Study of genetic variations of Proprotein Convertase Subtilisin/Kexin type 9 and malaria infection on plasma lipid levels in Malian children

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protein secreted by the liver. Non-synonymous single nucleotide variations (SNPs) in its gene have been linked to reduced or elevated cholesterol levels, depending on whether they decrease (loss of function, LOF) or increase (gain of function, GOF) the protein's activity.
This study was conducted to assess the effect of PCSK9 gene mutation on lipid metabolism during malaria infection in children aged 3 months to 14 years. We enrolled children aged 3 months to 14 years from a case-control study, which was carried out from June 1999 to December 2003.
Polymorphisms E670G, I474V, A443T and C679X were present in the Bandiagara population at varying frequencies. The E670G polymorphism was the most frequent (56.4%, including 49.84% heterozygous and 6.51 homozygous mutations), followed by I474V (41.7%), A443T (27.7%) and C679X (8%).
Median levels of total cholesterol, HDL and LDL were low during malaria attack. The presence of GOF mutation was significantly associated with lower triglycerides (OR=0.67 ; 95% CI [0.47–0.94], p< 0.5) and HDL (OR= 0.79; 95% CI [0.68–0.91], p< 0.5). However, median triglyceride levels were higher in children with severe malaria. In contrast to gain-of-function, the LOF polymorphism was significantly associated with protection against the occurrence of severe malaria, which is associated with low total cholesterol.
Understanding the mechanisms of this association could lead to the development of new drugs interacting with PCSK9 and may improve the management of severe malaria