key: cord-0854254-jzlng03z
authors: Penna, Claudia; Mercurio, Valentina; Tocchetti, Carlo G.; Pagliaro, Pasquale
title: Sex‐Related Differences in COVID‐19 Lethality
date: 2020-07-22
journal: Br J Pharmacol
DOI: 10.1111/bph.15207
sha: d85bb9b5232627323da1a718db6601bf62c88813
doc_id: 854254
cord_uid: jzlng03z

Many countries have been affected by the world‐wide outbreak of COVID‐19. Among Western countries, Italy has been particularly hit at the beginning of the pandemic, immediately after China. In Italy and elsewhere women seem to be less affected then men by severe/fatal COVID‐19 infection, regardless of their age. Despite the evidence that women and men are affected differently by this infection, very few studies consider different therapeutic approaches for the two sexes. Undoubtedly, understanding the mechanisms at the bases of these differences may help to find appropriate and sex specific therapies. Here, we consider that other mechanisms are involved to explain this difference, in addition to the protection attributable to oestrogens. Several X‐linked genes (such as ACE2) and Y‐linked genes (SRY, SOX9) may explain sex differences. Cardiovascular comorbidities are among the major enhancers of virus lethality. In addition, the number of sex‐independent non‐genetic factors that can change susceptibility and mortality is enormous, and many other factors are likely to be considered, including gender and cultural habits in different countries.

The outbreak of novel coronavirus disease 2019 likely initiated in China [Zhou et al. 2020c ] and rapidly turned into a global pandemic with Europe, U.S.A. and South America being particularly affected [https://coronavirus.jhu.edu/map.html, accessed on June 28 th 2020]. Sex differences are emerging in terms of case fatality (deaths/reported cases), and sex disaggregated data are now starting to be available for many countries. Looking at male/female ratio for death in confirmed cases it appears that the ratio is always above 1.1 in 34 out of the 35 countries that provide sex disaggregated data (only for Pakistan, the ratio is 0.9). Many European countries (Spain, Italy, England, Belgium, Greece, Denmark and The Netherlands) have a male/female ratio for death in confirmed cases equal or above 1.7 (https://globalhealth5050.org/covid19/, accessed on May 13 th 2020). In particular, on May 11, 28.903 COVID-19 positive patients had died in Italy (Table 1) . Their mean age was 80 years (median 81, range 0-100, IQR 74 -87) (https://www.iss.it/coronavirus, accessed on May 13 th 2020). Deceased women were 10.934 (lethality 9.6%), whereas men were 17.018 (lethality 17.1%). For 951 Italian deaths, sex was not reported. At the moment of the revision of this article this trend is confirmed in the majority of countries which provide disaggregated data (https://globalhealth5050.org/covid19/sex-disaggregated-data-tracker/, accessed on June 28 th 2020). In 47 countries the male/female ratio for death results above 1 and in four countries (Albania, Costa Rica, Thailand, and The Netherlands) this ratio is even above 2. Only in five countries (Finland, Maldives, Pakistan, Slovenia and Yemen) the male/female ratio for death is below 1, ranging from 0.94 to 0.55 (https://globalhealth5050.org/covid19/sex-disaggregateddata-tracker/, accessed on June 28 th 2020). In the vast majority of countries, the mortality rate among confirmed cases is lower in women than in men. The difference in lethality between sexes may suggest that women are either less prone to develop severe complications or that they are less likely to succumb to the severe complications that ultimately lead to death. The reasons for this sex-based tolerance are still unknown. Among Italian patients in the age range 10-49 years, only 84 out of 32.345 women died (0.26% lethality), while in the range age of 50-90 years they were 7975/67.263 (11.9% lethality). Of note, 0.89% of men died (225 deaths over 25276 cases) in the range 10-49 years, and 21.8% (15236/69844) in the range 50-90 years.

Therefore, lethality seems to increase with age in both sexes, but it is 3.42 fold higher in young men than young women (10-49 years), and 1.84 fold in older men than in older women (50-90 years) (https://www.iss.it/coronavirus, accessed on May 13 th 2020). This trend in Italian patients is confirmed in data disaggregated by age and sex (https://globalhealth5050.org/covid19/age-and-sex-data/#1589893973981-6ca5e520-eb20;

accessed on June 28 th 2020).

