Investigating a causal role for neutrophil count on P. falciparum severe malaria: a Mendelian Randomization study
Investigating a causal role for neutrophil count on P. falciparum severe malaria: a Mendelian Randomization study
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调查中性粒细胞计数与恶性疟原虫严重疟疾的因果关系：孟德尔随机研究
DOI：
10.1101/2023.09.06.23295065
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Constantinescu A
中科院分区：
文献类型：
--
作者：
Constantinescu A
背景疟疾引起BYP。恶性疟疾给生活在撒哈拉以南非洲的人们造成了巨大的公共卫生负担。严重疟疾与高发病率和高死亡率以及脑疟疾、严重贫血或呼吸窘迫等并发症有关。生活在疟疾流行地区的人，由于一种称为“良性民族性中性粒细胞减少症”(BEN)的遗传现象，其循环中的中性粒细胞数量通常会减少。中性粒细胞可抵御细菌感染，但已被证明在临床前疟疾模型中是有害的，这增加了中性粒细胞数量减少调节易感人群疟疾严重程度的可能性。我们通过对循环中性粒细胞计数进行全基因组关联研究(GWAS)和孟德尔随机化(MR)分析对以非洲血统为主的重症疟疾患者的中性粒细胞计数进行了验证。结果我们对英国Biobank中与非洲大陆血统群体有关联的个人进行了中性粒细胞计数的GWAS研究(N=5,976)。我们在一个非欧洲人群中发现了以前未知的调节中性粒细胞数量的基因。随后进行了中性粒细胞计数和严重疟疾(疟疾，N=17,056)之间的两个样本的双向磁共振分析。我们确定了73个与中性粒细胞计数相关的基因座(R2=0.1)，其中包括众所周知的导致BEN的rs2814778变异。中性粒细胞计数和严重贫血之间的影响被发现是最有力的证据，尽管可信区间超过了零。MR分析没有证据表明合并的严重疟疾综合征或个别亚型(严重疟疾贫血、脑型疟疾、其他严重疟疾)对中性粒细胞计数的影响。结论我们的中性粒细胞计数GWA揭示了非洲血统个体中存在的独特基因座。我们注意到，小样本量降低了我们在GWA中识别低等位基因频率和/或低效应大小的变异的能力。我们的工作突出了在非洲进行大规模生物库研究和进一步探索中性粒细胞与严重疟疾贫血之间的联系的必要性。
BackgroundMalaria caused byP. falciparumimposes a tremendous public health burden on people living in sub-Saharan Africa. Severe malaria is associated with high morbidity and mortality and results from complications such as cerebral malaria, severe anaemia or respiratory distress. Individuals living in malaria endemic regions often have a reduced circulating neutrophil count due to a heritable phenomenon called ‘benign ethnic neutropenia’ (BEN). Neutrophils defend against bacterial infections but have been shown to be detrimental in pre-clinical malaria models, raising the possibility that reduced neutrophil counts modulate severity of malaria in susceptible populations. We tested this hypothesis by performing a genome-wide association study (GWAS) of circulating neutrophil count and a Mendelian randomization (MR) analysis of neutrophil counts on severe malaria in individuals of predominantly African ancestry.ResultsWe carried out a GWAS of neutrophil count in individuals associated to an African continental ancestry group within UK Biobank (N=5,976). We identified previously unknown loci regulating neutrophil count in a non-European population. This was followed by a two-sample bi-directional MR analysis between neutrophil count and severe malaria (MalariaGEN, N=17,056). We identified 73 loci (r2=0.1) associated with neutrophil count, including the well-known rs2814778 variant responsible for BEN. The greatest evidence for an effect was found between neutrophil count and severe anaemia, although the confidence intervals crossed the null. MR analyses failed to suggest evidence for an effect of the combined severe malaria syndromes or individual subtypes (severe malaria anaemia, cerebral malaria, other severe malaria) on neutrophil count.ConclusionOur GWAS of neutrophil count revealed unique loci present in individuals of African ancestry. We note that a small sample-size reduced our power to identify variants with low allele frequencies and/or low effect sizes in our GWAS. Our work highlights the need for conducting large-scale biobank studies in Africa and for further exploring the link between neutrophils and severe malarial anemia.
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影响因子：
20.3
作者：
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通讯作者：
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影响因子：
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西印度群岛和非洲的白细胞减少症
DOI：
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发表时间：
1967
期刊：
影响因子：
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作者：
J. Rippey
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J. Rippey
中性粒细胞对脑型疟疾中涉及的 PfEMP1 变异体施加强大的选择压力
DOI：
--
发表时间：
2021
期刊：
bioRxiv
影响因子：
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作者：
Tamir Zelter;J. Strahilevitz;Karina Simantov;O. Yajuk;Anja M B Jensen;R. Dzikowski;Z. Granot
通讯作者：
Z. Granot
DOI：
10.1136/bmj.n2233
发表时间：
2021-10-26
期刊：
BMJ (Clinical research ed.)
影响因子：
--
作者：
Skrivankova VW;Richmond RC;Woolf BAR;Davies NM;Swanson SA;VanderWeele TJ;Timpson NJ;Higgins JPT;Dimou N;Langenberg C;Loder EW;Golub RM;Egger M;Davey Smith G;Richards JB
通讯作者：
Richards JB