Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population.
Modulation of Malaria Phenotypes by Pyruvate Kinase (PKLR) Variants in a Thai Population.
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在泰国人群中，丙酮酸激酶（PKLR）变体对疟疾表型的调节。
DOI：
10.1371/journal.pone.0144555
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Gros P
中科院分区：
文献类型：
--
作者：
van Bruggen R;Gualtieri C;Iliescu A;Louicharoen Cheepsunthorn C;Mungkalasut P;Trape JF;Modiano D;Sirima BS;Singhasivanon P;Lathrop M;Sakuntabhai A;Bureau JF;Gros P
丙酮酸激酶（PKLR）是糖酵解和ATP产生所需的关键红细胞酶。我们已经表明，小鼠中的Pklr缺陷降低了由夏氏疟原虫AS感染诱导的血液期疟疾的严重程度（降低了寄生虫血症，增加了存活率）。同样地，在用恶性疟原虫离体感染的人红细胞中的研究表明，宿主PK缺陷等位基因的存在减少了感染表型。我们的特点的PKLR基因的遗传多样性，包括单倍型结构和存在的罕见的编码变异，在两个人口从泰国和塞内加尔的疟疾流行区。我们研究了PKLR基因型对丰富的纵向数据集的影响，包括血液学和疟疾相关表型。在泰国人群中发现了一种编码和可能的破坏性变体（R41Q），其次要等位基因频率约为4.7%。精氨酸41（R41）在丙酮酸激酶家族中高度保守，其取代为谷氨酰胺（R41Q）影响蛋白质稳定性。R41Q的杂合性被证明与恶性疟原虫攻击次数的显著减少相关，同时与间日疟原虫感染次数的增加相关。这些结果强烈表明，PKLR蛋白变异体可能会影响频率，和不同的疟原虫寄生虫在人类生活在地方性疟疾地区的疟疾发作的强度。
Pyruvate kinase (PKLR) is a critical erythrocyte enzyme that is required for glycolysis and production of ATP. We have shown that Pklr deficiency in mice reduces the severity (reduced parasitemia, increased survival) of blood stage malaria induced by infection with Plasmodium chabaudi AS. Likewise, studies in human erythrocytes infected ex vivo with P. falciparum show that presence of host PK-deficiency alleles reduces infection phenotypes. We have characterized the genetic diversity of the PKLR gene, including haplotype structure and presence of rare coding variants in two populations from malaria endemic areas of Thailand and Senegal. We investigated the effect of PKLR genotypes on rich longitudinal datasets including haematological and malaria-associated phenotypes. A coding and possibly damaging variant (R41Q) was identified in the Thai population with a minor allele frequency of ~4.7%. Arginine 41 (R41) is highly conserved in the pyruvate kinase family and its substitution to Glutamine (R41Q) affects protein stability. Heterozygosity for R41Q is shown to be associated with a significant reduction in the number of attacks with Plasmodium falciparum, while correlating with an increased number of Plasmodium vivax infections. These results strongly suggest that PKLR protein variants may affect the frequency, and the intensity of malaria episodes induced by different Plasmodium parasites in humans living in areas of endemic malaria.