Although these are cumulative/raw data, they confirm that there is a reduced susceptibility of women to severe outcomes from COVID-19 infection. Due to the differences between pre and post-menopausal phases [Horstman et al. 2012] , it is reasonable to speculate that the potential role played by hormones may be present in protecting against severe outcome, but it is not the only factor. Therefore, we need to consider other possible reasons for this difference in sex-related lethality. First, is this difference confirmed also in populations from other countries? According to the latest publications, such differences in lethality between the 2 sexes have been shown elsewhere (see Table 1 and https://globalhealth5050.org/covid19/).

For instance, in a number of different articles from China, similar data are reported [Chen et al. , 2020b Guan et al. 2019; Huang et al. 2020; Wang et al. 2020; Zhou et al. 2020a ].

In these studies, severe or deceased patients admitted to intensive care units (ICUs) were predominantly men, while women ranged between 30% Despite this striking evidence for this infection, very few studies consider different therapeutic approaches for the two sexes. As no specific antiviral drugs are yet proposed to treat COVID-19 and control disease evolution, a better understanding of the pathogenic mechanisms in the two sexes induced by SARS-CoV-2 is mandatory to characterize new targets.

Both young and old women are dying less than age-matched males. Beside hormone differences, which, however, do not appear to be the only factor, there are different potential mechanisms that may explain why women are less prone to severe COVID-19 infections.

First of all, the expression and activity of two important factors may be considered, namely angiotensin-converting enzyme-2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) [Cheng et al. 2015; Kuba et al. 2005 ]. While ACE2 is the receptor for the spike (S) protein of coronaviruses, TMPRSS2 splits the S-protein at sites S1/S2 and S2, favouring the attachment and fusion of the virus to cell membranes, respectively. ACE2 is largely expressed in organs mainly targeted and damaged by SARS-CoV-2 [Pagliaro and Penna 2005] .

Both ACE2 and TMPRSS2 have been proposed as modulators of the different susceptibility to SARS-CoV in both sexes [Hoffmann et al. 2020 ].

ACE2 is located on the X chromosome, and is one of the genes escaping X inactivation [Tukiainen et al. 2017] . Therefore, it is likely that this plays an important role in determining protection in women. It can be hypothesized that the second X chromosome could protect females from fatal polymorphisms that make the COVID-19 more aggressive in males, e.g. by favouring coronavirus binding. Indeed, in a recent study, worse outcome in older COVID-19

patients has been attributed to the presence of lower ACE-2 levels and the subsequent upregulation of Angiotensin II (Ang II) proinflammatory pathways throughout the body, which could make patients more prone to systemic "deleterious" effects of Ang II [AlGhatrif et al. 2020 ]. ACE and ACE2 and their major products, Ang II and Ang-1-7, respectively, are linked in a sort of ying/yang process, when one decreases the other increases and viceversa [Pagliaro and Penna 2005; Koni and Miyamori 2007; Wang et al. 2015 Wang et al. , 2016 .

Clearly, ACE2 permits virus entry into cells, but ACE2 overexpression may protect against damage (by reducing Ang II and forming Ang-1-7) [Bukowska et al. 2017; Patel et al. 2016 ]. However, ACE2 can be "shed" from endothelial cells, by a disintegrin and metalloproteinase 17 (ADAM17) resulting in the release of a soluble circulating ACE2-ectodomain with catalytic function ]. Therefore, the picture is complicated by a different ACE/ACE2 ratio in various tissues and by different roles of membrane-bound and soluble ACE2. For example, it has been proposed that soluble ACE2 could quench the coronavirus by limiting its attachment to cellular ACE2 [Monteil et al. 2020 ].

However, Sama and colleagues [Sama et al. 2020 ] demonstrated that male sex is correlated with elevated plasma ACE2 in heart failure (HF) COVID-19 patients. Nevertheless, the authors recognize they have no evidence of a correlation between the levels of membrane-bound ACE2 and enzyme shedding in the two sexes. Actually, soluble ACE2 is increased in HF with preserved and reduced ejection fraction ]. Moreover, the expression of ACE2 seems reduced in post-menopausal women [Hilliard et al. 2013; Gagliardi et al. 2020 ].

