Growing evidence suggests that hypertension is the frequently observed comorbidity with severe COVID-19 [7, 29, 30]. Through integrative screening of genetic factors associated with both hypertension and severe COVID-19, we revealed that the cis-eQTL rs12474050 of SPEG is a potential host factor predisposing to higher DBP and severe COVID-19 in females. The risk allele rs12474050*T correlates with lower expression of SPEG in multiple tissues, including muscle-skeletal, heart-atrial appendage, and heart-left ventricle. However, among 49 GTEx tissues, higher expression of SPEG was indeed detected in muscle-skeletal, heart-atrial appendage, and heart-left ventricle of females compared to males, suggesting SPEG expression is under sex-specific regulation. Coincidently, the Fagerberg et al. and Singh et al. demonstrated SPEG was highest decoded in endometrium [31, 32]. The close relationship between endometrium and cardiomyocyte was presented by Fan et al. via the endometrium-derived stem cells could repair myocardial ischemia injury [33]. Such observation rationalizes our hypothesis that SPEG is highly gender-associated with severe COVID-19 in female. Compared to male, female tends to have higher risk to heart related diseases, such as atrial fibrillation [34, 35]. Our analyses implicate the interplay among sex, hypertension, cardiovascular diseases, and severe COVID-19. This may be due to the important functions of SPEG in heart, especially in cardiomyocytes. Furthermore, we revealed that upon SARS-CoV-2 infection the expression of SPEG was upregulated in cardiomyocytes. As SARS-CoV-2 infection could damage the heart both directly and indirectly [36, 37], the upregulation of SPEG, partially increased in higher magnitude in female cardiomyocytes, would be a compensatory response and self-cardioprotective action due to the infection of SARS-CoV-2 in heart. Taken together, the expression of SPEG is influenced by sex and SARS-CoV-2 infection, and SPEG is a critical host factor involved in severe COVID-19 in female.
Previous research suggests that SPEG played pivotal roles in the development, maintenance, and function of cardiac and skeletal muscles [8, 9]. The SPEG gene encoded SPEG belongs to the Unc89 subfamily, myosin light chain kinase (MLCK) protein family [38]. The Unc89 subfamily members could induce phosphorylation of junctophilin 2 (JPH2), ryanodine receptor (RyR2), sarcoplasmic / endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a), and α-tropomyosin (TPM1) in cardiac muscle [9]. As a result, via the triggering of phosphorylation by SPEG, the JPH2, RyR2, SERCA2a, and TPM1 were tightly involved in excitation–contraction (E-C) coupling [39, 40]. The E-C coupling is a key physiological process of conversion of electrical stimuli into a mechanical action in skeletal muscle contraction and is a core phenotype as one of the biological functions of SPEG. SPEG mutations have been found in patients with centronuclear myopathy which is an inherited neuromuscular disorder characterized by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy [41]. In addition, the lower expression of SPEG was observed in human end-stage HF [42]. Further in vivo studies suggests that SPEG is essential for proper myocyte formation and maturation, and for cardiac development and function [43]. Consequently, Quick et al. reported that specific tamoxifen-inducible acute down-regulation of SPEG in cardiomyocytes of over 8 weeks mice resulted in disruption of transverse tubule integrity, impaired calcium handling, altered E-C coupling, and HF [44]. In conclusion, previous research displays abundant pieces of information for critical role of SPEG in cardiovascular system, and the involvement of SPEG in female patients of severe COVID-19 is warranted for further investigation, which will provide new insights or treatment options for severe COVID-19 in female.
Our integrative genetic screening of SNPs associated with both hypertension and severe COVID-19 revealed that the cis-eQTL rs12474050 of SPEG is associated with severe COVID-19 in female. Both single cell RNAseq and bulk RNAseq analyses confirmed the upregulation of SPEG in cardiac cell cardiomyocytes upon SARS-CoV-2 infection. Furthermore, SPEG expression is higher in normal heart tissues of female than that of male. This pattern was also hold for cardiomyocytes of female COVID-19 patients compared to that of male COVID-19 patients. Our finding suggests that SPEG play an important role in heart damage of female COVID-19 patients. This has even broad implication regarding to the substantially increased risk of heart disease in COVID-19 survivors according to two recent large-scale studies, including a 2021 study based on 13,638 health records [45] from Florida and a 2022 study considering 153,760 COVID-19 survivors and thousands of controls [46]. COVID-19 might induce cardiac injury through systemic inflammation and ischemic pathways, also including stress cardiomyopathy, acute and fulminant myocarditis. Nevertheless, female-gender differences in cardiovascular diseases from SARS-CoV-2 are not fully understood. Some reports demonstrated these may be due to COVID-19 induced microvascular coagulopathy and worsening consequent thrombocytopenia [47, 48] thereafter to cause heart damage. Additionally, stress cardiomyopathy was frequently found in COVID-19 female patients [49]. Regarding to the crucial function of SPEG in heart-left ventricular E-C coupling, we deduce that SPEG is involved in severe COVID-19 or long COVID induced heart damage particular in woman. Further investigations using cardiomyocytes with SPEG knockout or an inducible heart-specific SPEG knockout mouse model will be warranted in order to systematically delineate the exact mechanisms.