Secondary Logo

Journal Logo

Review Article

Gender and genetic factors impacting COVID-19 severity

Ranjan, Jai; Ravindra, Akshatha; Mishra, Baijayantimala

Author Information
Journal of Family Medicine and Primary Care: November 2021 - Volume 10 - Issue 11 - p 3956-3963
doi: 10.4103/jfmpc.jfmpc_769_21
  • Open

Abstract

Introduction

The pandemic due to SARS coronavirus-2, coronavirus disease-19 or COVID-19 is a cause of global concern and is impacting lives and economy globally. As of 5th July, 2021, over 183 million cases are reported globally with about 30.5 million from India. It has also resulted in 3.97 million deaths worldwide.[1] Currently, many countries have reported a second wave of infection with India reporting more than 4 lakhs COVID-19 cases daily, in May, 2021. Infection due to SARS-CoV-2 leads to varied clinical manifestations, which can vary from asymptomatic to severe acute respiratory syndrome and death. The degree of severity has been reported to be different in different geographical locations with a mortality rate of 0.7 deaths per 100,000 in South Korea to 86.8 per 100,000 in Belgium.[2]

Various host factors that have been attributed to COVID-19 disease severity are male gender, old age, patients with diabetes mellitus, hypertension, and cardiovascular diseases.[3] Worldwide higher risk of severe disease and mortality are reported among males, including in India.[45] Globally, males have been shown to have significantly higher mortality compared to females with about 1.17 million deaths reported among males as compared to 900,000 deaths among females.[6] Similarly in India, 68% of mortality due to COVID-19 was among men while women constituted 32% of the total deaths reported.[7] The comparative mortality depending on gender is depicted in Figure 1.

F1-4
Figure 1:
Gender disparity in COVID-19 mortality (Based on the data available from [6] & [7])

A higher percentage of severe disease among males has also been reported in other coronaviruses like severe acute respiratory syndrome coronavirus (SARS-CoV)[8] and Middle East respiratory syndrome coronavirus.[9] Several studies have attributed different host factors for severity.

The importance of primary care physicians was highlighted during the second wave of COVID-19 in India. Nonavailability of hospital beds and scarcity of equipment such as ventilators to the patients in need were commonly seen during the second wave.[10] Family physicians or primary care physicians play a key role in COVID-19 management. They help in the early diagnosis of the disease, in assessing the clinical severity of COVID-19 among the patients, and are also responsible for triaging patients and providing emergency care, thus, decreasing the burden on hospitals.[11] A better understanding of various gender and genetic factors among these physicians will be of immense help in devising effective patient management and triage strategies. The present review describes the various gender and genetic factors impacting COVID-19 disease.

Methodology

A literature search was performed using Google Scholar and PubMed. Keywords “COVID-19 + sex differences,” “COVID-19 + androgens,” “COVID-19 + ACE2 receptor,” and “COVID-19 + smoking alcoholism pregnancy” were used. The articles which highlight the association of host factors to COVID-19 were selected and included in our study.

Discussion

Host receptors

SARS-CoV-2, the etiological agent of COVID-19 is a positive-sense RNA virus of 29,903 bases, belonging to the genus Betacoronavirus. The virus genome encodes for spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. Spike proteins are projected from the envelope and are mainly responsible for the entry of virus into the host cells.[12]

The entry of virus to host cell is mediated by the binding of the receptor-binding domain (RBD) of the spike protein of virus to the peptidase domain of the angiotensin-converting enzyme-2 (ACE-2) receptor on the host cell.