Interestingly, transgender males exposed to oestrogen (estradiol) and androgen deprivation (spirolactone) therapies display significantly higher ACE2 expression levels and a higher number of ACE2-expressing Sertoli cells in the testis. Since both oestrogens and androgens decrease with age [Horstman et al. 2012] , this decline in hormones likely contributes to the reduction of ACE2 expression in both sexes with aging. However, a 2017 study showed no differences in ACE and ACE2 serum activity between the 2 sexes, while a lower ACE2 serum activity was observed in younger compared to older women [Fernández-Atucha et al. 2017 ].

Overall, it appears that differences in the expression of ACE and ACE2 may be organ-specific and age-dependent in both sexes, in animals [Xie et al. 2006 ] and humans [Hilliard et al. 2013; Gagliardi et al. 2020 ] with a less clear role for soluble ACE2 Monteil et al. 2020; Sama et al. 2020 ].

Whether ACE2 levels in the lung are related to the susceptibility and severity of COVID-19 infection is a matter of investigation [Gheblawi et al. 2020 ]. In a preprint paper it is reported that men may have higher expression of ACE2 in the lungs compared to women , with potential important consequences on COVID-19 infections, since the respiratory tract is the entry route for SARS-CoV-2. However, polymorphisms in both ACE and ACE2 genes can explain the increased capillary permeability, coagulation, fibrosis and apoptosis of alveolar cells, observed in SARS and COVID-19 [Tikellis and Thomas 2012; Gemmati et al. 2020 ]. These effects can explain lung damage and respiratory failure (see also below Sex, Pulmonary Disease and COVID -19) .

All in all, the role of ACE2 in the pathophysiology of COVID-19 is not completely clear: it may act as a Trojan horse, but most evidence indicates that a low membrane-bound ACE/ACE2 ratio may be beneficial. Indeed, ACE may be pro-inflammatory and pro-oxidant, whereas ACE2 may mediate anti-oxidant and anti-inflammatory effects [Pagliaro and Penna, 2005; . Soluble ACE2 is higher in HF; whether this is protective or dangerous, or is just an epiphenomenon is not clear yet. Nevertheless, the inhibition of ACE2 shedding, by regulating the activity of ADAM17 enzyme, has been suggested as a potential therapeutic approach in HF ].

Throughout the body, due to the expression of ACE2 on the X chromosome influenced by oestrogens, the ACE/ACE2 ratio may be shifted towards the ACE2/Ang-1-7/MAS receptor axis more in women than in men [Hilliard et al. 2013; Chappell et al. 2014; Tukiainen et al. 2017; Li et al. 2020 ]. This might explain why women are protected against severe COVID-19

outcome. However, we have to acknowledge that there are tissue-and organ-specific differences of the ACE/ACE2 ratio, which can be also influenced by exercise [Crisafulli and

Pagliaro 2020] and medical conditions [Colucci et al. 2011; Chappell et al. 2014; Yuan et al. 2015; Li et al. 2020] . Whether the lethality of SARS-CoV-2 is mainly due to virus entry and replication or to exaggerated inflammatory response is not clear yet. Nevertheless, the beneficial effects by anti-inflammatory drugs (see below) suggest an important role for inflammation and "cytokine storm" in COVID-19 lethality (see below).

Although some studies suggest that TMPRSS2 is involved in determining severity of influenza in animals and humans [Cheng et al. 2015; Sakai et al. 2015] , its role during coronavirus infections and in the modulation of COVID-19 severity is still unclear.

Nevertheless, we have to consider that TMPRSS2 is mainly a testosterone regulated gene and may have a higher expression in men than in women [Tomlins et al. 2005 expression levels and function are also regulated by oestrogen-dependent signalling [Setlur et al. 2008] . Intriguingly, an age-dependent, different and overlapping expression of ACE2 and TMPRSS2 has been recently described in bronchial cells [Lukassen et al. 2020] ; whether this may explain sex differences is still unknown. Therefore, the role of TMPRSS2 in determining sex differences in COVID-19 severity needs to be further studied, as protease inhibitors seem effective in limiting SARS-CoV-2 cell entry [Hoffmann et al 2020] .

