Epistasis between the haptoglobin common variant and α+thalassemia influences risk of severe malaria in Kenyan children

Blood. 2014 Mar 27;123(13):2008-16. doi: 10.1182/blood-2013-10-533489. Epub 2014 Jan 29.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Child
  • Child, Preschool
  • Epistasis, Genetic*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Haptoglobins / genetics*
  • Humans
  • Infant
  • Infant, Newborn
  • Kenya / epidemiology
  • Malaria, Falciparum / epidemiology*
  • Malaria, Falciparum / genetics*
  • Male
  • Meta-Analysis as Topic
  • Risk Factors
  • Severity of Illness Index
  • alpha-Thalassemia / epidemiology*
  • alpha-Thalassemia / genetics*

Substances

  • HP protein, human
  • Haptoglobins