RGD Reference Report - Epistasis between the haptoglobin common variant and alpha+thalassemia influences risk of severe malaria in Kenyan children. - Rat Genome Database

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

Authors: Atkinson, SH  Uyoga, SM  Nyatichi, E  Macharia, AW  Nyutu, G  Ndila, C  Kwiatkowski, DP  Rockett, KA  Williams, TN 
Citation: Atkinson SH, etal., Blood. 2014 Mar 27;123(13):2008-16. doi: 10.1182/blood-2013-10-533489. Epub 2014 Jan 29.
RGD ID: 11041793
Pubmed: PMID:24478401   (View Abstract at PubMed)
PMCID: PMC3968387   (View Article at PubMed Central)
DOI: DOI:10.1182/blood-2013-10-533489   (Journal Full-text)

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 alpha(+)thalassemia. Hb S heterozygotes and alpha(+)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 alpha(+)thalassemia in predicting risk of severe malaria: Hp2-1 in combination with heterozygous or homozygous alpha(+)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 alpha(+)thalassemia in combination with Hp2-2 was not protective. This epistatic interaction together with varying frequencies of alpha(+)thalassemia across Africa may explain the inconsistent relationship between Hp genotype and malaria reported in previous studies.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Plasmodium falciparum malaria severityIAGP 11041793DNA:missense mutation:cds:p.K54E (human)RGD 
Plasmodium falciparum malaria severityISOHP (Homo sapiens)11041793; 11041793DNA:missense mutation:cds:p.K54E (human)RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Invasive parasitic infection severityIAGP 11041793DNA:missense mutation:cds:p.K54E (human)RGD 
Objects Annotated

Genes (Rattus norvegicus)
Hp  (haptoglobin)

Genes (Mus musculus)
Hp  (haptoglobin)

Genes (Homo sapiens)
HP  (haptoglobin)


Additional Information