Neither the African-Centric S47 Nor P72 Variant of TP53 Is Associated With Reduced Risk of Febrile Malaria in a Malian Cohort Study

Abstract

Background: TP53 has been shown to play a role in inflammatory processes, including malaria. We previously found that p53 attenuates parasite-induced inflammation and predicts clinical protection to Plasmodium falciparum infection in Malian children. Here, we investigated whether p53 codon 47 and 72 polymorphisms are associated with differential risk of P. falciparum infection and uncomplicated malaria in a prospective cohort study of malaria immunity.

Methods: p53 codon 47 and 72 polymorphisms were determined by sequencing TP53 exon 4 in 631 Malian children and adults enrolled in the Kalifabougou cohort study. The effects of these polymorphisms on the prospective risk of febrile malaria, incident parasitemia, and time to fever after incident parasitemia over 6 months of intense malaria transmission were assessed using Cox proportional hazards models.

Results: Confounders of malaria risk, including age and hemoglobin S or C, were similar between individuals with or without p53 S47 and R72 polymorphisms. Relative to their respective common variants, neither S47 nor R72 was associated with differences in prospective risk of febrile malaria, incident parasitemia, or febrile malaria after parasitemia.

Conclusions: These findings indicate that p53 codon 47 and 72 polymorphisms are not associated with protection against incident P. falciparum parasitemia or uncomplicated febrile malaria.

Keywords: P47S; P72R; malaria; p53 polymorphisms; prospective cohort study.

Figure 1.

p53 Codon 47 and 72 polymorphisms and malaria risk in the Kalifabougou cohort during the 2011 malaria season. Kaplan-Meier curves of time to first febrile malaria episode (defined as >2500 parasites per microliter by blood smear and axillary temperature >37.5°C) (A, B) and time to first polymerase chain reaction (PCR)–confirmed Plasmodium falciparum parasitemia (C, D), stratified by the indicated p53 variant genotypes. For C and D, the analysis included only individuals who started the malaria season negative for P. falciparum by PCR. Significance was determined by Cox proportional hazards, using the Wald test statistic. Tables show the number of individuals at risk at the indicated days since enrollment. Abbreviation: HR, hazard ratio.

Figure 2.

TP53 expression by codon 47 and 72 polymorphisms. Expression of TP53 by indicated p53 codon 47 (A) and 72 (B) polymorphisms in whole-blood samples from 80 Malian children at their healthy, uninfected baseline in May 2011, before the malaria season [11]. Significance was determined by means of Wilcoxon test (A) or analysis of variance (B). Gene expression is reported as log₂ counts per million (CPM).

Figure 3.

p53 Codon 47 and 72 polymorphisms and risk of febrile malaria after incident parasitemia. Kaplan-Meier plots of time to first febrile malaria using first polymerase chain reaction–confirmed Plasmodium falciparum blood-stage infection as the start time stratified by p53 codon 47 (A) or codon 72 (B) variant polymorphisms. Significance was determined by Cox proportional hazards using the Wald test statistic. Tables show the number of individuals at risk at the indicated time since enrollment. Abbreviation: HR, hazard ratio.