title: CR1 Knops blood group alleles are not associated with severe malaria in the Gambia.
abstract: The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value <0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels.
authors.affiliation: The Center for Global Health & Diseases, Case Western Reserve University, School of Medicine, Cleveland, OH 44106-4983, USA. paz@po.cwru.edu
authors.forename: P A
authors.initials: PA
authors.lastname: Zimmerman
authors.forename: J
authors.initials: J
authors.lastname: Fitness
authors.forename: J M
authors.initials: JM
authors.lastname: Moulds
authors.forename: D T
authors.initials: DT
authors.lastname: McNamara
authors.forename: L J
authors.initials: LJ
authors.lastname: Kasehagen
authors.forename: J Alexandra
authors.initials: JA
authors.lastname: Rowe
authors.forename: A V S
authors.initials: AV
authors.lastname: Hill
mesh_terms: D000595:Amino Acid Sequence; D001789:Blood Group Antigens / Q000235:genetics*; D016022:Case-Control Studies; D017931:DNA Primers; D005714:Gambia / Q000453:epidemiology; D005787:Gene Frequency / Q000235:genetics; D006801:Humans; D016778:Malaria, Falciparum / Q000453:epidemiology / Q000235:genetics*; D015336:Molecular Probe Techniques; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011951:Receptors, Complement / Q000235:genetics*; D012641:Selection, Genetic
chemical_list: D001789:Blood Group Antigens; D017931:DNA Primers; D011951:Receptors, Complement