Several other X-linked genes (such as ILs, FOXP3, XIST, TLR7/8) and Y-linked genes (SRY, SOX9) may also explain sex differences [Ghosh and Klein 2017] . These and other immune regulatory genes encoded by the X and Y chromosomes may explain lower viral loads and reduced inflammation in women compared to men [Conti and Younes 2020; Márquez et al. 2020 ] (Table 2 ). In particular, the two X chromosomes seem to regulate the immune system even if one of them is inactive. The X chromosome regulates the immune system also modulating other proteins, including CD40L, CXCR3 and TLR8. These can be up-regulated in women and can determine the response to viral infections as well as to vaccinations. A Differentially Expressed Genes (DEGs) network was constructed to identify a specific gene signature characterizing SARS-CoV-2 infection [Fagone et al. 2020 [Cai 2020 ] and a decrease in enzyme activity have been described [Yuan et al. 2015] . We can speculate that higher levels of ACE2 (more virus receptors) may allow for more virus entry, while ACE2 downregulation (less protection conferred by ACE2 anti-inflammatory function) may explain, at least in part, COVID-19 severity in smokers.

Respiratory droplets which spread every time while breathing, coughing or sneezing, are the main route of transmission of SARS-CoV-2. Therefore, attachment of the virus to ACE2 expressed on the respiratory tract is the first step enabling entry into host cells.

Therefore, COVID-19 primarily affects the respiratory system, being secondary acute respiratory distress syndrome (ARDS) quite prevalent in COVID-19 patients Zhou et al. 2020c] . In this respect the comparison with epidemiological evidence from influenza outbreaks and pandemics is very interesting. Opposite to COVID-19, in influenza, morbidity and mortality are often higher for women than men. Moreover, during influenza Importantly, ACE2 may be protective against ARDS. In fact, ACE2 down-regulation favours more severe lung failure in mice [Kuba et al. 2005; Cheng et al. 2020; Hanff et al. 2020 ]. Another study [Xie et al. 2006 ] in rats evidenced that ACE2 lung expression is drastically reduced with aging in both sexes. As mentioned, the binding of SARSCoV-2 spike to ACE2 downregulates ACE2, thus decreasing Bradykinin and Ang II catabolism, as well as

Ang-1-7 formation. The dysregulation of these factors may explain the pathogenesis of respiratory failure and pulmonary hypertension [Gurwitz 2020; Horn 2020] . Moreover, Bradykinin accumulation may explain inflammatory processes, cough and fever. Bradykinin also favours both the complement system and coagulation, mechanisms typical of angioedema, sepsis, and cardiovascular dysfunction also in COVID-19 patients [Colarusso et al. 2020 ].

Actually, a large number of COVID-19 patients exhibit severe cardiovascular damage [Moccia et al. 2020 ] and, as reported above, patients with preexisting cardiovascular diseases (CVDs) appear to have an increased risk of death (also see below).

Cardiovascular disease is more prevalent in males, and subjects with cardiovascular dysfunction infected with SARS-CoV-2 have a worse prognosis. As said above, the poor report, obesity is present in 12% of the deceased patients). All these conditions are characterized by a deranged ACE/ACE2 ratio in humans and animals [Koni and Miyamori 2007; Colucci et al. 2011; Santos et al. 2013 ]. It appears that a deranged ACE/ACE2 ratio is responsible, not only for a high incidence of dramatic ARDS, but also for cardiovascular complications and the high lethality of COVID-19. Oestrogens upregulate the expression of ACE2 in human atrial tissue [Bukowska et al. 2017] , explaining the higher ACE2 expression in the heart of women. Already in 2002, immediately after ACE2 discovery, a sexdependent role of ACE2 in HF, with less severe impairment in female than in male mice, has been described and subsequently confirmed [Crackower et al. 2002; Patel et al. 2016 ]. SARS-CoV-2 downregulates ACE2, and this may favour the ACE/ATR1 axis and may predispose to

CVDs [Horn et al. 2020] . Indeed, downregulation of ACE2 has been observed in pulmonary arterial hypertension. ACE2 downregulation and inflammatory response may favour endothelial dysfunction and coagulopathy, thus worsening the CVD [Guzik et al. 2020; Moccia et al. 2020] . Therefore, the lower ACE/ACE2 in the female heart may limit coagulopathy and COVID-19-induced CVD worsening [Gemmati et al. 2020; Moccia et al. 2020 ].

