Plasma advanced oxidative protein products are associated with anti-oxidative stress pathway genes and malaria in a longitudinal cohort

Guicheng Zhang,Ruth Aguilar,Peter N Lesouëf,Michelle Mcnamara-Smith,Evelin Schwarzer,Jack Goldblatt,Arnoldo Barbosa,Selma Wiertsema,Augusto J Nhabomba,Maria Nelia Manaca,Carlota Dobaño,Catherine M Hayden,Siew-Kim Khoo,Tiziana Marrocco,Llorenç Quintó,Oleksii A Skorokhod,Caterina Guinovart,Pedro L Alonso

doi:10.1186/1475-2875-13-134

Abstract

BackgroundAdvanced oxidation protein products (AOPP) are newly identified efficient oxidative stress biomarkers. In a longitudinal birth cohort the effects were investigated of genetic polymorphisms in five oxidative pathway genes on AOPP levels.MethodsThis study is part of a three-arm randomized, double-blind, placebo-controlled trial. Three hundred and twelve children were included in the present study with AOPP levels measured at 2.5, 5.5, 10.5, 15 and 24 months of age. Twelve polymorphisms were genotyped in five oxidative stress pathway genes: glutathione reductase (GSR), glutamylcysteine synthetase (GCLC), glutathione S-transferase (GST) P1, haem oxygenase 1 (HMOX1) and superoxide dismutase 2 (SOD2) in 298 children. There were 284 children assessed for anaemia and clinical malaria infection at the age of 24 months.ResultsTwo principal components (PCA1 and PCA2) were derived from the AOPP levels measured at the five time points. PCA1 was significantly associated with anaemia (p = 0.0002), and PCA2 with clinical malaria infection (p = 0.047). In the K-Means Cluster Analysis based on levels of AOPP, children were clustered into two groups: Group A (lower AOPP levels) and Group B (higher AOPP levels). The cluster membership was significantly associated with anaemia (p =0.003) as well as with the GSR RS3594 polymorphism (p = 0.037). Mixed linear regression analyses found that the single nucleotide polymorphisms GCLC RS10948751 and HMOX1 RS17885925 were significantly associated with AOPP levels (p = 0.030 and p = 0.027, respectively).ConclusionPlasma AOPP levels were predictive for anaemia and oxidative stress markers for clinical malaria infection in two year old children. Several polymorphisms in GCLC, GSR and HMOX1 genes were associated with oxidative stress status of these children.

Highlights

Advanced oxidation protein products (AOPP) are newly identified efficient oxidative stress biomarkers
Plasma AOPP Plasma AOPP levels were measured in 302 children at 2.5 months, 300 at 5.5 months, 296 at 10.5 months, 283 at 15 months and 274 at 24 months of age, showing decreasing levels by age (Table 2). 235 children had plasma AOPP measured at all five time points
The levels of AOPP at the first four time points (2.5, 5.5, 10.5 and 15 months of age) significantly and positively contributed to the first component score (PCA1) that accounted for 30% of the variation of plasma AOPP levels at the five time points

Summary

Introduction

Advanced oxidation protein products (AOPP) are newly identified efficient oxidative stress biomarkers. Oxidative stress is a common pathogenic mechanism underlying the development of many diseases and conditions including malaria infection, in which both the host and the parasite are under its effects. Adapting to the oxidative stress exerted by the host immune response against malaria infection, Plasmodium falciparum has developed an elaborate reduction-oxidation (redox) system to maintain adequate antioxidant defence throughout its complex life cycle [1]. Numerous studies have reported on associations of the genetic variants in GSR [11], GCLC [14,15], HMOX1 [16] and SOD2 [17] with oxidative stress related disorders and conditions including malaria [16,18,19]

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