Candidate human genetic polymorphisms and severe malaria in a Tanzanian population.
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 sp...
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2012
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oai:doaj.org-article:53266a31cff4474f82c5d21744ba03472021-11-18T08:10:48ZCandidate human genetic polymorphisms and severe malaria in a Tanzanian population.1932-620310.1371/journal.pone.0047463https://doaj.org/article/53266a31cff4474f82c5d21744ba03472012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23144702/?tool=EBIhttps://doaj.org/toc/1932-6203Human 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.Alphaxard ManjuranoTaane G ClarkBehzad NadjmGeorge MtoveHannah WangaiNuno SepulvedaSusana G CampinoCaroline MaxwellRaimos OlomiKirk R RockettAnna JeffreysMalariaGen ConsortiumEleanor M RileyHugh ReyburnChristopher DrakeleyPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 10, p e47463 (2012) |
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EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Alphaxard Manjurano Taane G Clark Behzad Nadjm George Mtove Hannah Wangai Nuno Sepulveda Susana G Campino Caroline Maxwell Raimos Olomi Kirk R Rockett Anna Jeffreys MalariaGen Consortium Eleanor M Riley Hugh Reyburn Christopher Drakeley Candidate human genetic polymorphisms and severe malaria in a Tanzanian population. |
| description |
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. |
| format |
article |
| author |
Alphaxard Manjurano Taane G Clark Behzad Nadjm George Mtove Hannah Wangai Nuno Sepulveda Susana G Campino Caroline Maxwell Raimos Olomi Kirk R Rockett Anna Jeffreys MalariaGen Consortium Eleanor M Riley Hugh Reyburn Christopher Drakeley |
| author_facet |
Alphaxard Manjurano Taane G Clark Behzad Nadjm George Mtove Hannah Wangai Nuno Sepulveda Susana G Campino Caroline Maxwell Raimos Olomi Kirk R Rockett Anna Jeffreys MalariaGen Consortium Eleanor M Riley Hugh Reyburn Christopher Drakeley |
| author_sort |
Alphaxard Manjurano |
| title |
Candidate human genetic polymorphisms and severe malaria in a Tanzanian population. |
| title_short |
Candidate human genetic polymorphisms and severe malaria in a Tanzanian population. |
| title_full |
Candidate human genetic polymorphisms and severe malaria in a Tanzanian population. |
| title_fullStr |
Candidate human genetic polymorphisms and severe malaria in a Tanzanian population. |
| title_full_unstemmed |
Candidate human genetic polymorphisms and severe malaria in a Tanzanian population. |
| title_sort |
candidate human genetic polymorphisms and severe malaria in a tanzanian population. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/53266a31cff4474f82c5d21744ba0347 |
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