Therefore, re-establishing an adequate ACE/ACE2 ratio may lead to better outcomes in COVID-19. Indeed, COVID-19 depletes and downregulates ACE2 [Moccia et al. 2020 ].

Therefore, the anti-inflammatory effect of drugs that activate ACE2, may be exploited as a potential therapy in this setting (Fig 1) Animal studies on drugs that can limit SARS-CoV-2 effects are lacking. Preliminary studies report that this virus may infect ferrets, hamsters and cats, inducing mild symptoms, but not pigs or birds [Chan et al. 2020; Shi et al. 2020 ]. Interestingly, a very recent preliminary study shows that mice over-expressing human ACE2 may develop COVID-19 like signs in response to infection with SARS-CoV-2 . These animals showed different susceptibility and, intriguingly, the male mice showed a higher death rate than the female.

Drugs that can increase ACE2 activity include losartan (NCT04312009, NCT04311177, NCT04340557, NCT04343001; clinicaltrials.gov), diminazene diaceturate, This article is protected by copyright. All rights reserved.

resorcinolnaphthalein, and xantenone . Also angiotensin AT1 receptor antagonists have been considered as anti-COVID-19 therapeutics [Gurwitz 2020 ].

Furthermore, recombinant ACE2 has been proposed in both pneumonia [Khan et al. 2017 ] and COVID-19 [Monteil et al. 2020 ].

Currently, remdesivir, used against Ebola, chloroquine/hydroxychloroquine, used against malaria [Yazdany and Kim 2020; Luo et al. 2020] , are being used for COVID-19

patients. Between the submission and revision of this review article, safety concerns have been raised about the chloroquine/hydroxylchloroquine use in COVID-19 and the discussion is still open [Paliani and Cardona 2020] .

A "cytokine storm" has been proposed several times as responsible of COVID-19

lethality [e.g. Moccia et al. 2020; Qin et al. 2020] ; therefore, the anti-IL-6 receptor antibody, tocilizumab (used for the treatment of rheumatoid arthritis and CRS after CAR-T therapies [Alvi et al. 2019 ]), has been proposed in many clinical studies, and it is now in Phase II and Phase III studies in COVID-19 patients [ Lu et al. 2020; Luo et al. 2020 ]. Monoclonal antibodies, anti-IL-1 and anti-IL-6 and plasma derived from COVID-19 recovered patients have been proposed (https://www.sciencenews.org/article/coronavirus-covid-19-can-plasmarecovered-patients-treat-sick). Other anti-inflammatory drugs, including JAK inhibitors, and glucocorticoids may also be useful [Zhang et al. 2019 ]. Indeed, a preliminary study showed that dexamethasone is able to reduce 28-day mortality among COVID-19 patients receiving invasive mechanical ventilation. Also, blockade of the kallikrein-kinin system, upstream to Bradykinin, by lanadelumab (already used in hereditary angioedema) has been proposed for COVID-19 patients [Colarusso et al. 2020 ]. Promising drugs are blockers of TMPRSS2, such as camostat mesylate and nafamostat mesylate [for review see Zhou et al. 2020b ].

This article is protected by copyright. All rights reserved.

Coagulopathies are also a prominent aspect of severe Covid-19 patients. Thus, anticoagulant treatments may decrease mortality [Kollias et al. 2020; Tang et al. 2020] in an ACE/ACE2 dependent and sex-related way [Gemmati et al. 2020 ]. While waiting for vaccines and new therapeutic strategies to fight this terrible pandemic, different antiviral options are under clinical trial as combination therapies. These include hydroxylchloroquine alone or in combination with azithromycin, and remdesivir, as well as lopinavir/ritonavir alone or with interferon (ClinicalTrials.gov identifier: NCT04332094; NCT04332107; NCT04322123;

NCT04335552; NCT04336332; NCT04339816). To the best of our knowledge none of these studies considered different therapeutic approaches for men and women. Moreover, for many of these drugs the effects on ACE/ACE2 ratio is unknown. Even in vaccination sex is a variable that should be considered. Indeed, pathogen-specific and non-specific effects of vaccines present differences between sexes that can be exploited in fighting COVID-19 [Aaby et al. 2020 ]. Of note, the antibody response to vaccinations is actually thought to be greater in women than men, and possibly this might underlie future protection. Yet, caution must be used as women display more adverse events than men following vaccinations [Fischinger et al. 2019] .

