A common polymorphism in the mechanosensitive ion channel PIEZO1 is associated with protection from severe malaria in humans.
- 作者列表："Nguetse CN","Purington N","Ebel ER","Shakya B","Tetard M","Kremsner PG","Velavan TP","Egan ES
:Malaria caused by the apicomplexan parasite Plasmodium falciparum has served as a strong evolutionary force throughout human history, selecting for red blood cell polymorphisms that confer innate protection against severe disease. Recently, gain-of-function mutations in the mechanosensitive ion channel PIEZO1 were shown to ameliorate Plasmodium parasite growth, blood-brain barrier dysfunction, and mortality in a mouse model of malaria. In humans, the gain-of-function allele PIEZO1 E756del is highly prevalent and enriched in Africans, raising the possibility that it is under positive selection due to malaria. Here we used a case-control study design to test for an association between PIEZO1 E756del and malaria severity among children in Gabon. We found that the E756del variant is strongly associated with protection against severe malaria in heterozygotes. In subjects with sickle cell trait, heterozygosity for PIEZO1 E756del did not confer additive protection and homozygosity was associated with an elevated risk of severe disease, suggesting an epistatic relationship between hemoglobin S and PIEZO1 E756del. Using donor blood samples, we show that red cells heterozygous for PIEZO1 E756del are not dehydrated and can support the intracellular growth of P. falciparum similar to wild-type cells. However, surface expression of the P. falciparum virulence protein PfEMP-1 was significantly reduced in infected cells heterozygous for PIEZO1 756del, a phenomenon that has been observed with other protective polymorphisms, such as hemoglobin C. Our findings demonstrate that PIEZO1 is an important innate determinant of malaria susceptibility in humans and suggest that the mechanism of protection may be related to impaired export of P. falciparum virulence proteins.
: 由apicomplexan寄生虫恶性疟原虫引起的疟疾在整个人类历史中充当了强大的进化力量，选择了赋予对严重疾病的先天保护的红细胞多态性。最近，机械敏感性离子通道PIEZO1的功能获得突变被证明可以改善疟疾小鼠模型中疟原虫的生长、血脑屏障功能障碍和死亡率。在人类中，功能获得等位基因PIEZO1 E756del在非洲人中高度流行和富集，增加了由于疟疾而处于正选择的可能性。在这里，我们使用病例对照研究设计来测试PIEZO1 E756del与加蓬儿童疟疾严重程度之间的关联。我们发现E756del变体与杂合子中防止严重疟疾密切相关。在有镰状细胞特征的受试者中，PIEZO1 E756del的杂合性不赋予加性保护，并且纯合性与严重疾病的风险升高相关，表明血红蛋白S和PIEZO1 E756del之间存在上位关系。使用供体血液样品，我们显示压电1 E756del杂合的红细胞没有脱水，并且可以支持恶性疟原虫类似于野生型细胞的细胞内生长。然而，恶性疟原虫毒力蛋白PfEMP-1的表面表达在被感染的细胞中显著降低，该现象与其他保护性多态性一起被观察到，如血红蛋白C。我们的研究结果表明，PIEZO1是人类疟疾易感性的重要先天决定因素，并表明保护机制可能与恶性疟原虫毒力蛋白的输出受损有关。
METHODS:BACKGROUND:Thalassemia is one of the most common monogenetic diseases in the south of China and Southeast Asia. Hemoglobin Bart's hydrops fetalis syndrome was caused by a homozygous Southeast Asian deletion (-/-) in the HBA gene. Few studies have proved the potential of screen for Bart's hydrops fetalis using fetal cell-free DNA. However, the number of cases is still relatively small. Clinical trials of large samples would be needed. OBJECTIVE:In this study, we aimed to develop a noninvasive method of target-captured sequencing and genotyping by the Bayesian method using cell-free fetal DNA to identify the fetal genotype in pregnant women who are at risk of having hemoglobin Bart hydrops fetalis in a large-scale study. STUDY DESIGN:In total, 192,173 couples from 30 hospitals were enrolled in our study and 878 couples were recruited, among whom both the pregnant women and their husbands were detected to be carriers of Southeast Asian type (-/αα) of α-thalassemia. Prenatal diagnosis was performed by chorionic villus sampling, amniocentesis, or cordocentesis using gap-polymerase chain reaction considered as the golden standard. RESULTS:As a result, we found that the sensitivity and specificity of our noninvasive method were 98.81% and 94.72%, respectively, in the training set as well as 100% and 99.31%, respectively, in the testing set. Moreover, our method could identify all of 885 maternal samples with the Southeast Asian carrier and 36 trisomy samples with 100% of sensitivity in T13, T18, and T21 and 99.89% (1 of 917) and 99.88% (1 of 888) of specificity in T18 and T21, respectively. CONCLUSION:Our method opens the possibility of early screening for maternal genotyping of α-thalassemia, fetal aneuploidies in chromosomes 13/18/21, and hemoglobin Bart hydrops fetalis detection in 1 tube of maternal plasma.
METHODS:OBJECTIVES:Sickle cell disease (SCD) is a serious illness with disabling acute and chronic pain that needs better therapies, but insufficient patient participation in research is a major impediment to advancing SCD pain management. The purpose of this article is to discuss the challenges of conducting an SCD study and approaches to successfully overcoming those challenges. DESIGN:In a repeated-measures, longitudinal study designed to characterize SCD pain phenotypes, we recruited 311 adults of African ancestry. Adults with SCD completed 4 study visits 6 months apart, and age- and gender-matched healthy controls completed 1 visit. RESULTS:We recruited and completed measures on 186 patients with SCD and 125 healthy controls. We retained 151 patients with SCD with data at 4 time points over 18 months and 125 healthy controls (1 time point) but encountered many challenges in recruitment and study visit completion. Enrollment delays often arose from patients' difficulty in taking time from their complicated lives and frequent pain episodes. Once scheduled, participants with SCD cancelled 49% of visits often because of pain; controls canceled 30% of their scheduled visits. To facilitate recruitment and retention, we implemented a number of strategies that were invaluable in our success. CONCLUSION:Patients' struggles with illness, chronic pain, and their life situations resulted in many challenges to recruitment and completion of study visits. Important to overcoming challenges was gaining the trust of patients with SCD and a participant-centered approach. Early identification of potential problems allowed strategies to be instituted proactively, leading to success.
METHODS:OBJECTIVES:Sickle cell anemia is the commonest genetic disorder in India, and the frequency of the sickle cell gene is very high in the remote tribal areas where facilities are generally limited. Therefore, a rapid and affordable point-of-care test for sickle cell disease is needed. METHODS:The diagnostic accuracy of HemoTypeSC was evaluated against automated high-performance liquid chromatography (HPLC) as the gold standard for its efficacy in a newborn screening program. RESULTS:A total of 1,559 individuals (980 newborns and 579 adults) from four participating centers were analyzed by both methods. HemoTypeSC correctly identified 209 of 211 total hemoglobin (Hb) SS cases, for a 99.1%/99.9% total HbSS sensitivity/specificity. Overall, HemoTypeSC exhibited sensitivity and specificity of 98.1% and 99.1% for all possible phenotypes (HbAA, HbAS, and HbSS) detected. HPLC is relatively expensive and not available in most laboratories in remote tribal areas. CONCLUSIONS:We conclude that the rapid, point-of-care testing device HemoTypeSC test is suitable for population and newborn screening for the HbS phenotype.