title: Candidate human genetic polymorphisms and severe malaria in a Tanzanian population.
abstract: Human genetic background strongly influences susceptibility to malaria infection and progression to severe disease and death. Classical genetic studies identified haemoglobinopathies and erythrocyte-associated polymorphisms, as protective against severe disease. High throughput genotyping by mass spectrometry allows multiple single nucleotide polymorphisms (SNPs) to be examined simultaneously. We compared the prevalence of 65 human SNP's, previously associated with altered risk of malaria, between Tanzanian children with and without severe malaria. Five hundred children, aged 1-10 years, with severe malaria were recruited from those admitted to hospital in Muheza, Tanzania and compared with matched controls. Genotyping was performed by Sequenom MassArray, and conventional PCR was used to detect deletions in the alpha-thalassaemia gene. SNPs in two X-linked genes were associated with altered risk of severe malaria in females but not in males: heterozygosity for one or other of two SNPs in the G6PD gene was associated with protection from all forms of severe disease whilst two SNPs in the gene encoding CD40L were associated with respiratory distress. A SNP in the adenyl cyclase 9 (ADCY9) gene was associated with protection from acidosis whilst a polymorphism in the IL-1α gene (IL1A) was associated with an increased risk of acidosis. SNPs in the genes encoding IL-13 and reticulon-3 (RTN3) were associated with increased risk of cerebral malaria. This study confirms previously known genetic associations with protection from severe malaria (HbS, G6PD). It identifies two X-linked genes associated with altered risk of severe malaria in females, identifies mutations in ADCY9, IL1A and CD40L as being associated with altered risk of severe respiratory distress and acidosis, both of which are characterised by high serum lactate levels, and also identifies novel genetic associations with severe malaria (TRIM5) and cerebral malaria(IL-13 and RTN3). Further studies are required to test the generality of these associations and to understand their functional consequences.
authors.affiliation: Joint Malaria Programme, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
authors.forename: Alphaxard
authors.initials: A
authors.lastname: Manjurano
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Behzad
authors.initials: B
authors.lastname: Nadjm
authors.forename: George
authors.initials: G
authors.lastname: Mtove
authors.forename: Hannah
authors.initials: H
authors.lastname: Wangai
authors.forename: Nuno
authors.initials: N
authors.lastname: Sepulveda
authors.forename: Susana G
authors.initials: SG
authors.lastname: Campino
authors.forename: Caroline
authors.initials: C
authors.lastname: Maxwell
authors.forename: Raimos
authors.initials: R
authors.lastname: Olomi
authors.forename: Kirk R
authors.initials: KR
authors.lastname: Rockett
authors.forename: Anna
authors.initials: A
authors.lastname: Jeffreys
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Riley
authors.forename: Hugh
authors.initials: H
authors.lastname: Reyburn
authors.forename: Christopher
authors.initials: C
authors.lastname: Drakeley
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics; D000090103:Antiviral Restriction Factors; D023201:CD40 Ligand / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics*; D006801:Humans; D007223:Infant; D018793:Interleukin-13 / Q000235:genetics; D053582:Interleukin-1alpha / Q000235:genetics; D016015:Logistic Models; D016778:Malaria, Falciparum / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012737:Sex Factors; D013636:Tanzania; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; C508584:IL1A protein, human; D018793:Interleukin-13; D053582:Interleukin-1alpha; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C476198:RTN3 protein, human; D000070584:Tripartite Motif Proteins; D023201:CD40 Ligand; D005954:Glucosephosphate Dehydrogenase; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D000262:Adenylyl Cyclases; C413923:adenylate cyclase 9