{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T15:44:49Z","timestamp":1771515889973,"version":"3.50.1"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T00:00:00Z","timestamp":1672790400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p>The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 6.4 million deaths worldwide. The prevalent comorbidity between hypertension and severe COVID-19 suggests common genetic factors may affect the outcome of both diseases. As both hypertension and severe COVID-19 demonstrate sex-biased prevalence, common genetic factors between the two diseases may display sex-biased differential associations. By evaluating COVID-19 association signals of 172-candidate hypertension single nucleotide polymorphisms (SNPs) derived from more than 1 million European individuals in two sex-stratified severe COVID-19 genome-wide association studies from UK BioBank with European ancestry, we revealed one functional cis expression quantitative trait locus of <jats:italic>SPEG<\/jats:italic> (rs12474050) showing sex-biased association with severe COVID-19 in women. The risk allele rs12474050*T associates with higher blood pressure. In our study, we found it is significantly correlated with lower <jats:italic>SPEG<\/jats:italic> expression in muscle-skeletal but with higher expression in both brain cerebellum and cerebellar hemisphere. Additionally, nominal significances were detected for the association between rs12474050*T and lower <jats:italic>SPEG<\/jats:italic> expression in both heart left ventricle and atrial appendage; among these tissues, the <jats:italic>SPEG<\/jats:italic> expression is nominally significantly higher in females than in males. Further analysis revealed <jats:italic>SPEG<\/jats:italic> is mainly expressed in cardiomyocytes in heart and is upregulated upon SARS-CoV-2 infection, with significantly higher upregulation of <jats:italic>SPEG<\/jats:italic> only observed in female but not in male COVID-19 patients compared to both normal female and male individuals, suggesting upregulation of <jats:italic>SPEG<\/jats:italic> is a female-specific protective mechanism against COVID-19 induced heart damage. Taken together, our analyses suggest the involvement of <jats:italic>SPEG<\/jats:italic> in both hypertension and severe COVID-19 in women, which provides new insights for sex-biased effect of severe COVID-19 in women.<\/jats:p>","DOI":"10.3389\/fgene.2022.1041470","type":"journal-article","created":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T15:24:40Z","timestamp":1672845880000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic screening for hypertension and COVID-19 reveals functional variation of SPEG potentially associated with severe COVID-19 in women"],"prefix":"10.3389","volume":"13","author":[{"given":"Yu-Si","family":"Luo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang-Chun","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guo-Feng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Meng","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-Yang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hu-Yan","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ping-Ping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Nie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jia-Hong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Mou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhong-Shan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,1,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1001\/jama.2021.0107","article-title":"Researchers investigate what COVID-19 does to the heart","volume":"325","author":"Abbasi","year":"2021","journal-title":"Jama"},{"key":"B2","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.ajhg.2014.07.004","article-title":"SPEG interacts with myotubularin, and its deficiency causes centronuclear myopathy with dilated cardiomyopathy","volume":"95","author":"Agrawal","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1177\/00033197211053903","article-title":"Does COVID-19 cause hypertension?","volume":"73","author":"Akpek","year":"2022","journal-title":"Angiology"},{"key":"B4","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1016\/S2213-8587(21)00346-6","article-title":"Sexual dimorphism in COVID-19: Potential clinical and public health implications","volume":"10","author":"Bechmann","year":"2022","journal-title":"Lancet. Diabetes Endocrinol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev.physiol.70.113006.100455","article-title":"Calcium cycling and signaling in cardiac myocytes","volume":"70","author":"Bers","year":"2008","journal-title":"Annu. Rev. Physiol."},{"key":"B6","doi-asserted-by":"publisher","first-page":"eabn3777","DOI":"10.1126\/sciadv.abn3777","article-title":"Severe COVID-19 induces autoantibodies against angiotensin II that correlate with blood pressure dysregulation and disease severity","volume":"8","author":"Briquez","year":"2022","journal-title":"Sci. Adv."},{"key":"B7","doi-asserted-by":"publisher","first-page":"933148","DOI":"10.3389\/fgene.2022.933148","article-title":"Inflammation and immunity connect hypertension with adverse COVID-19 outcomes","volume":"13","author":"Cai","year":"2022","journal-title":"Front. Genet."