Epistasis between the haptoglobin common variant and α+thalassemia influences risk of severe malaria in Kenyan children.
Haptoglobin (Hp) scavenges free hemoglobin following malaria-induced hemolysis. Few studies have investigated the relationship between the common Hp variants and the risk of severe malaria, and their results are inconclusive. We conducted a case-control study of 996 children with severe Plasmodium falciparum malaria and 1220 community controls and genotyped for Hp, hemoglobin (Hb) S heterozygotes, and α(+)thalassemia. Hb S heterozygotes and α(+)thalassemia homozygotes were protected from severe malaria (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.07-0.18 and OR, 0.69; 95% CI, 0.53-0.91, respectively). The risk of severe malaria also varied by Hp genotype: Hp2-1 was associated with the greatest protection against severe malaria and Hp2-2 with the greatest risk. Meta-analysis of the current and published studies suggests that Hp2-2 is associated with increased risk of severe malaria compared with Hp2-1. We found a significant interaction between Hp genotype and α(+)thalassemia in predicting risk of severe malaria: Hp2-1 in combination with heterozygous or homozygous α(+)thalassemia was associated with protection from severe malaria (OR, 0.73; 95% CI, 0.54-0.99 and OR, 0.48; 95% CI, 0.32-0.73, respectively), but α(+)thalassemia in combination with Hp2-2 was not protective. This epistatic interaction together with varying frequencies of α(+)thalassemia across Africa may explain the inconsistent relationship between Hp genotype and malaria reported in previous studies.
Department of Paediatrics, Oxford University Hospitals National Health Service Trust, University of Oxford, and.
Sarah H
SH
Atkinson
Sophie M
SM
Uyoga
Emily
E
Nyatichi
Alex W
AW
Macharia
Gideon
G
Nyutu
Carolyne
C
Ndila
Dominic P
DP
Kwiatkowski
Kirk A
KA
Rockett
Thomas N
TN
Williams
D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006242:Haptoglobins / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007630:Kenya / Q000453:epidemiology; D016778:Malaria, Falciparum / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D015201:Meta-Analysis as Topic; D012307:Risk Factors; D012720:Severity of Illness Index; D017085:alpha-Thalassemia / Q000453:epidemiology* / Q000235:genetics*
C485359:HP protein, human; D006242:Haptoglobins