Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease

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-g...

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Vydáno v:	PLoS genetics Ročník 14; číslo 3; s. e1007293
Hlavní autoři:	Raffield, Laura M., Ulirsch, Jacob C., Naik, Rakhi P., Lessard, Samuel, Handsaker, Robert E., Jain, Deepti, Kang, Hyun M., Pankratz, Nathan, Auer, Paul L., Bao, Erik L., Smith, Joshua D., Lange, Leslie A., Lange, Ethan M., Li, Yun, Thornton, Timothy A., Young, Bessie A., Abecasis, Goncalo R., Laurie, Cathy C., Nickerson, Deborah A., McCarroll, Steven A., Correa, Adolfo, Wilson, James G., Lettre, Guillaume, Sankaran, Vijay G., Reiner, Alex P.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States Public Library of Science 01.03.2018 Public Library of Science (PLoS)
Témata:	Adult alpha-Globins - genetics alpha-Thalassemia - genetics Anemia, Sickle Cell - blood Anemia, Sickle Cell - genetics Anemia, Sickle Cell - physiopathology Biology and Life Sciences Black or African American Cohort Studies DNA Copy Number Variations Erythrocytes, Abnormal Glomerular Filtration Rate Glycated Hemoglobin - metabolism Hemoglobin, Sickle - genetics Humans Medicine and Health Sciences People and places Phenotype Sickle Cell Trait Young Adult
ISSN:	1553-7404, 1553-7390, 1553-7404
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Abstract	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.
AbstractList	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. 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. 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.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.
Author	Wilson, James G. Li, Yun Bao, Erik L. Handsaker, Robert E. Abecasis, Goncalo R. Correa, Adolfo Young, Bessie A. Raffield, Laura M. Ulirsch, Jacob C. Kang, Hyun M. Auer, Paul L. Lange, Ethan M. Thornton, Timothy A. Sankaran, Vijay G. Lessard, Samuel Lettre, Guillaume Nickerson, Deborah A. Lange, Leslie A. Smith, Joshua D. McCarroll, Steven A. Pankratz, Nathan Naik, Rakhi P. Laurie, Cathy C. Jain, Deepti Reiner, Alex P.
AuthorAffiliation	17 Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, United States of America 4 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America 6 Department of Medicine, Université de Montréal, Montréal, Quebec, Canada 18 Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, United States of America 20 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America 7 Montreal Heart Institute, Montréal, Quebec, Canada 10 Department of Biostatistics, University of Washington, Seattle, Washington, United States of America 5 Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America 16 Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America 22 Department of Physiology and Biophysics, Un
AuthorAffiliation_xml	– name: 13 Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America – name: 4 Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America – name: 10 Department of Biostatistics, University of Washington, Seattle, Washington, United States of America – name: 3 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America – name: 15 Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, United States of America – name: 19 Seattle Epidemiologic Research and Information Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America – name: 17 Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, United States of America – name: 9 Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America – name: 8 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America – name: 18 Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, United States of America – name: 20 Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America – name: 6 Department of Medicine, Université de Montréal, Montréal, Quebec, Canada – name: 12 Department of Laboratory Medicine & Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America – name: 2 Division of Hematology/Oncology, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America – name: 22 Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America – name: 7 Montreal Heart Institute, Montréal, Quebec, Canada – name: 14 Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America – name: Case Western Reserve University School of Medicine, UNITED STATES – name: 23 Department of Epidemiology, University of Washington, Seattle, Washington, United States of America – name: 11 Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America – name: 21 Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America – name: 1 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America – name: 5 Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America – name: 16 Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America
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Notes	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Membership of TOPMed and Hematology & Hemostasis, Diabetes, Structural Variation, and Kidney Function TOPMed Working Group is in included in the Supplemental Material. GL, VGS, and APR also contributed equally to this work. The authors have declared that no competing interests exist.
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Snippet	Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However,...
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SubjectTerms	Adult alpha-Globins - genetics alpha-Thalassemia - genetics Anemia, Sickle Cell - blood Anemia, Sickle Cell - genetics Anemia, Sickle Cell - physiopathology Biology and Life Sciences Black or African American Cohort Studies DNA Copy Number Variations Erythrocytes, Abnormal Glomerular Filtration Rate Glycated Hemoglobin - metabolism Hemoglobin, Sickle - genetics Humans Medicine and Health Sciences People and places Phenotype Sickle Cell Trait Young Adult
Title	Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease
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