A recent study [Fagone et al. 2020 ] investigated the transcriptomic profile in primary human lung cells upon infection with SARS-CoV-2. In this study the transcriptomic profile of lung tissue from healthy men and women were compared with the transcriptomic induced by the virus. It emerged that at ages 40-60 years, the transcriptomic feature of female lung tissue was more similar to those induced by SARS-CoV-2 than in male tissue. The authors suggest that a lower threshold of acute response to SARS-CoV-2 infection in men may, at least partly, explain the lower lethality in women. Nevertheless, the potential factors that might induce this "COVID-19-resistant lung phenotype" in middle-aged women is not clear. In this study, targeting the mammalian target of rapamycin (mTOR) pathway using sirolimus, appeared to be a promising therapeutic approach to fight COVID-19. Also mitogen-activated protein kinase kinase (MEK), I kappa B Kinase (IKK) and serine-threonine kinase (AKT) inhibitors have been proposed as candidate drugs [Fagone et al. 2020] . Of note some of these enzymes are linked to ACE2 anti-inflammatory action [Dhawale et al. 2016 ]. Nevertheless, this study does not envisage different therapeutic approaches for men and women.

Significant sex-related differences are present in the rate of severe cases of COVID-19. Several potential factors underlying these differences in pathogenic mechanisms are identified at the molecular level. All the above-mentioned drugs, targeting these mechanisms, would warrant clinical studies. In particular, the ACE/ACE2 ratio must be considered (Fig. 1 ) and drugs that positively influence this ratio should be taken into account. Beside a plethora of factors that may influence outcome, sex should be one of the criteria to consider in order to select the appropriate therapies for the appropriate patients. Indeed, given the striking differences in lethality between the two sexes, we believe that studying sex differences may help to find appropriate therapies for all patients. Only large unbiased studies considering all factors and hypotheses mentioned here concerning sex differences may explain why women are less at risk of dying from COVID-19 and might help to find patients tailored therapies. It is, therefore, recommended that sex-disaggregated data are provided for all COVID19 studies.

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al., 2018) , and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander et al., 2019) . List of abbreviations: ACE2, angiotensin-converting enzyme-2; BBOX1, Gamma-Butyrobetaine Hydroxylase 1; C3, complement C3; CCL20, Chemokine ligand 20; CXCL1, Chemokine ligand 1; CXCR3, C-X-C Motif Chemokine Receptor 3; DEGs, differentially expressed genes; EDN1, endothelin 1; ERG, v-ets erythroblastosis virus E26 oncogene homolog (avian); FOXP3, Forkhead box transcription factor; HEY2, Hairy/enhancer-of-split related with YRPW motif protein; ILs, interleukines; MYLK, myosin light chain kinase; PDK4, Pyruvate dehydrogenase lipoamide kinase isozyme 4; SOX9, sex-determining region Y box 9; SRY, sex-determining region Y; THBD, thrombomodulin; TLRs, Toll-like receptors; TMPRSS2, transmembrane protease serine 2; VTCN1, V-Set Domain Containing T Cell Activation Inhibitor 1; XIST, X Inactive Specific Transcript.

Possible role of ACE/ACE2 ratio in therapies against COVID-19 in the two sexes. It has been proposed that pathological conditions presenting with a high ACE/ACE2 ratio predispose towards worse COVID-19 outcomes [Gemmati et al. 2020; Pagliaro and Penna 2020] . ACE2 is a membrane-bound enzyme, whose gene lies on X chromosome and is upregulated by oestrogens in males and females. Throughout the body ACE/ACE2 ratio may be lower in women than men and this is theoretically protective thanks to the anti-inflammatory properties of ACE2. However, it must be kept in mind that ACE2 in the lung may act as the entry gate for COVID-19, and the ACE/ACE2 ratio may be different in tissues and organs, and that this ratio is influenced by many factors including, exercise, aging and diseases [Crisafulli and Pagliaro 2020] . Therefore, more studies are necessary to clarify the role of ACE/ACE2 in the two sexes.

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Analysis Working Group; Statistical Methods groups-Analysis Working Group; Enhancing GTEx (eGTEx) groups; NIH Common Fund

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