Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease.
Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease.
复制标题
DOI：
10.1371/journal.pgen.1007293
复制
发表时间：
2018-03
期刊：
影响因子：
4.5
通讯作者：
Reiner AP
中科院分区：
文献类型：
--
作者：
Raffield LM;Ulirsch JC;Naik RP;Lessard S;Handsaker RE;Jain D;Kang HM;Pankratz N;Auer PL;Bao EL;Smith JD;Lange LA;Lange EM;Li Y;Thornton TA;Young BA;Abecasis GR;Laurie CC;Nickerson DA;McCarroll SA;Correa A;Wilson JG;NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Hematology & Hemostasis, Diabetes, and Structural Variation TOPMed Working Groups;Lettre G;Sankaran VG;Reiner AP
α-地中海贫血的共遗传对包括卒中在内的镰状细胞病（SCD）并发症的严重程度有显著的保护作用。然而，关于非洲共同祖先α-地中海贫血突变（−α3.7缺失）和β-珠蛋白性状（HbS性状[SCT]和HbC性状）与红细胞参数、贫血和慢性肾脏疾病（CKD）等重要临床表型之间的关联和相互作用的信息很少。在来自Jackson心脏研究的2,916名非裔美国人社区队列中，我们证实了SCT、HbC特征和−α3.7缺失与较低的平均红细胞体积/平均红细胞血红蛋白、较高的红细胞计数和红细胞分布宽度之间的预期关联。除了最近公认的SCT与较低的肾小球滤过率和糖化血红蛋白（HbA1c）的关联外，我们还观察到−α3.7缺失与较高的HbA1c水平的新关联。- α3.7缺失的每一个额外拷贝的共同遗传显著降低了SCT患者贫血和慢性肾脏疾病的风险（p -互作分别= 0.031和0.019）。此外，一种新的α-珠蛋白调节变异的共遗传与α3.7缺失个体的红细胞参数正常化相关，并且显著地抵消了来自镰状细胞病合作研究（CSSCD）的1139例镰状细胞性贫血患者α-地中海贫血对卒中的保护作用（p -互作= 0.0049）。功能分析确定rs11865131位于主要α -珠蛋白增强子MCS-R2中，是最有可能的致病变异。这些发现表明，常见的α-和β-珠蛋白变异相互作用，影响非裔美国人的血液学和临床表型，对SCD和SCT患者的风险分层和咨询具有潜在的意义。最近的研究表明，遗传导致镰状细胞病的β-珠蛋白基因变异的单一拷贝可能与医疗风险有关，例如肾功能恶化。在镰状细胞病患者中，其他珠蛋白基因变异的共同遗传，特别是α-地中海贫血，可以改变个体的临床后遗症（如中风）的风险。在本文中，我们的研究结果表明，遗传导致非洲人群α-地中海贫血的3.7kb缺失可以降低非洲裔美国人镰状细胞特征社区居民贫血和慢性肾脏疾病的风险。另一个α-珠蛋白基因位点，位于一个众所周知的非编码调控元件的上游，被发现修改α-地中海贫血3.7kb拷贝数变异与非裔美国人普通人群和镰状细胞病患者的红细胞特征之间的关联，与中风风险有关。通过功能精细定位和报告基因分析，我们将rs11865131和rs11248850定位为这些表型关联的两个最可能的因果变异。需要进一步的分子研究来了解这些变异影响α-珠蛋白产生的复杂调控机制。
Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (−α3.7 deletion) and β-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the −α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the −α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the −α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the −α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and β-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT. Recent work has shown that inheriting a single copy of the β-globin gene variant which causes sickle cell disease can be associated with medical risks, such as worsening kidney function. In individuals with sickle cell disease, co-inheritance of other globin gene variants, notably α-thalassemia, can modify an individual’s risk of clinical sequelae such as stroke. In this paper, our results suggest that inheritance of the same 3.7kb deletion that causes α-thalassemia in African populations can lower the risk of anemia and chronic kidney disease among African American community-dwelling individuals with sickle cell trait. Another α-globin genetic locus, located upstream within a well-known non-coding regulatory element, was found to modify associations of the α-thalassemia 3.7kb copy number variant with red blood cell traits in the African American general population and, in sickle cell disease patients, with risk of stroke. Using functional fine mapping and reporter assays, we localized rs11865131 and rs11248850 as the two most likely causal variants for these phenotypic associations. Additional molecular studies will be required to understand the complex regulatory mechanism by which these variants influence α-globin production.
登录
查看更多内容
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
2.1
作者：
Lin, DY;Zeng, D;Millikan, R
通讯作者：
Millikan, R
影响因子：
158.5
作者：
EMBURY, SH;DOZY, AM;MENTZER, WC
通讯作者：
MENTZER, WC
影响因子：
5.3
作者：
JARMAN, AP;WOOD, WG;HIGGS, DR
通讯作者：
HIGGS, DR
DOI：
10.1182/asheducation-2010.1.418
发表时间：
2010-12-01
影响因子：
3
作者：
Key, Nigel S.;Derebail, Vimal K.
通讯作者：
Derebail, Vimal K.