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Published on: November 10, 2015
Malaria severity: Possible influence of the E670G PCSK9 polymorphism: A preliminary case-control study in Malian
Charles Arama1, Issa Diarra1, Bourèma Kouriba1
1Malaria Research and Training Center, International Centers for Excellence in Research, Université des Sciences, des Techniques et des Technologies de Bamako, Bamako, Mali.
Insights
Genetic variations in Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) may influence malaria severity. The E670G polymorphism showed a trend towards increased susceptibility to severe malaria in Malian children.
Area of Science:
- Genetics
- Infectious Diseases
- Biochemistry
Background:
- Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) regulates plasma cholesterol by affecting low-density lipoprotein receptor degradation.
- PCSK9 gene polymorphisms are associated with altered cholesterol levels.
- Plasmodium spp. proliferation and infectivity are partly dependent on host cholesterol.
Purpose of the Study:
- To investigate the association between PCSK9 gene polymorphisms and malaria susceptibility and severity in Malian children.
- To examine the frequency distribution of specific PCSK9 polymorphisms (C679X, A443T, I474V, E670G) in healthy and malaria-infected children.
Main Methods:
- Dried blood spots were collected from 752 Malian children (healthy, uncomplicated malaria, severe malaria).
- Genomic DNA was extracted and genotyped for four PCSK9 polymorphisms using Taqman assays.
- Statistical analysis evaluated genotype distributions and allele frequencies in relation to malaria status.
Main Results:
- The minor allele frequencies for A443T, I474V, E670G, and C679X were 0.12, 0.20, 0.26, and 0.02, respectively.
- No significant genotype distribution differences were found across health conditions for most polymorphisms.
- A trend towards an association between the hypercholesterolemic E670G polymorphism and increased malaria severity was observed (P=0.031).
Conclusions:
- Carriers of the minor allele of the E670G PCSK9 polymorphism may have increased susceptibility to severe malaria.
- Further research is warranted to explore the role of PCSK9 in malaria pathophysiology and cholesterol regulation.
Aim:
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is a hepatic secretory protein which promotes the degradation of low-density lipoprotein receptors leading to reduced hepatic uptake of plasma cholesterol. Non-synonymous single-nucleotide polymorphisms in its gene have been linked to hypo- or hyper- cholesterolemia, depending on whether they decrease or increase PCSK9 activity, respectively. Since the proliferation and the infectivity of Plasmodium spp. partially depend on cholesterol from the host, we hypothesize that these PCSK9 genetic polymorphisms could influence the course of malaria infection in individuals who carry them. Here we examined the frequency distribution of one dominant (C679X) and two recessive (A443T, I474V) hypocholesterolemic polymorphisms as well as that of one recessive hypercholesterolemic polymorphism (E670G) among healthy and malaria-infected Malian children.
Methods:
Dried blood spots were collected in Bandiagara, Mali, from 752 age, residence and ethnicity-matched children: 253 healthy controls, 246 uncomplicated malaria patients and 253 severe malaria patients. Their genomic DNA was extracted and genotyped for the above PCSK9 polymorphisms using Taqman assays. Associations of genotype distributions and allele frequencies with malaria were evaluated.
Results:
The minor allele frequency of the A443T, I474V, E670G, and C679X polymorphisms in the study population sample was 0.12, 0.20, 0.26, and 0.02, respectively. For each polymorphism, the genotype distribution among the three health conditions was statistically insignificant, but for the hypercholesterolemic E670G polymorphism, a trend towards association of the minor allele with malaria severity was observed (P = 0.035). The association proved to be stronger when allele frequencies between healthy controls and severe malaria cases were compared (Odd Ratio: 1.34; 95% Confidence Intervals: 1.04-1.83); P = 0.031).
Conclusions:
Carriers of the minor allele of the E670G PCSK9 polymorphism might be more susceptible to severe malaria. Further investigation of the cholesterol regulating function of PCSK9 in the pathophysiology of malaria is needed.
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