X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria.
X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria.
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DOI：
10.1371/journal.pmed.0040066
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发表时间：
2007-03
期刊：
影响因子：
15.8
通讯作者：
Diallo DA
中科院分区：
文献类型：
--
作者：
Guindo A;Fairhurst RM;Doumbo OK;Wellems TE;Diallo DA
葡萄糖-6-磷酸脱氢酶（G6PD）在控制恶性疟原虫宿主红细胞的氧化应激中起重要作用。这种酶的突变产生与疟疾保护相关的x连锁缺陷状态，特别是在A -型G6PD缺陷普遍存在的非洲。一些报告提出，具有正常和缺陷红细胞马赛克群体（由于随机X染色体失活）的杂合子雌性具有与具有均匀缺陷红细胞群体的半合子雄性相似或更强的疟疾抗性。这些建议是自相矛盾的，它们与目前假设的保护机制不一致。我们在疟疾高度流行的西非马里农村的两个民族人群中，对严重或非复杂疟疾病例中的A型G6PD缺乏症进行了大型病例对照研究。我们的研究结果表明，在半合子男性儿童中，G6PD缺乏的统一状态赋予了对严重的、危及生命的疟疾的显著保护，并且它可能同样保护了纯合子女性儿童。杂合雌性G6PD缺乏的嵌合状态没有明显的保护作用。在G6PD状态不同的情况下，雌雄虫的寄生密度也无显著差异。对我们的数据和先前一项研究的数据进行荟萃分析的合并优势比证实，半合子雄性对严重疟疾具有高度显著的保护作用，而杂合子雌性则没有。在不同形式的严重疟疾中，对脑型疟疾的保护主要是明显的，这是这些研究中最常见的危及生命的疟疾形式。非洲的A -型G6PD缺乏症受到强烈的自然选择的影响，因为它为半合子雄性提供了对威胁生命的疟疾的优先保护。在杂合子雌性中很少或没有这种保护。尽管这些结论与至少一项先前研究的数据一致，但据我们所知，它们迄今尚未实现，因此它们为G6PD缺乏症作为x -联性状保护疟疾提供了新的视角。在西非马里农村的两个人群中，半合子男性儿童缺乏G6PD -对严重的、危及生命的疟疾具有显著的保护作用。“蚕豆病”是一种由葡萄糖-6-磷酸脱氢酶（G6PD）缺乏引起的疾病，这种疾病被认为是世界上最常见的酶缺乏症。这种疾病被命名为蚕豆病，以意大利语中的蚕豆（fava）命名，G6PD缺乏症患者吃了蚕豆会产生典型的反应。G6PD酶在红细胞中特别重要，它可以保护红细胞免受某些药物或其他压力造成的损害。G6PD有许多正常变异，其中G6PD a和G6PD B在非洲很常见。然而，该基因的异常突变可能导致贫血，因为红细胞在对某些药物或食物的反应中会分解，或者在其他情况下会分解。G6PD缺乏症在世界各地的分布并不均匀；在非洲和地中海地区尤为常见，在某些非洲地区，高达20%-25%的人可能患有此病。虽然G6PD缺乏可能会导致严重的临床结果，因为红细胞被分解，但G6PD缺乏可能会预防疟疾。这里的研究人员想要发现，在几乎所有儿童都在儿童早期感染疟疾的地区，导致G6PD缺乏症的G6PD a突变（写为G6PD a -）是否能保护儿童免受疟疾发作恶化为严重的、危及生命的疾病。他们还想看看男孩和女孩对G6PD -缺乏的保护程度是否不同。研究这个的原因与G6PD缺乏症的基因有关。G6PD的基因编码在X染色体上，男性只有一个拷贝，而女性有两个拷贝。因此，当男性只继承一个突变基因时，就会出现G6PD缺陷，而女性需要继承两个异常基因（或者正常基因被关闭，这在一定比例的女性细胞中通过称为x失活的过程发生）。这项研究是在西非马里的两个地区进行的，在那里，疟疾几乎影响到所有5岁以下的儿童。在每个研究地点招募的儿童来自两个不同的文化群体，班迪亚加拉的多贡人，以及康加巴和克拉的马林克人。研究人员研究了到每个地区的医疗诊所就诊的患有简单疟疾（即轻微症状）或严重疟疾的儿童。所有患者均按照该地区的标准做法正常治疗。研究人员收集了每个儿童的血液样本，以了解血液中有多少疟疾寄生虫，并分析每个患者的DNA，以确定他们是否患有导致G6PD* a -型缺乏的G6PD* a基因突变。总共有3197名儿童被招募到这项研究中，其中2765名患有无并发症的疟疾，432名患有严重疟疾。在这两个种族中，患有严重疟疾的儿童比患有非复杂性疟疾的儿童更不可能拥有突变形式的G6PD*A基因，这表明基因突变保护了儿童免于从疟疾发展到严重疟疾。研究人员随后观察G6PD突变形式对男孩和女孩的保护作用是否不同。研究人员发现，遗传了G6PD*A -突变基因的男孩对严重疟疾有抵抗力，而女孩没有。这些数据表明，导致G6PD*A -缺陷的G6PD*A突变给儿童提供了抵抗严重疟疾的实质性保护，但这种保护似乎只适用于男孩，而不是只有一个突变基因拷贝的女孩。与正常男孩相比，G6PD缺乏症男孩患严重疟疾的风险似乎降低了约三分之二。目前，这种保护差异的原因尚不清楚，因为尚不清楚缺乏G6PD活性的红细胞如何影响疟疾寄生虫。请通过本摘要的在线版本http://dx.doi.org/10.1371/journal.pmed.0040066访问这些网站。Medline Plus上有一篇关于葡萄糖-6-磷酸脱氢酶缺乏症的文章，维基百科上有关于葡萄糖-6-磷酸脱氢酶缺乏症的条目（维基百科是一个免费的互联网百科全书，任何人都可以编辑）关于疟疾的信息可以从美国疾病控制中心获得
Glucose-6-phosphate dehydrogenase (G6PD) is important in the control of oxidant stress in erythrocytes, the host cells for Plasmodium falciparum. Mutations in this enzyme produce X-linked deficiency states associated with protection against malaria, notably in Africa where the A− form of G6PD deficiency is widespread. Some reports have proposed that heterozygous females with mosaic populations of normal and deficient erythrocytes (due to random X chromosome inactivation) have malaria resistance similar to or greater than hemizygous males with populations of uniformly deficient erythrocytes. These proposals are paradoxical, and they are not consistent with currently hypothesized mechanisms of protection. We conducted large case-control studies of the A− form of G6PD deficiency in cases of severe or uncomplicated malaria among two ethnic populations of rural Mali, West Africa, where malaria is hyperendemic. Our results indicate that the uniform state of G6PD deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria, and that it may have likewise protected homozygous female children. No such protection was evident from the mosaic state of G6PD deficiency in heterozygous females. We also found no significant differences in the parasite densities of males and females with differences in G6PD status. Pooled odds ratios from meta-analysis of our data and data from a previous study confirmed highly significant protection against severe malaria in hemizygous males but not in heterozygous females. Among the different forms of severe malaria, protection was principally evident against cerebral malaria, the most frequent form of life-threatening malaria in these studies. The A− form of G6PD deficiency in Africa is under strong natural selection from the preferential protection it provides to hemizygous males against life-threatening malaria. Little or no such protection is present among heterozygous females. Although these conclusions are consistent with data from at least one previous study, they have not heretofore been realized to our knowledge, and they therefore give fresh perspectives on malaria protection by G6PD deficiency as an X-linked trait. In two populations in rural Mali, West Africa, G6PD A- deficiency in hemizygous male children conferred significant protection against severe, life-threatening malaria. “Favism” is a condition that results from