The spike protein (S-protein) is a clove-shaped homo trimer composed of a monomer made up of two segments S1 and S2. The S1 forms the ectodomain, while S2 forms the stalk, transmembrane, and intracellular domain. The RBD lies in the S1 part of the S-protein. RBD is composed of core domain and receptor binding motif, which is an extension of the RBD. S-protein is primed by transmembrane protease, serine 2 (TMPRSS2). It clips S2 and exposes viral fusion peptide and results in viral fusion to the plasma membrane. The S1 subunit of the virus attaches to the ACE-2 receptor to gain entry into the cells. Single nucleotide polymorphisms (SNPs) are the mutations, which result in the production of different proteins, different susceptibilities to infections, and can also affect the disease severity. SNPs of TMPRSS2 gene, namely, rs2070788 and rs383510, have been reported to increase the susceptibility of the host to influenza virus by increasing the expression of TMPRSS2 Figure 2 depicts the factors influencing TMPRSS2 expression.[13] Chiappelli has hypothesized that the same can also be extrapolated to the COVID-19, wherein the same SNPs can be associated with increased severity of infection,[14] whereas a study by Hussain et al.[15] has shown that SNPs in ACE-2 region, rs73635825 (S19P) and rs143936283 (E329G), result in decreased susceptibility to SARS-CoV-2. This is because of decreased binding affinity of these residues with SARS-CoV-2. It is hypothesized that S-protein also binds to basigin, which is also called extracellular matrix metalloproteinase inducer (EMMPRIN), i.e. CD147 present on the host cell surface, and leads to invasion of virus into the cell.[16] Overexpression of EMMPRIN in the cells can promote SARS-CoV-2 viral infection by facilitating the entry of SARS-CoV-2 in cells.[17]

F2-4
Figure 2:
Factors influencing TMPRSS2 expression

Gender and sex hormones

Increased susceptibility of males to SARS-CoV-2 is attributed to androgens such as testosterone and dihydrotestosterone. Androgens bind to androgen receptors (ARs) which in turn act as an enhancer to the promoter-bound RNA polymerase machinery. This activates the expression of TMPRSS2 [Figure 3].[18] More S1/S2 regions are primed by the TMPRSS2 and more viruses gain entry into the host cells through ACE-2 receptors. The effect of androgen on susceptibility to COVID-19 infection is substantiated by the studies wherein patients with androgenic alopecia are found to have a severe infection.[19] Patients on androgen deprivation therapies (ADT) for prostate cancer are reported to have lower severity of infection.[20] A significant reduction in ICU admissions due to COVID-19 was observed among males taking antiandrogens such as dutasteride or finasteride by Goren et al.[21] This is due to the downregulation of TMPRSS2 by the use of AR antagonists, which in turn leads to lower disease severity by the decreased entry of SARS-CoV-2 into the cells.

F3-4
Figure 3:
Androgen-androgen receptor complex acting as enhancer to promote TMPRSS2 expression

AR is hypothesized to play a major role in disease severity in the case of COVID-19 infection. The gene for AR is present on X-chromosome Xq 11-12 and is comprised of three domains: ligand-binding domain, DNA-binding domain, and transactivation domain. The N-terminal of the later domain contains the DNA segment known as cytosine, adenine, guanine trinucleotide repeats or CAG repeats in a polymorphic polyglutamine (polyQ) tract.[22] The polymorphism of CAG repeats has been shown to be responsible for different rates of COVID-19 mortality among various racial populations. Normally, this CAG segment is repeated 11–31 times within the gene. The longer length of CAG repeats results in the decreased transactivational activity of ARs.[23] The short length of CAG repeats is associated with androgenic alopecia and is also proposed to lead to increased disease severity.[24] This is due to the fact that the short CAG repeats display higher expression of AR genes, generating an increase number of functional AR leading to higher sensitivity for androgen and thereby an increase in the viral entry in the host cells. A more severe disease leading to mortality is also predominantly noted among African-Americans having AR gene polymorphism with shorter CAG repeats.[25]

In contrast, recent study by Baldassarri et al.[22] shows that the presence of shorter polyQ tract among the European males led to better protection from COVID-19 among them. This was postulated to be because of proinflammatory action of long polyQ repeats, leading to more severe inflammatory response. Thus, more studies are required to better understand its relationship with COVID-19.

Gender and immune response

Immune response in both sexes differs because of the expression of different toll-like receptors (TLR). A higher expression of TLR-2 and TLR-4 is seen among males, while females show a higher expression of TLR-3, 7, and 9.[26] TLR-4 has a high affinity for S-protein of SARS-CoV-2.[27] Stimulation of TLR-4 has been shown to result in a strong cytokine response,[28] which can be one of the possible reasons for more severe infections among men. However, in females even though TLR-7 expression is higher, the production of proinflammatory cytokine IL-6 is lesser.[29] This might explain milder infections in females.

Additionally, in males, androgens lead to increased neutrophils which translates to increased interleukin and tumor growth factor-b production[30] leading to cytokine storm.[31] In females, estrogen is associated with T-cell proliferation and X-linked genes are said to increase the immune response.[26] This might be a reason for milder disease among females.

