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Globin Variants Modify Hematologic and Other Clinical Phenotypes in Sickle Cell Trait and Disease

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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 The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Raffield, L. M., J. C. Ulirsch, R. P. Naik, S. Lessard, R. E. Handsaker, D. Jain, H. M. Kang, et al. 2018. “Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease.” PLoS Genetics 14 (3): e1007293. doi:10.1371/journal.pgen.1007293. http://dx.doi.org/10.1371/ journal.pgen.1007293. Published Version doi:10.1371/journal.pgen.1007293 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:37068183 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA RESEARCH ARTICLE Common α-globin variants modify hematologic and other clinical phenotypes in sickle cell trait and disease Laura M. Raffield1☯, Jacob C. Ulirsch2,3,4☯, Rakhi P. Naik5☯, Samuel Lessard6,7, Robert E. Handsaker4,8,9, Deepti Jain10, Hyun M. Kang11, Nathan Pankratz12, Paul L. Auer13, Erik L. Bao2,3,4, Joshua D. Smith14, Leslie A. Lange15, Ethan M. Lange15, Yun Li1,16,17, Timothy A. Thornton11, Bessie A. Young18,19, Goncalo R. Abecasis20, Cathy C. Laurie10, Deborah A. Nickerson14, Steven A. McCarroll4,8,9, Adolfo Correa21, James G. Wilson22, NHLBI a1111111111 Trans-Omics for Precision Medicine (TOPMed) Consortium, Hematology & Hemostasis, a1111111111 Diabetes, and Structural Variation TOPMed Working Groups¶, Guillaume Lettre6,7³, Vijay a1111111111 G. Sankaran2,3,4³*, Alex P. Reiner23³* a1111111111 1 Department of Genetics, University of North Carolina, Chapel Hill, North Carolina, United States of a1111111111 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 OPEN ACCESS Medicine, Universite de MontreÂal, MontreÂal, Quebec, Canada, 7 Montreal Heart Institute, MontreÂal, Quebec, Citation: Raffield LM, Ulirsch JC, Naik RP, Lessard Canada, 8 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, S, Handsaker RE, Jain D, et al. (2018) Common α- Massachusetts, United States of America, 9 Department of Genetics, Harvard Medical School, Boston, globin variants modify hematologic and other 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 clinical phenotypes in sickle cell trait and disease. Arbor, Michigan, United States of America, 12 Department of Laboratory Medicine & Pathology, School of PLoS Genet 14(3): e1007293. https://doi.org/ Medicine, University of Minnesota, Minneapolis, Minnesota, United States of America, 13 Zilber School of 10.1371/journal.pgen.1007293 Public Health, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin, United States of America, Editor: Scott M. Williams, Case Western Reserve 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, University School of Medicine, UNITED STATES Colorado, United States of America, 16 Department of Biostatistics, University of North Carolina, Chapel Hill, Received: January 29, 2018 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, Accepted: March 6, 2018 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, Published: March 28, 2018 United States of America, 20 Department of Computational Medicine and Bioinformatics, University of Copyright: © 2018 Raffield et al. This is an open Michigan, Ann Arbor, Michigan, United States of America, 21 Department of Medicine, University of access article distributed under the terms of the 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, Creative Commons Attribution License, which 23 Department of Epidemiology, University of Washington, Seattle, Washington, United States of America permits unrestricted use, distribution, and reproduction in any medium, provided the original ☯ These authors contributed equally to this work. author and source are credited. ³ GL, VGS, and APR also contributed equally to this work. ¶ Membership of TOPMed and Hematology & Hemostasis, Diabetes, Structural Variation, and Kidney Data Availability Statement: Data are available Function TOPMed Working Group is in included in the Supplemental Material. from the dbGaP (accession phs000964.v2.p1, * [email protected] (APR); [email protected] (VGS) phs000286.v5.p1, and phs000366.v1.p1) for researchers who meet the criteria for access to confidential data. Funding: The Jackson Heart Study (JHS) is Abstract supported and conducted in collaboration with Co-inheritance of α-thalassemia has a significant protective effect on the severity of compli- Jackson State University (HHSN268201300049C and HHSN268201300050C), Tougaloo College cations of sickle cell disease (SCD), including stroke. However, little information exists on (HHSN268201300048C), and the University of the association and interactions for the common African ancestral α-thalassemia mutation Mississippi Medical Center (HHSN268201300046C PLOS Genetics | https://doi.org/10.1371/journal.pgen.1007293 March 28, 2018 1 / 21 Common α-globin variants and sickle cell trait and disease and HHSN268201300047C) contracts from the (−α3.7 deletion) and β-globin traits (HbS trait [SCT] and HbC trait) on important clinical phe- National Heart, Lung, and Blood Institute (NHLBI) notypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a and the National Institute for Minority Health and Health Disparities (NIMHD). Whole genome community-based cohort of 2,916 African Americans from the Jackson Heart Study, we con- sequencing (WGS) for the Trans-Omics in firmed the expected associations between SCT, HbC trait, and the −α3.7 deletion with lower Precision Medicine (TOPMed) program was mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and supported by the National Heart, Lung and Blood red cell distribution width. In addition to the recently recognized association of SCT with lower Institute (NHLBI). WGS for ªNHLBI TOPMed: The Jackson Heart Studyº (phs000964.v1.p1) was estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel performed at the University of Washington association of the −α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional Northwest Genomics Center copy of the −α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease (HHSN268201100037C). Centralized read mapping among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, and genotype calling, along with variant quality metrics and filtering were provided by the TOPMed co-inheritance of a novel α-globin regulatory variant was associated with normalization of red Informatics Research Center (3R01HL-117626- cell parameters in individuals with the −α3.7 deletion and significantly negated the protective 02S1). Phenotype harmonization, data effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Coopera- management, sample-identity QC, and general study coordination, were provided by the TOPMed tive Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays deter- Data Coordinating Center (3R01HL-120393-02S1). mined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most The functional studies described in this work were likely causal variant. These findings suggest that common α- and β-globin variants interact to supported by National Institutes of Health grants influence hematologic and clinical phenotypes in African Americans, with potential implica- R01DK103794 and R33HL120791 (to VGS). LMR is supported by NHLBI T32 HL129982, and RPN is tions for risk-stratification and counseling of individuals with SCD and SCT. supported by NHLBI grant K08HL125100. JGW is supported by U54GM115428 from the National Institute of General Medical Sciences. GL's laboratory is funded by grants from the Doris Duke Charitable Foundation, the Canadian Institutes of Author summary Health Research (MOP #123382) and the Canada Recent work has shown that inheriting a single copy of the β-globin gene variant which Research Chair program. This work was also supported by R01HL129132
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