a deficiency in an enzyme called glucose-6-phosphate dehydrogenase (G6PD), and this disorder is thought to be the commonest enzyme-deficiency disease worldwide. The disease is named favism after the Italian word for broad beans (fava), which cause a classic reaction when eaten by people with G6PD deficiency. The G6PD enzyme is particularly important in red blood cells, where it protects against damage that can be caused by certain drugs or other stresses. There are a number of normal variants of G6PD, with G6PD A and G6PD B being common in Africa. However, abnormal mutations in the gene can lead to anemia as a result of the red blood cells breaking down in response to certain drugs or types of food, or in other situations. G6PD deficiency is not spread evenly around the world; it is particularly common in Africa and the Mediterranean, and up to 20%–25% of people in certain African regions can have the condition. Although there can be serious clinical outcomes from G6PD deficiency that result from the red blood cells being broken down, G6PD deficiency may protect against malaria. The researchers here wanted to find out whether, in regions where virtually all children get malaria during early childhood, a mutation in G6PD A (written as G6PD A−) that leads to G6PD deficiency protects children from having their malaria episodes worsen into severe, life-threatening disease. They also wanted to look at whether the degree of protection from G6PD A− deficiency differed between boys and girls. The reason for looking at this had to do with the genetics of G6PD deficiency. The gene coding for G6PD is carried on the X chromosome, of which males have only one copy, whereas females have two. Therefore, males will be G6PD deficient when they inherit only one mutant gene, but females need to inherit two abnormal genes (or have the normal gene turned off, which happens by a process known as X-inactivation in a proportion of female cells). This study was carried out in two regions of Mali, West Africa, where malaria affects virtually all children under the age of 5 years. The children recruited at each study site came from two distinct cultural groups, the Dogon people of Bandiagara and the Malinké people of Kangaba and Kela. The researchers studied children coming to the medical clinics in each area with either uncomplicated malaria (i.e., mild symptoms) or severe malaria. All patients were treated normally according to the standard practices for this region. Blood samples were collected from each child in order to see how many malaria parasites were in the blood, as well as to analyze each patient's DNA to work out whether they had a mutant form of the G6PD*A gene that causes the G6PD A− form of deficiency. Overall, 3,197 children were recruited into the study, 2,765 of whom had uncomplicated malaria and 432 had severe malaria. In both ethnic groups, children with severe malaria were much less likely to have the mutant form of the G6PD*A gene than children with uncomplicated malaria, showing that the gene mutation protected children from having their malaria progress to severe malaria. The researchers then looked at whether the protection given by the mutant forms of G6PD affected boys and girls differently. The researchers found that protection against severe malaria occurred in boys but not girls who had inherited one mutant G6PD*A− gene. These data show that the mutation in G6PD*A that leads to the G6PD A− deficiency gives children substantial protection against severe malaria, but this protection seems to be the case for boys and not girls who have only one mutant copy of the gene. There seems to be around a two-thirds drop in risk of severe malaria in boys with G6PD deficiency as compared to normal boys. At present the reason for this difference in protection is not clear, because it is not known how malaria parasites are affected by red blood cells that lack G6PD activity. Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040066. Medline Plus has an article on glucose-6-phosphate dehydrogenase deficiency Wikipedia has an entry on glucose-6-phosphate dehydrogenase deficiency (Wikipedia is a free internet encyclopedia that anyone can edit) Information on malaria is available from the US Centers for Disease Control
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影响因子：
64.8
作者：
Modiano, D;Luoni, G;Coluzzi, M
通讯作者：
Coluzzi, M
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56.9
作者：
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通讯作者：
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64.8
作者：
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通讯作者：
GREENWOOD, BM
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64.8
作者：
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通讯作者：
LUZZATTO, L