Estrogens decrease the production of proinflammatory cytokines (mediated by Th1) and increase the production of antiinflammatory cytokines.[32] Estrogen receptors (a and b) are present on B cells. Estrogen combines with these receptors and upregulates the expression of B-cell lymphoma-2 (Bcl-2), SHP-2, and CD22. Increased expression of these proteins is associated with decreased apoptosis.[33] This can increase the survival of B-cells and provide a protective antibody response to the viral infections.[34]

High level of estrogen among African women has also been proposed to be protective against severe COVID-19. Estrogen decreases endoplasmic reticulum (ER) stress by activating unfolded protein response pathway and restores ER integrity. This in turn decreases SARS-CoV-2 multiplication in the cells leading to lesser severity of infection.[35]

X-chromosome

Genes present on X-chromosome have an influence on the immune response.[36] X-chromosome has been studied for its effects in disease outcomes of HIV and various other viral infections.[37] The presence of pattern recognition receptor (PRR) genes (TLR-7 and 8), AR gene, ACE-2 gene, and genes for various interleukins (IL-RAP1, IL2-RG) on X-chromosome are responsible for its relationship with innate and adaptive immunity.[38] TLR-7 activity has been shown to have an influence on the disease severity of COVID-19. Viral infections such as influenza promote TLR-7 expression. On binding with a ligand, TLR-7 activates the myeloid differentiation response gene 88 (MyD88) pathway and activates IFN regulatory. This results in the production of proinflammatory cytokines. TLR-7 also stimulates B-cells to increase antibody production.[39] In a recently published study, loss-of-function variants of TLR-7 on X-chromosome have been detected in patients with severe COVID-19.[40] Impaired Interferon-I and Interferon-II responses were also reported among these individuals, signifying a decreased immune response.

MicroRNAs (miRNAs) are double-stranded, non-coding small RNAs, which control gene expression, regulate protein synthesis, and are supposed to play a role in immunity.[41] There are about 112 miRNAs, which are encoded by X-chromosome but only about 2 miRNAs are present on Y-chromosome. Thus, variations in regions of X-chromosome, which encode for these miRNAs, can have an influence on COVID-19 disease progression.[42]

Age

Children are found to be less affected with COVID-19 with majority of them presenting with milder symptoms.[43] Macias-Parra et al.[44] and Jat et al.[45] in their studies have found that majority of children presented with mild symptoms and had a better prognosis. It has been postulated that the presence of lesser ACE-2 receptors (leading to decreased viral entry into host cells) and a higher activity of the innate immune system because of more proportion of natural killer cell and lymphocytes (resulting in more viral lysis)[46] can be the reason behind less severe infection in children.[47]

Neutrophils in children show weak bactericidal effects and decreased chemotaxis.[48] Macrophages and monocytes are also immature and have decreased TLR-4 expression, resulting in lower cytokine responses.[49] The majority of severe clinical manifestations of COVID-19 are because of the cytokine storm. A lower cytokine response can also be considered as one of the causes for less severe infection among pediatric population.

Other factors such as a high level of melatonin, immunomodulatory effects of other vaccines, and difference in microbiota are also proposed to have a protective effect on children. Melatonin is known to block CD147, which facilitates entry of SARS-CoV-2 into cells and also decreases expression of ACE-2 on cell surface by inhibiting calmodulin. This in turn can result in decreased virus entry into the cells. Since children are known to have higher levels of melatonin, they are postulated to have less severe infections. Vaccination among children for various infections is known to produce cross-reacting antibodies, which also has a protective action from SARS-CoV-2. Certain studies have also shown that children are colonized with a heavy load of viruses and bacteria and hence competition among these and SARS-CoV-2 might lead to a lesser entry of it in the human cells and thus resulting in milder infections.[50]

A thorough understanding of the factors influencing disease progression in children is of vital importance. It will help in devising better treatment strategies for pediatric COVID-19.

