{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T01:00:18Z","timestamp":1790902818222,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T00:00:00Z","timestamp":1711411200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Heart, Lung and Blood Institute","doi-asserted-by":"publisher","award":["HU0001-14-1-0060"],"award-info":[{"award-number":["HU0001-14-1-0060"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Sickle cell trait (SCT), although generally a benign carrier state of hemoglobin S (HbAS), is a risk factor for exertional rhabdomyolysis (ERM), a rare but potentially fatal consequence of highly intense physical exercise, particularly among active-duty military personnel and high-performance athletes. The association between SCT and ERM is poorly understood. The objective of this study was to elucidate the genetic basis of ERM in an SCT-positive African American cohort. SCT-positive African Americans with a personal history of ERM (cases, n = 30) and without history of ERM (controls, n = 53) were enrolled in this study. Whole-genome sequencing was performed on DNA samples isolated from peripheral white blood cells. Participants\u2019 demographic, behavioral, and medical history information was obtained. An additional 131 controls were extracted from SCT-positive subjects of African descent from the 1000 Genomes Project. SCT carriers with ERM were characterized by myotoxicity features, significant muscle involvement dominated by muscle weakness, and severe pain and substantial increase in serum creatine kinase, with a mean value of 50,480 U\/L. A distinctive feature of the SCT individuals with ERM was exertional collapse, which was reported in 53.3% of the cases in the study cohort. An important factor for the development of ERM was the duration and frequency of strenuous physical activity in the cases compared to the controls. Whole-genome sequencing identified 79,696 protein-coding variants. Genome-wide association analysis revealed that the p.C477R, rs115958260 variant in the SLC44A3 gene was significantly associated with ERM event in SCT-positive African Americans. The study results suggest that a combination of vigorous exercise and a genetic predisposing factor is involved in ERM.<\/jats:p>","DOI":"10.3390\/genes15040408","type":"journal-article","created":{"date-parts":[[2024,3,26]],"date-time":"2024-03-26T11:34:58Z","timestamp":1711452898000},"page":"408","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genome-Wide Analysis of Exertional Rhabdomyolysis in Sickle Cell Trait Positive African Americans"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1561-7711","authenticated-orcid":false,"given":"Mingqiang","family":"Ren","sequence":"first","affiliation":[{"name":"Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward H\u00e9bert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nyamkhishig","family":"Sambuughin","sequence":"additional","affiliation":[{"name":"Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward H\u00e9bert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ognoon","family":"Mungunshukh","sequence":"additional","affiliation":[{"name":"Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward H\u00e9bert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"},{"name":"Department of Anatomy, Physiology, and Genetics, Center for Military Precision Health, Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0037-2464","authenticated-orcid":false,"given":"Daniel Baxter","family":"Edgeworth","sequence":"additional","affiliation":[{"name":"Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward H\u00e9bert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA"},{"name":"Henry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hupalo","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, and Genetics, Center for Military Precision Health, Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijun","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, and Genetics, Center for Military Precision Health, Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew D.","family":"Wilkerson","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, and Genetics, Center for Military Precision Health, Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clifton L.","family":"Dalgard","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Physiology, and Genetics, Center for Military Precision Health, Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis G.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward H\u00e9bert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7895-0888","authenticated-orcid":false,"given":"Patricia A.","family":"Deuster","sequence":"additional","affiliation":[{"name":"Consortium for Health and Military Performance, Department of Military and Emergency Medicine, F. Edward H\u00e9bert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.3324\/haematol.2018.206060","article-title":"The carrier state for sickle cell disease is not completely harmless","volume":"104","author":"Xu","year":"2019","journal-title":"Haematologica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1056\/NEJMoa1516257","article-title":"Sickle Cell Trait, Rhabdomyolysis, and Mortality among U.S. Army Soldiers","volume":"375","author":"Nelson","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_3","first-page":"1155","article-title":"Incidence of sickle cell trait\u2014United States, 2010","volume":"63","author":"Ojodu","year":"2014","journal-title":"MMWR Morb. Mortal. Wkly. 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