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PLoS Genet. 2018 Mar 28;14(3):e1007293. doi: 10.1371/journal.pgen.1007293. eCollection 2018 Mar.

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

Author information

1
Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
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.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.
4
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
5
Hematology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
6
Department of Medicine, Université de Montréal, Montréal, Quebec, Canada.
7
Montreal Heart Institute, Montréal, Quebec, Canada.
8
Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
9
Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America.
10
Department of Biostatistics, University of Washington, Seattle, Washington, United States of America.
11
Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, United States of America.
12
Department of Laboratory Medicine & Pathology, School of Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America.
13
Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America.
14
Department of Genome Sciences, University of Washington, Seattle, Washington, United States of America.
15
Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado, United States of America.
16
Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, United States of America.
17
Department of Computer Science, University of North Carolina, Chapel Hill, North Carolina, United States of America.
18
Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
19
Seattle Epidemiologic Research and Information Center, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, United States of America.
20
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.
21
Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
22
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
23
Department of Epidemiology, University of Washington, Seattle, Washington, United States of America.

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.

PMID:
29590102
PMCID:
PMC5891078
DOI:
10.1371/journal.pgen.1007293
[Indexed for MEDLINE]
Free PMC Article

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