Host genetic factors

HSD3B1 gene

The genetic makeup of the host also plays a vital role in determining the severity of the illness. HSD3B1 gene encodes for 3b-hydroxysteroid dehydrogenase-1, which transforms dehydroepiandrosterone into more active androgens. There are two forms of HSD3B1 gene, i.e., adrenal permissive HSD3B1 (1245C), which encodes for enzyme which is resistant to degradation, and adrenal restrictive form, which encodes for enzyme which is degraded easily. The presence of an adrenal permissive form of this gene might lead to increased androgen production and thus impacting disease severity. It can also result in associated features such as androgenic alopecia.[51] Spain recorded one of the highest COVID-19 mortality rates worldwide, i.e. 544 per million population in the initial phases of the pandemic, as compared to other European countries.[52] This could be due to the prevalence of adrenal permissive HSD3B1 allele among the Spanish population.[53]

Genetic variants

In recent studies, genetic variants (a group of alleles present on various chromosomes) are found to be associated with COVID-19 severity.[54] DNAH7 gene encodes for dynein axonemal chain 7. It is a component of ciliary axonemes. Variations in DNAH7 can result in decreased mucociliary clearance and eventually severe COVID-19 symptoms.[55] CLUAP1 gene is responsible for the formation of clusterin-associated protein 1, which helps in ciliogenesis.[56] CLUAP1 gene containing the super variant SNP rs2301762 can lead to alteration in the functioning of cilia and is known to be associated with severe disease.[57] Moreover, the effect of SARS-CoV-2 on cilia can be gauged by the fact that COVID-19 infection leads to ciliary dysregulation and anosmia.[58]

Acute myocardial damage has been reported among certain COVID-19 patients.[59] Genes DES and SPEG can be associated with cardiomyopathies and cardiac manifestations of the infection. Gene DES and gene SPEG encode for muscle-specific intermediate filament and muscle-enriched protein kinase, respectively.[60] SNPs in Chr2_221 located near the genes DES and SPEG are associated with cardiomyopathy. This can also be enhanced by SARS-CoV-2 leading to acute damage of the myocardial tissues.[59]

COVID-19 leads to platelet activation and may predispose patients to various thrombotic diseases.[61] STXBP5 encodes for syntaxin 1 binding protein. It promotes platelet secretion and is associated with thromboembolic disorders.[62] Chr6_148 is a super variant, which contains 101 SNPs. These SNPs are present in STXBP5 gene (89 in STXBP5 and 6 in STXBP5-AS1). Mutations in STXBP5 predispose to venous thromboembolic disease and might result in increased mortality in COVID-19 patients.[54]

Another genetic factor influencing disease severity is WSB1 gene. It functions as receptor binding molecule of interleukin-21 (IL-21).[63] Three variant SNPs are found on Chr17_26, which includes SNP rs60811869 which is an expression quantitative trait locus of WSB1 gene. Genetic variations in this region will also result in higher mortality among COVID-19 patients due to an altered immune system.

Of late, C9orf72 gene, which is an autophagy gene and is associated with vesicular trafficking and lysosomal activity, has also been shown to affect outcomes in COVID-19. It is responsible for the degradation of inflammatory mediators like TLRs. There are many hexanucleotide repeat expansions, which are present in it. Intermediate repeats (repeats of >10) show a higher degree of methylation among them and can result in severe infection due to decreased degradation of the inflammatory markers.[64]

Ellinghaus et al.[65] have recently shown that 3p21.31 gene cluster has a significant association with severity in COVID-19 positive patients with respiratory failure. This is a cluster of six genes, namely, SLC6A20, LZTFL1, FYCO1, CXCR6, CCR9, and XCR1. SLC6A20, which encodes for sodium-amino acid transporter, forms a complex with ACE-2 and facilitates entry of SARS-CoV-2. Increased expression of this gene can lead to more entry of the virus into the cell. Other genes in the cluster such as LZFTL1 and CXCR6 are to influence ciliogenesis and activity of natural killer cells. A variation in the genetic components of these genes can also have an effect on disease progression.[66] Various genome-wide association studies have been undertaken to ascertain the effect of different genetic variations on COVID-19. SNP rs11385942 on chromosome 3 has been identified as a risk variant in such studies, signifying the role of host genetics on COVID-19 severity.[67]

Pregnancy

Physiological conditions such as pregnancy are also postulated to have effects on COVID-19 infection. Usually, an increase in ACE-2 is seen during pregnancy and this poses a greater risk of acquiring SARS-CoV-2 infection during pregnancy.[68] A decrease in Th1 response compared to Th2 response is observed during pregnancy, which might lead to lesser clearance of virus-infected cells and severe COVID-19 infection.[69] Other factors that can result in severe COVID-19 in gravid females can be a decrease in natural killer cells and reduced dendritic cells. These need to be studied further to accurately ascertain the relationship between these immunological changes and the severity of COVID-19.[69]

Risk factors

Habits such as smoking and alcoholism are attributed to increased severity of many viral infections, possibly due to reduced level of natural killer (NK) cells among people who smoke.[70] Similarly, other habits such as substance abuse can also have an effect of COVID-19 infections.