},{"key":"B8","doi-asserted-by":"publisher","first-page":"2175","DOI":"10.1093\/cvr\/cvaa290","article-title":"Speg: A key regulator of cardiac calcium homeostasis","volume":"117","author":"Campbell","year":"2021","journal-title":"Cardiovasc. Res."},{"key":"B9","doi-asserted-by":"publisher","first-page":"515","DOI":"10.1136\/postgradmedj-2021-140674","article-title":"Hypertension as an independent risk factor for severity and mortality in patients with COVID-19: A retrospective study","volume":"98","author":"Chen","year":"2021","journal-title":"Postgrad. Med. J."},{"key":"B10","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1161\/CIRCULATIONAHA.113.005119","article-title":"Worldwide epidemiology of atrial fibrillation: A global burden of disease 2010 study","volume":"129","author":"Chugh","year":"2013","journal-title":"Circulation"},{"key":"B11","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1007\/s11596-022-2539-y","article-title":"Hypertension exacerbates severity and outcomes of COVID-19 in elderly patients: A retrospective observational study","volume":"42","author":"Dai","year":"2022","journal-title":"Curr. Med. Sci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"h7013","DOI":"10.1136\/bmj.h7013","article-title":"Atrial fibrillation as risk factor for cardiovascular disease and death in women compared with men: Systematic review and meta-analysis of cohort studies","volume":"532","author":"Emdin","year":"2016","journal-title":"BMJ"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1412","DOI":"10.1038\/s41588-018-0205-x","article-title":"Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits","volume":"50","author":"Evangelou","year":"2018","journal-title":"Nat. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1074\/mcp.M113.035600","article-title":"Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics","volume":"13","author":"Fagerberg","year":"2014","journal-title":"Mol. Cell. Proteomics."},{"key":"B15","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1186\/s13287-021-02423-5","article-title":"Human endometrium-derived stem cell improves cardiac function after myocardial ischemic injury by enhancing angiogenesis and myocardial metabolism","volume":"12","author":"Fan","year":"2021","journal-title":"Stem Cell Res. Ther."},{"key":"B16","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1038\/s41467-020-20885-8","article-title":"A fast and efficient colocalization algorithm for identifying shared genetic risk factors across multiple traits","volume":"12","author":"Foley","year":"2021","journal-title":"Nat. Commun."},{"key":"B17","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/s40292-022-00506-9","article-title":"Hypertension and COVID-19: Current evidence and perspectives","volume":"29","author":"Gallo","year":"2022","journal-title":"High. Blood Press. Cardiovasc. Prev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"454","DOI":"10.1016\/j.mayocp.2021.11.033","article-title":"The female-predominant persistent immune dysregulation of the post-COVID syndrome","volume":"97","author":"Ganesh","year":"2022","journal-title":"Mayo Clin. Proc."},{"key":"B19","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.ygeno.2006.12.004","article-title":"Obscurin-like 1, OBSL1, is a novel cytoskeletal protein related to obscurin","volume":"89","author":"Geisler","year":"2007","journal-title":"Genomics"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx Consortium atlas of genetic regulatory effects across human tissues","volume":"369","author":"Gtex","year":"2020","journal-title":"Science"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell"},{"key":"B22","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1016\/j.devcel.2020.11.020","article-title":"Modeling human TBX5 haploinsufficiency predicts regulatory networks for congenital heart disease","volume":"56","author":"Kathiriya","year":"2021","journal-title":"Dev. Cell"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1969","DOI":"10.1161\/CIRCRESAHA.117.310083","article-title":"Calcium signaling and cardiac arrhythmias","volume":"120","author":"Landstrom","year":"2017","journal-title":"Circ. Res."},{"key":"B24","doi-asserted-by":"publisher","first-page":"304","DOI":"10.20452\/pamw.15272","article-title":"Hypertension in patients with coronavirus disease 2019 (COVID-19): A pooled analysis","volume":"130","author":"Lippi","year":"2020","journal-title":"Pol. Arch. Intern. Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"5732","DOI":"10.3390\/ijms22115732","article-title":"Striated Preferentially Expressed Protein kinase (SPEG) in muscle development, function, and disease","volume":"22","author":"Luo","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"931562","DOI":"10.3389\/fgene.2022.931562","article-title":"Evaluation of a functional single nucleotide polymorphism of the SARS-CoV-2 receptor ACE2 that is potentially involved in long COVID","volume":"13","author":"Luo","year":"2022","journal-title":"Front. Genet."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2508","DOI":"10.3390\/cells9112508","article-title":"Cardiovascular manifestations of COVID-19 infection","volume":"9","author":"Magadum","year":"2020","journal-title":"Cells"},{"key":"B28","doi-asserted-by":"publisher","first-page":"778434","DOI":"10.3389\/fmed.2021.778434","article-title":"COVID-19 post-acute sequelae among adults: 12 month mortality risk","volume":"8","author":"Mainous","year":"2021","journal-title":"Front. