Variation and impact of polygenic hematologic traits in monogenic sickle cell disease.
Variation and impact of polygenic hematologic traits in monogenic sickle cell disease.
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DOI：
10.3324/haematol.2022.281180
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发表时间：
2023-03-01
期刊：
影响因子：
10.1
通讯作者：
Lettre, Guillaume
中科院分区：
文献类型：
--
作者：
Pincez, Thomas;Lo, Ken Sin;Garrett, Melanie E.;Brugnara, Carlo;Ashley-Koch, Allison E.;Telen, Marilyn J.;Joly, Philippe;Bartolucci, Pablo;Lettre, Guillaume
镰状细胞病（SCD）中观察到的一些并发症受血液学特征（HT）变化的影响，如胎儿血红蛋白（HbF）水平和中性粒细胞计数。先前在大部分健康个体中进行的大规模全基因组关联研究已经确定了数千种与HT相关的变异，这些变异随后被用于开发多祖先多基因性状评分（PTS）。在这里，我们测试了这些PTS是否与SCD患者的HT相关，以及它们是否可以改善与SCD相关并发症相关的统计模型。在2056例SCD患者中，我们发现PTS预测的HT方差低于非洲血统的非SCD个体。这在Duffy/DARC位点尤其显著，在那里我们观察到SCD基因型和Duffy零变异体（rs2814778）之间的epistatic相互作用，导致中性粒细胞计数的影响减弱了两倍。作为常规实践的一部分，这些HT的PTS与SCD的并发症无关。相比之下，我们发现HbF的简单PTS仅包括6个变异，解释了很大一部分表型变异（20.5-27.1%），与急性胸综合征和卒中风险相关，并改进了血管闭塞危象率的统计建模。使用孟德尔随机化，我们发现HbF增加4.8%可降低39%的卒中风险（P=0.0006）。综上所述，我们的研究结果强调了在提出在精准医学倡议中实施PTS之前，在大量患病人群中验证PTS的重要性。
Several of the complications observed in sickle cell disease (SCD) are influenced by variation in hematologic traits (HT), such as fetal hemoglobin (HbF) level and neutrophil count. Previous large-scale genome-wide association studies carried out in largely healthy individuals have identified thousands of variants associated with HT, which have then been used to develop multi-ancestry polygenic trait scores (PTS). Here, we tested whether these PTS associate with HT in SCD patients and if they can improve statistical models associated with SCD-related complications. In 2,056 SCD patients, we found that the PTS predicted less HT variance than in non-SCD individuals of African ancestry. This was particularly striking at the Duffy/DARC locus, where we observed an epistatic interaction between the SCD genotype and the Duffy null variant (rs2814778) that led to a two-fold weaker effect on neutrophil count. PTS for these HT which are measured as part of routine practice were not associated with complications in SCD. In contrast, we found that a simple PTS for HbF that includes only six variants explained a large fraction of the phenotypic variation (20.5-27.1%), associated with acute chest syndrome and stroke risk, and improved the statistical modeling of the vaso-occlusive crisis rate. Using Mendelian randomization, we found that increasing HbF by 4.8% reduces stroke risk by 39% (P=0.0006). Taken together, our results highlight the importance of validating PTS in large diseased populations before proposing their implementation in the context of precision medicine initiatives.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S
影响因子：
30.5
作者：
Duchene J;Novitzky-Basso I;Thiriot A;Casanova-Acebes M;Bianchini M;Etheridge SL;Hub E;Nitz K;Artinger K;Eller K;Caamaño J;Rülicke T;Moss P;Megens RTA;von Andrian UH;Hidalgo A;Weber C;Rot A
通讯作者：
Rot A
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
1.9
作者：
Farawela, Hala M.;El-Ghamrawy, Mona;AbdelRahman, Hala A.
通讯作者：
AbdelRahman, Hala A.