Polymorphisms in the RNASE3 gene are associated with susceptibility to cerebral malaria in Ghanaian children.
BACKGROUND
Cerebral malaria (CM) is the most severe outcome of Plasmodium falciparum infection and a major cause of death in children from 2 to 4 years of age. A hospital based study in Ghana showed that P. falciparum induces eosinophilia and found a significantly higher serum level of eosinophil cationic protein (ECP) in CM patients than in uncomplicated malaria (UM) and severe malaria anemia (SA) patients. Single nucleotide polymorphisms (SNPs) have been described in the ECP encoding-gene (RNASE3) of which the c.371G>C polymorphism (rs2073342) results in an arginine to threonine amino acid substitution p.R124T in the polypeptide and abolishes the cytotoxicity of ECP. The present study aimed to investigate the potential association between polymorphisms in RNASE3 and CM.


RESULTS
The RNASE3 gene and flanking regions were sequenced in 206 Ghanaian children enrolled in a hospital based malaria study. An association study was carried out to assess the significance of five SNPs in CM (n=45) and SA (n=56) cases, respectively. The two severe case groups (CM and SA) were compared with the non-severe control group comprising children suffering from UM (n=105). The 371G allele was significantly associated with CM (p=0.00945, OR=2.29, 95% CI=1.22-4.32) but not with SA. Linkage disequilibrium analysis demonstrated significant linkage between three SNPs and the haplotype combination 371G/*16G/*94A was strongly associated with susceptibility to CM (p=0.000913, OR=4.14, 95% CI=1.79-9.56), thus, defining a risk haplotype. The RNASE3 371GG genotype was found to be under frequency-dependent selection.


CONCLUSIONS
The 371G allele of RNASE3 is associated with susceptibility to CM and forms part of a risk associated haplotype GGA defined by the markers: rs2073342 (G-allele), rs2233860 (G-allele) and rs8019343 (A-allele) respectively. Collectively, these results suggest a hitherto unrecognized role for eosinophils in CM pathogenesis.
Department of Clinical Biochemistry and Immunology, Statens Serum Institut, Copenhagen, Denmark.
Bright
B
Adu
Daniel
D
Dodoo
Selorme
S
Adukpo
Ben A
BA
Gyan
Paula L
PL
Hedley
Bamenla
B
Goka
George O
GO
Adjei
Severin O
SO
Larsen
Michael
M
Christiansen
Michael
M
Theisen
D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D047150:Eosinophil Cationic Protein / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005869:Ghana / Q000453:epidemiology; D006239:Haplotypes; D006801:Humans; D007223:Infant; D016779:Malaria, Cerebral / Q000201:enzymology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
D017931:DNA Primers; D047150:Eosinophil Cationic Protein