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1038\/s41586-021-03569-1","article-title":"A molecular single-cell lung atlas of lethal COVID-19","volume":"595","author":"Melms","year":"2021","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1964","DOI":"10.1056\/NEJMc2105869","article-title":"Thrombotic thrombocytopenia after Ad26.COV2.S vaccination","volume":"384","author":"Muir","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"B31","doi-asserted-by":"publisher","first-page":"740260","DOI":"10.3389\/fimmu.2021.740260","article-title":"Cardiac fibrosis is a risk factor for severe COVID-19","volume":"12","author":"Mustroph","year":"2021","journal-title":"Front. Immunol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1016\/j.ydbio.2005.03.015","article-title":"Disruption in the tropomodulin1 (Tmod1) gene compromises cardiomyocyte development in murine embryonic stem cells by arresting myofibril maturation","volume":"282","author":"Ono","year":"2005","journal-title":"Dev. Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.amjms.2021.12.010","article-title":"Endothelial dysfunction in covid-19 infection","volume":"363","author":"Otifi","year":"2022","journal-title":"Am. J. Med. Sci."},{"key":"B34","doi-asserted-by":"publisher","first-page":"eabf7872","DOI":"10.1126\/scitranslmed.abf7872","article-title":"SARS-CoV-2 infection of human iPSC\u2013derived cardiac cells reflects cytopathic features in hearts of patients with COVID-19","volume":"13","author":"Perez-Bermejo","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"B35","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1161\/CIRCRESAHA.116.309977","article-title":"SPEG (Striated Muscle Preferentially Expressed Protein Kinase) is essential for cardiac function by regulating junctional membrane complex activity","volume":"120","author":"Quick","year":"2017","journal-title":"Circ. Res."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1282","DOI":"10.1097\/HJH.0000000000002819","article-title":"Coronavirus disease 2019 and cardiovascular complications: Focused clinical review","volume":"39","author":"Saeed","year":"2021","journal-title":"J. Hypertens."},{"key":"B38","doi-asserted-by":"publisher","first-page":"108175","DOI":"10.1016\/j.celrep.2020.108175","article-title":"A single-cell RNA expression map of human coronavirus entry factors","volume":"32","author":"Singh","year":"2020","journal-title":"Cell Rep."},{"key":"B39","doi-asserted-by":"publisher","first-page":"4578","DOI":"10.1093\/bioinformatics\/btab503","article-title":"UCSC cell browser: Visualize your single-cell data","volume":"37","author":"Speir","year":"2021","journal-title":"Bioinformatics"},{"key":"B40","doi-asserted-by":"publisher","first-page":"100095","DOI":"10.1016\/j.xhgg.2022.100095","article-title":"A year of COVID-19 GWAS results from the GRASP portal reveals potential genetic risk factors","volume":"3","author":"Thibord","year":"2022","journal-title":"HGG Adv."},{"key":"B41","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1126\/science.abe2813","article-title":"COVID-19 can affect the heart","volume":"370","author":"Topol","year":"2020","journal-title":"Science"},{"key":"B42","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1038\/s41587-020-00796-1","article-title":"Hypertension delays viral clearance and exacerbates airway hyperinflammation in patients with COVID-19","volume":"39","author":"Trump","year":"2021","journal-title":"Nat. Biotechnol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhl\u00e9n","year":"2015","journal-title":"Science"},{"key":"B44","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1177\/00099228221085346","article-title":"The prevalence of Post-COVID-19 hypertension in children","volume":"61","author":"Uysal","year":"2022","journal-title":"Clin. Pediatr."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1001\/jama.2020.1585","article-title":"Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China","volume":"323","author":"Wang","year":"2020","journal-title":"JAMA"},{"key":"B46","unstructured":"Numbers at a glance for global COVID-19 cases2022"},{"key":"B47","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41591-022-01689-3","article-title":"Long-term cardiovascular outcomes of COVID-19","volume":"28","author":"Xie","year":"2022","journal-title":"Nat. Med."},{"key":"B48","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.ijid.2020.03.017","article-title":"Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: A systematic review and meta-analysis","volume":"94","author":"Yang","year":"2020","journal-title":"Int. J. Infect. Dis."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1041470\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T15:24:43Z","timestamp":1672845883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.1041470\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,4]]},"references-count":47,"alternative-id":["10.3389\/fgene.2022.1041470"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.1041470","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,4]]},"article-number":"1041470"}}