alpha subunit (G-alpha-s) and the malaria parasite at a cellular level. Obstruction of signal transduction via the erythrocyte G-alpha-s subunit reduced invasion by Plasmodium falciparum parasites. We sought to determine whether this signal pathway had an impact at the disease level by testing polymorphisms in the gene encoding G-alpha-s (GNAS) for association with severe malaria in a large multi-centre study encompassing family and case-control studies from The Gambia, Kenya and Malawi, and a case-control study from Ghana. We gained power to detect association using meta-analysis across the seven studies, with an overall sample size approximating 4,000 cases and 4,000 controls. Out of 12 SNPs investigated in the 19 kb GNAS region, four presented signals of association (P < 0.05) with severe malaria. The strongest single-locus association demonstrated an odds ratio of 1.13 (1.05-1.21), P = 0.001. Three of the loci presenting significant associations were clustered at the 5-prime end of the GNAS gene. Accordingly, haplotypes constructed from these loci demonstrated significant associations with severe malaria [OR = 0.88 (0.81-0.96), P = 0.005 and OR = 1.12 (1.03-1.20), P = 0.005]. The evidence presented here indicates that the influence of G-alpha-s on erythrocyte invasion efficacy may, indeed, alter individual susceptibility to disease.
  Human Genetics 10/2008; 124(5):499-506. · 5.07 Impact Factor
• Article: Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria.

  Andrew E Fry, Michael J Griffiths, Sarah Auburn, Mahamadou Diakite, Julian T Forton, Angela Green, Anna Richardson, Jonathan Wilson, Muminatou Jallow, Fatou Sisay-Joof, Margaret Pinder, Norbert Peshu, Thomas N Williams, Kevin Marsh, Malcolm E Molyneux, Terrie E Taylor, Kirk A Rockett, Dominic P Kwiatkowski
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  ABSTRACT: There is growing epidemiological and molecular evidence that ABO blood group affects host susceptibility to severe Plasmodium falciparum infection. The high frequency of common ABO alleles means that even modest differences in susceptibility could have a significant impact on the health of people living in malaria endemic regions. We performed an association study, the first to utilize key molecular genetic variation underlying the ABO system, genotyping >9000 individuals across three African populations. Using population- and family-based tests, we demonstrated that alleles producing functional ABO enzymes are associated with greater risk of severe malaria phenotypes (particularly malarial anemia) in comparison with the frameshift deletion underlying blood group O: case-control allelic odds ratio (OR), 1.2; 95% confidence interval (CI), 1.09-1.32; P = 0.0003; family-studies allelic OR, 1.19; 95% CI, 1.08-1.32; P = 0.001; pooled across all studies allelic OR, 1.18; 95% CI, 1.11-1.26; P = 2 x 10(-7). We found suggestive evidence of a parent-of-origin effect at the ABO locus by analyzing the family trios. Non-O haplotypes inherited from mothers, but not fathers, are significantly associated with severe malaria (likelihood ratio test of Weinberg, P = 0.046). Finally, we used HapMap data to demonstrate a region of low F(ST) (-0.001) between the three main HapMap population groups across the ABO locus, an outlier in the empirical distribution of F(ST) across chromosome 9 (approximately 99.5-99.9th centile). This low F(ST) region may be a signal of long-standing balancing selection at the ABO locus, caused by multiple infectious pathogens including P. falciparum.
  Human Molecular Genetics 02/2008; 17(4):567-76. · 7.64 Impact Factor
• Article: Implications of inter-population linkage disequilibrium patterns on the approach to a disease association study in the human MHC class III.

  Neil Hanchard, Mahamadou Diakite, Oliver Koch, Brendan Keating, Margaret Pinder, Muminatou Jallow, Fatou Sisay-Joof, Anastasia Nijnik, Jonathan Wilson, Irina Udalova, Dominic Kwiatkowski, Kirk Rockett
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  ABSTRACT: There is presently much interest in utilizing patterns of linkage disequilibrium (LD) to further genetic association studies. This is particularly pertinent in the class III region of the human major histocompatibility complex (MHC), which has been extensively studied as a disease susceptibility locus in a number of ethnic groups. To date, however, few studies of LD in the MHC have considered non-Caucasian populations. With the advent of large-scale haplotyping of the human genome, the question of utilizing LD patterns across populations has come to the fore. We have previously used LD mapping to direct an MHC class III association study in a UK Caucasian population. As an extension of this, we sought to determine to what extent the pattern of LD observed in that study could be used to conduct a similar study in a West African Gambian population. We found that broad patterns of LD were similar in the two populations, resulting in similar candidate region delineations, but at a higher resolution, marker-specific patterns of LD and population-dependent allele frequencies confounded the choice of regional tagging SNPs. Our results have implications for the applicability of large-scale haplotype maps such as the HapMap to complex regions like the MHC.
  Immunogenetics 07/2006; 58(5-6):465-70. · 2.93 Impact Factor