title: The genetic risk of acute seizures in African children with falciparum malaria.
abstract: OBJECTIVE
  It is unclear why some children with falciparum malaria develop acute seizures and what determines the phenotype of seizures. We sought to determine if polymorphisms of malaria candidate genes are associated with acute seizures.
  
  
  METHODS
  Logistic regression was used to investigate genetic associations with malaria-associated seizures (MAS) and complex MAS (repetitive, prolonged, or focal seizures) in four MalariaGEN African sites, namely: Blantyre, Malawi; Kilifi, Kenya; Kumasi, Ghana; and Muheza, Tanzania. The analysis was repeated for five inheritance models (dominant, heterozygous, recessive, additive, and general) and adjusted for potential confounders and multiple testing.
  
  
  RESULTS
  Complex phenotypes of seizures constituted 71% of all admissions with MAS across the sites. MAS were strongly associated with cluster of differentiation-ligand-rs3092945 in females in Kilifi (p = 0.00068) and interleukin (IL)-17 receptor E-rs708567 in the pooled analysis across the sites (p = 0.00709). Complex MAS were strongly associated with epidermal growth factor module-containing mucin-like hormone receptor (EMR)1-rs373533 in Kumasi (p = 0.00033), but none in the pooled analysis. Focal MAS were strongly associated with IL-20 receptor A-rs1555498 in Muheza (p = 0.00016), but none in the pooled analysis. Prolonged MAS were strongly associated with complement receptor 1-rs17047660 in Kilifi (p = 0.00121) and glucose-6-phosphate dehydrogenase-rs1050828 in females in the pooled analysis (p = 0.00155). Repetitive MAS were strongly associated with EMR1-rs373533 in Kumasi (p = 0.00003) and cystic fibrosis transmembrane conductance receptor-rs17140229 in the pooled analysis (p = 0.00543). MAS with coma/cerebral malaria were strongly associated with EMR1-rs373533 in Kumasi (p = 0.00019) and IL10-rs3024500 in the pooled analysis across the sites (p = 0.00064).
  
  
  CONCLUSIONS
  We have identified a number of genetic associations that may explain the risk of seizures in >2,000 cases admitted to hospitals with MAS across four sites in Africa. These associations differed according to phenotype of seizures and site.
authors.affiliation: Kenya Medical Research Institute, Centre for Geographic Medicine Research Coast, Kilifi, Kenya. skariuki@kemri-wellcome.org
authors.forename: Symon M
authors.initials: SM
authors.lastname: Kariuki
authors.forename: Kirk
authors.initials: K
authors.lastname: Rockett
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Hugh
authors.initials: H
authors.lastname: Reyburn
authors.forename: Tsiri
authors.initials: T
authors.lastname: Agbenyega
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Gretchen L
authors.initials: GL
authors.lastname: Birbeck
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Charles R J C
authors.initials: CR
authors.lastname: Newton
mesh_terms: D017954:Africa South of the Sahara; D002135:Calcium-Binding Proteins; D002675:Child, Preschool; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D016778:Malaria, Falciparum / Q000150:complications* / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D009077:Mucins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011951:Receptors, Complement / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D012307:Risk Factors; D012640:Seizures / Q000209:etiology / Q000235:genetics*
chemical_list: C094471:ADGRE1 protein, human; D002135:Calcium-Binding Proteins; D008562:Membrane Glycoproteins; D009077:Mucins; D011951:Receptors, Complement; D043562:Receptors, G-Protein-Coupled; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005954:Glucosephosphate Dehydrogenase