title: Genetic determinants of glucose-6-phosphate dehydrogenase activity in Kenya.
abstract: BACKGROUND
  The relationship between glucose-6-phosphate dehydrogenase (G6PD) deficiency and clinical phenomena such as primaquine-sensitivity and protection from severe malaria remains poorly defined, with past association studies yielding inconsistent and conflicting results. One possibility is that examination of a single genetic variant might underestimate the presence of true effects in the presence of unrecognized functional allelic diversity.
  
  
  METHODS
  We systematically examined this possibility in Kenya, conducting a fine-mapping association study of erythrocyte G6PD activity in 1828 Kenyan children across 30 polymorphisms at or around the G6PD locus.
  
  
  RESULTS
  We demonstrate a strong functional role for c.202G>A (rs1050828), which accounts for the majority of variance in enzyme activity observed (P=1.5×10⁻²⁰⁰, additive model). Additionally, we identify other common variants that exert smaller, intercorrelated effects independent of c.202G>A, and haplotype analyses suggest that each variant tags one of two haplotype motifs that are opposite in sequence identity and effect direction. We posit that these effects are of biological and possible clinical significance, specifically noting that c.376A>G (rs1050829) augments 202AG heterozygote risk for deficiency trait by two-fold (OR = 2.11 [1.12 - 3.84], P=0.014).
  
  
  CONCLUSIONS
  Our results suggest that c.202G>A is responsible for the majority of the observed prevalence of G6PD deficiency trait in Kenya, but also identify a novel role for c.376A>G as a genetic modifier which marks a common haplotype that augments the risk conferred to 202AG heterozygotes, suggesting that variation at both loci merits consideration in genetic association studies probing G6PD deficiency-associated clinical phenotypes.
authors.affiliation: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. ssshah03@gmail.com.
authors.forename: Shivang S
authors.initials: SS
authors.lastname: Shah
authors.forename: Alex
authors.initials: A
authors.lastname: Macharia
authors.forename: Johnstone
authors.initials: J
authors.lastname: Makale
authors.forename: Sophie
authors.initials: S
authors.lastname: Uyoga
authors.forename: Katja
authors.initials: K
authors.lastname: Kivinen
authors.forename: Rachel
authors.initials: R
authors.lastname: Craik
authors.forename: Christina
authors.initials: C
authors.lastname: Hubbart
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wellems
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
mesh_terms: D000483:Alleles; D002874:Chromosome Mapping; D015331:Cohort Studies; D004912:Erythrocytes / Q000201:enzymology; D005260:Female; D056426:Genetic Loci; D014644:Genetic Variation; D005838:Genotype; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000235:genetics* / Q000473:pathology; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007630:Kenya; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D005954:Glucosephosphate Dehydrogenase