Arama Charles, Diarra Issa, Kouriba Bourèma, Sirois Francine, Fedoryak Olesya, Thera Mahamadou A, Coulibaly Drissa, Lyke Kirsten E, Plowe Christopher V, Chrétien Michel, Doumbo Ogobara K, Mbikay Majambu
Malaria Research and Training Center, International Centers for Excellence in Research, Université des Sciences, des Techniques et des Technologies de Bamako, Bamako, Mali.
Laboratoire de protéolyse fonctionnelle, Institut de recherches cliniques de Montréal, Montréal, Québec, Canada.
PLoS One. 2018 Feb 15;13(2):e0192850. doi: 10.1371/journal.pone.0192850. eCollection 2018.
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.
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.
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).
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.
前蛋白转化酶枯草杆菌蛋白酶/九型凯新蛋白酶（PCSK9）是一种肝脏分泌蛋白，它促进低密度脂蛋白受体的降解，导致肝脏对血浆胆固醇的摄取减少。其基因中的非同义单核苷酸多态性与低胆固醇血症或高胆固醇血症有关，这取决于它们分别是降低还是增加PCSK9的活性。由于疟原虫属的增殖和感染性部分依赖于宿主的胆固醇，我们推测这些PCSK9基因多态性可能会影响携带它们的个体的疟疾感染进程。在此，我们研究了一种显性（C679X）和两种隐性（A443T、I474V）低胆固醇血症多态性以及一种隐性高胆固醇血症多态性（E670G）在健康和感染疟疾的马里儿童中的频率分布。
在马里的班迪亚加拉收集了752名年龄、居住地点和种族匹配的儿童的干血斑：253名健康对照、246名非复杂性疟疾患者和253名重症疟疾患者。提取他们的基因组DNA，并使用Taqman分析对上述PCSK9多态性进行基因分型。评估基因型分布和等位基因频率与疟疾的关联。
研究人群样本中A443T、I474V、E670G和C679X多态性的次要等位基因频率分别为0.12、0.20、0.26和0.02。对于每种多态性，三种健康状况之间的基因型分布在统计学上无显著差异，但对于高胆固醇血症的E670G多态性，观察到次要等位基因与疟疾严重程度之间存在关联趋势（P = 0.035）。当比较健康对照和重症疟疾病例之间的等位基因频率时，这种关联更强（优势比：1.34；95%置信区间：1.04 - 1.83；P = 0.031）。
E670G PCSK9多态性次要等位基因的携带者可能更容易患重症疟疾。需要进一步研究PCSK9在疟疾病理生理学中的胆固醇调节功能。
