Polymorphisms in genes of interleukin 12 and its receptors and their association with protection against severe malarial anaemia in children in western Kenya.
BACKGROUND
Malarial anaemia is characterized by destruction of malaria infected red blood cells and suppression of erythropoiesis. Interleukin 12 (IL12) significantly boosts erythropoietic responses in murine models of malarial anaemia and decreased IL12 levels are associated with severe malarial anaemia (SMA) in children. Based on the biological relevance of IL12 in malaria anaemia, the relationship between genetic polymorphisms of IL12 and its receptors and SMA was examined.


METHODS
Fifty-five tagging single nucleotide polymorphisms covering genes encoding two IL12 subunits, IL12A and IL12B, and its receptors, IL12RB1 and IL12RB2, were examined in a cohort of 913 children residing in Asembo Bay region of western Kenya.


RESULTS
An increasing copy number of minor variant (C) in IL12A (rs2243140) was significantly associated with a decreased risk of SMA (P = 0.006; risk ratio, 0.52 for carrying one copy of allele C and 0.28 for two copies). Individuals possessing two copies of a rare variant (C) in IL12RB1 (rs429774) also appeared to be strongly protective against SMA (P = 0.00005; risk ratio, 0.18). In addition, children homozygous for another rare allele (T) in IL12A (rs22431348) were associated with reduced risk of severe anaemia (SA) (P = 0.004; risk ratio, 0.69) and of severe anaemia with any parasitaemia (SAP) (P = 0.004; risk ratio, 0.66). In contrast, AG genotype for another variant in IL12RB1 (rs383483) was associated with susceptibility to high-density parasitaemia (HDP) (P = 0.003; risk ratio, 1.21).


CONCLUSIONS
This study has shown strong associations between polymorphisms in the genes of IL12A and IL12RB1 and protection from SMA in Kenyan children, suggesting that human genetic variants of IL12 related genes may significantly contribute to the development of anaemia in malaria patients.
Zhang
Lyna
L
Malaria Branch, Division of Parasitic Diseases, National Center for Zoonotic, Vector-Borne & Enteric Diseases, Coordinating Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30341, USA. chn6@cdc.gov
Prather
Donald
D
Vanden Eng
Jodi
J
Crawford
Sara
S
Kariuki
Simon
S
ter Kuile
Feiko
F
Terlouw
Dianne
D
Nahlen
Bernard
B
Lal
Altaf A
AA
Slutsker
Laurence
L
Udhayakumar
Venkatachalam
V
Shi
Ya Ping
YP
D000740:Anemia / Q000209:etiology / Q000235:genetics*; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053765:Interleukin-12 Subunit p35 / Q000235:genetics*; D007630:Kenya; D008288:Malaria / Q000150:complications / Q000235:genetics*; D008297:Male; D010641:Phenotype; D010963:Plasmodium falciparum / Q000302:isolation & purification*; D020641:Polymorphism, Single Nucleotide; D053707:Receptors, Interleukin-12 / Q000235:genetics*
C508858:IL12A protein, human; C508438:IL12RB1 protein, human; D053765:Interleukin-12 Subunit p35; D053707:Receptors, Interleukin-12