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Reference: Cox, SE, Doherty, C, Atkinson, SH et al., (2007). Haplotype Association between Haptoglobin (Hp2) and Hp Promoter SNP (A-61C) May Explain Previous Controversy of Haptoglobin and Malaria Protection. PLoS ONE, 2 (4), e362-e362.Citable link to this page:

 

Haplotype Association between Haptoglobin (Hp2) and Hp Promoter SNP (A-61C) May Explain Previous Controversy of Haptoglobin and Malaria Protection

Abstract: BACKGROUND: Malaria is one of the strongest recent selective pressures on the human genome, as evidenced by the high levels of varying haemoglobinopathies in human populations-despite the increased risk of mortality in the homozygous states. Previously, functional polymorphisms of Hp, coded by the co-dominant alleles Hp1 and Hp2, have been variously associated with several infectious diseases, including malaria susceptibility. METHODOLOGY/PRINCIPAL FINDINGS: Risk of a clinical malarial episode over the course of a malarial transmission season was assessed using active surveillance in a cohort of Gambian children aged 10-72 months. We report for the first time that the major haplotype for the A-61C mutant allele in the promoter of haptoglobin (Hp)-an acute phase protein that clears haemoglobin released from haemolysis of red cells-is associated with protection from malarial infection in older children, (children aged >/=36 months, >500 parasites/ul and temperature >37.5 degrees C; OR = 0.42; [95% CI 0.24-0.73] p = 0.002) (lr test for interaction, /=36 months, p = 0.014). Protection was also observed using two other definitions, including temperature >37.5 degrees C, dipstick positive, plus clinical judgement of malaria blinded to dipstick result (all ages, OR = 0.48, [95% CI 0.30-0.78] p = 0.003; >/=36 months, OR = 0.31, [95% CI 0.15-0.62] p = 0.001). A similar level of protection was observed for the known protective genetic variant, sickle cell trait (HbAS). CONCLUSIONS/SIGNIFICANCE: We propose that previous conflicting results between Hp phenotypes/genotypes and malaria susceptibility may be explained by differing prevalence of the A-61C SNP in the populations studied, which we found to be highly associated with the Hp2 allele. We report the -61C allele to be associated with decreased Hp protein levels (independent of Hp phenotype), confirming in vitro studies. Decreased Hp expression may lead to increased oxidant stress and increased red cell turnover, and facilitate the development of acquired immunity, similar to a mechanism suggested for sickle cell trait.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Publisher's version Funder: Medical Research Council   Notes:Copyright © 2007 Cox et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Bibliographic Details

Publisher: Public Library of Science

Publisher Website: http://www.plos.org/

Journal: PLoS ONEsee more from them

Publication Website: http://journals.plos.org/plosone/

Issue Date: 2007

pages:e362-e362Identifiers

Urn: uuid:7f9cd796-62e9-42a3-9239-76b646ca7797

Source identifier: 45966

Eissn: 1932-6203

Doi: https://doi.org/10.1371/journal.pone.0000362

Issn: 1932-6203 Item Description

Type: Journal article;

Language: eng

Version: Publisher's versionKeywords: Humans Malaria Genetic Predisposition to Disease Haptoglobins Likelihood Functions Longitudinal Studies Haplotypes Polymorphism, Single Nucleotide Child, Preschool Promoter Regions, Genetic Tiny URL: pubs:45966

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Autor: Cox, SE - - - Doherty, C - - - Atkinson, SH - institutionUniversity of Oxford Oxford, MSD, Paediatrics - - - Nweneka, CV - - - Fu

Fuente: https://ora.ox.ac.uk/objects/uuid:7f9cd796-62e9-42a3-9239-76b646ca7797



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