Frequency of RANTES gene polymorphisms and their association with incidence of malaria: a longitudinal study on children in Iganga district, Uganda

Abstract

BackgroundThe severity and outcome of malaria is influenced by host immunity in which chemokines such as Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES) play an important role. Previous studies show that variations in the RANTES gene affect RANTES protein production, hence altering host immunity. In this study, the relationship between presence of mutations in RANTES and incidence of malaria in a cohort of children living in a malaria-endemic area of Uganda was determined.MethodsThis was a longitudinal study comprising of 423 children aged between 6 months and 9 years, who were actively followed up for 1 year. Malaria episodes occurring in the cohort children were detected and the affected children treated with national policy drug regimen. Mutations in the RANTES gene were determined by PCR–RFLP method and their frequencies were calculated. A multivariate negative binomial regression model was used to estimate the impact of RANTES mutations on malaria incidence. In all statistical tests, a P-value of <0.05 was considered as significant.ResultsThe frequencies of the −403A and In1.1C allele were 53.7 and 19.2 %, respectively. No mutations were found at the −28 locus. After adjustment of incidence rates for age, blood group, insecticide-treated bed net (ITN) use, malaria history and the sickle cell trait, 1n1.1T/C heterozygotes and homozygotes showed a non-significant trend towards higher incidence rates compared to wild-type individuals (IRR = 1.10; P = 0.55 and IRR = 1.25; P = 0.60, respectively). Similarly, there was no significant difference in malaria incidence rates between RANTES −403G/A heterozygotes or homozygotes and those without mutations (IRR = 1.09; P = 0.66 and IRR = 1.16; P = 0.50, respectively). No relation was seen between RANTES polymorphisms, baseline parasite densities and the time to first re-infection after administration of anti-malaria drugs.ConclusionsThis study showed that the −403A mutation occurs in nearly half of the study population and the In1.1C allele occurs in one in every four children. Despite the high frequency of these mutations, there was no clear association with malaria incidence. Other studies evaluating more markers, that could potentially modulate RANTES gene transcription alongside other genetic modifiers of malaria susceptibility, may provide further explanations to these less dramatic findings.

Prevalence of polymorphisms in glucose-6-phosphate dehydrogenase, sickle haemoglobin and nitric oxide synthase genes and their relationship with incidence of uncomplicated malaria in Iganga, Uganda

“…None of the ABO bloodgroups showed any significant influence on malaria incidence rates in this cohort. In a previous study in the same cohort of children, age, prior malaria history (reported by guardian) and ITN use were identified as independent predictors of malaria incidence [ 31 ].…”

“…In the present study, the prevalences of G6PD c.202 G > A (rs 1050828) , HBB c.20A > T (rs 334) and NOS2 − 954 G > C (rs 1800482) gene polymorphisms and their impact on incidence of uncomplicated in the clinical trials site of Iganga in Eastern Uganda was determined. This is an extension of an earlier longitudinal study [ 31 ] and benefits from data previously collected regarding the independent predictors of malaria risk in the same children’s cohort [ 31 ]. Adjustment for these confounders allowed for determination of the effect of the selected host gene markers on incidence of uncomplicated malaria in the study cohort.…”

“…In this project, the study children were recruited during November and followed up for 1 year. The inclusion criteria, detailed enrolment and follow up are described in an earlier publication [ 31 ]. Study personnel sought for verbal community consent to participate in a brief demographic survey, and written informed consent of each child’s guardian was subsequently obtained before enrolment into the study.…”

Haptoglobin gene diversity and incidence of uncomplicated malaria among children in Iganga, Uganda

“…No interventional studies were undertaken in this study area at the time this study cohort was assembled. Inclusion criteria of the cohort study was as described in an earlier study [19] and followed; 1) age six months to nine years; 2) agreement to come to study clinic for any febrile episode or illness; 3) agreement to avoid medications administered outside the study; 4) agreement to remain in study area during the twelve months follow up; 5) absence of known chronic disease and 6) written informed consent provided by parent or guardian.…”

“…The association between haptoglobin genotype and incidence of uncomplicated malaria was estimated using a multivariate negative binomial regression model. From a previous analysis in the same children's cohort, age, malaria history and insecticide bed net (ITN) were identi ed as independent predictors of malaria incidence [19]. These factors were treated in the nal multivariate analysis to determine the extent to which haptoglobin genotypes affected the incidence of uncomplicated malaria in the children's cohort.…”