Smoking

Smoking is found to have a direct relationship with the worsening of COVID-19 symptoms in the majority of studies.[71] Benzano et al.[72] in their study found a significant correlation between smoking and COVID-19 severity with about 82% patients with severe COVID-19 being smokers.

This can be due to the upregulation of ACE-2 receptors in current smokers, which result in increased uptake of the SARS-CoV-2 virus by the host cells.[73] Recent studies have also demonstrated that a significant increase in ARs and ACE-2 receptors is seen among elderly male smokers.[18] This can in turn lead to an increase in viral entry into cells and severe clinical manifestations of the disease. This is corroborated in the study by Maggi et al.[74]

In contrast, Purohit and Panda in their study showed a protective influence of smoking against SARS-CoV-2 infection. The probable causes for such an observation could be squamous cell metaplasia (SQM) and ACE-2 expression. SQM is seen among smokers and usually results in the altered cell surface, which could hamper the entry of the virus into the cell. Certain studies have also shown that nicotine decreases the expression of ACE-2, hence decreasing infection. Further analysis of smoking and its effect on COVID-19 is still warranted to better understand the interplay of various factors.[75]

Alcoholism and substance abuse

Alcohol consumption is known to reduce immunity to viral infections and makes the host more vulnerable to COVID-19.[76] This was substantiated by Saurabh et al.[77] in their study, wherein alcohol consumption was found to be a risk factor for the development of symptomatic COVID-19. Substance abuse leads to cardiomyopathy, lung injury, and pulmonary hypertension, which results in a bad prognosis of COVID-19 infection.[78] This has been substantiated in studies by Wang et al.[79] and Althobaiti et al.[80]

Figure 4 depicts the summary of gender and host genetic factors influencing COVID-19 severity.

F4-4
Figure 4:
Summary of gender and genetic factors influencing COVID-19 severity

Conclusion

Host factors such as TMPRSS2 and ACE-2 expression, androgen, and ARs play a major role in contributing to higher severity and mortality in male gender. Understanding the interplay of gender and host genetic factors influencing COVID-19 mortality is the need of the hour to devise appropriate management and research should be carried out to find out the role of antiandrogen in decreasing the severity of COVID-19. It will also be of immense help for primary caregivers to devise effective triage and management protocols for future COVID-19 surges.

Key Messages

  • Gender and genetic factors influence the severity of COVID-19.
  • The presence of androgens in males has shown to be a risk factor for severe SARS-CoV-2 infection.
  • Antiandrogens or ADT as used in prostate cancer can also be used for the treatment of COVID-19.
  • X-chromosome carries genes that are responsible for immune response.
  • Estrogen is protective against severe COVID-19.
  • Children usually have milder symptoms because of the presence of higher proportion of lymphocytes, high level of melatonin, and cross protection conferred by other vaccines.
  • Genetic variation among hosts, i.e. SNPs in DNAH7, DES, SPEG, STXBP5, and chromosome 3 cluster of genes influence the disease severity of COVID-19.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgement

None

References

1. COVID-19 Map [Internet], Johns Hopkins Coronavirus Resource Center. Available from: https://coronavirus.jhu.edu/map.htmlLast accessed on 2021 Jul 5
2. Bilinski A, Emanuel EJ. COVID-19 and excess all-cause mortality in the US and 18 comparison countries JAMA. 2020;324:2100–2
3. Rashedi J, Mahdavi Poor B, Asgharzadeh V, Pourostadi M, Samadi Kafil H, Vegari A, et al Risk factors for COVID-19 Infez Med. 2020;28:469–74
4. Peckham H, de Gruijter NM, Raine C, Radziszewska A, Ciurtin C, Wedderburn LR, et al Male sex identified by global COVID-19 meta-analysis as a risk factor for death and ITU admission Nat Commun. 2020;11:6317
5. Sharifi N, Ryan CJ. Androgen hazards with COVID-19 Endocr Relat Cancer. 2020;27:E1–3
6. March-2021-data-tracker-update.pdf. Available from: https://globalhealth5050.org/wp-content/uploads/March-2021-data-tracker-update.pdfLast accessed on 2021 Apr 15
7. India's total recovered cases are now double the active cases, Press Information Bureau, Government of India. Available from: pib.gov.in/Pressreleaseshare.aspx?PRID=1643359Last accessed on 2021 Apr 15
8. Channappanavar R, Fett C, Mack M, Ten Eyck PP, Meyerholz DK, Perlman S. Sex-based differences in susceptibility to severe acute respiratory syndrome coronavirus infection J Immunol. 2017;198:4046–53
9. Alghamdi IG, Hussain II, Almalki SS, Alghamdi MS, Alghamdi MM, El-Sheemy MA. The pattern of Middle East respiratory syndrome coronavirus in Saudi Arabia:A descriptive epidemiological analysis of data from the Saudi Ministry of Health Int J Gen Med. 2014;7:417–23
10. Jain VK, Iyengar Karthikeyan P, Vaishya R. Differences between First wave and Second wave of COVID-19 in India Diabetes Metab Syndr. 2021;15:1047–8
11. World Health Organisation, Regional Office for the Western Pacific. Role of primary care in the COVID-19 response. 2020 Apr 21. Available from: https://apps.who.int/iris/handle/10665/331921Last accessed on 2021 Jul 5
12. Yao H, Song Y, Chen Y, Wu N, Xu J, Sun C, et al Molecular architecture of the SARS-CoV-2 virus Cell. 2020;183:730–8.e13
13. Cheng Z, Zhou J, To KK-W, Chu H, Li C, Wang D, et al Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A (H1N1) influenza and A (H7N9) influenza J Infect Dis. 2015;212:1214–21
14. Chiappelli F. CoViD-19 susceptibility Bioinformation. 2020;16:501–4
15. Hussain M, Jabeen N, Raza F, Shabbir S, Baig AA, Amanullah A, et al Structural variations in human ACE2 may influence its binding with SARS-CoV-2 spike protein J Med Virol. 2020;92:1580–6
16. Wang K, Chen W, Zhou Y-S, Lian J-Q, Zhang Z, Du P, et al SARS-CoV-2 invades host cells via a novel route:CD147-spike protein bioRxiv.. 2020 2020.03.14.988345 doi:10.1101/2020.03.14.988345
17. Wang K, Chen W, Zhang Z, Deng Y, Lian J-Q, Du P, et al CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells Signal Transduct Target Ther. 2020;5:1–10
18. Qiao Y, Wang X-M, Mannan R, Pitchiaya S, Zhang Y, Wotring JW, et al Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2 Proc Natl Acad Sci U S A. 2020;118:e2021450118 doi:10.1073/pnas. 2021450118
19. Wambier CG, Vaño-Galván S, McCoy J, Gomez-Zubiaur A, Herrera S, Hermosa-Gelbard Á, et al Androgenetic alopecia present in the majority of patients hospitalized with COVID-19:The “Gabrin sign J Am Acad Dermatol. 2020;83:680–2
20. Montopoli M, Zumerle S, Vettor R, Rugge M, Zorzi M, Catapano CV, et al Androgen-deprivation therapies for prostate cancer and risk of infection by SARS-CoV-2:A population-based study (N=4532) Ann Oncol. 2020;31:1040–5
21. Goren A, Wambier CG, Herrera S, McCoy J, Vaño-Galván S, Gioia F, et al Anti-androgens may protect against severe COVID-19 outcomes:Results from a prospective cohort study of 77 hospitalized men J Eur Acad Dermatol Venereol. 2021;35:e13–5
22. Baldassarri M, Picchiotti N, Fava F, Fallerini C, Benetti E, Daga S, et al Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males EBioMedicine. 2021;65:103246 doi:10.1016/j.ebiom. 2021.103246
23. Ragia G, Manolopoulos VG. Assessing COVID-19 susceptibility through analysis of the genetic and epigenetic diversity of ACE2-mediated SARS-CoV-2 entry Pharmacogenomics. 2020;21:1311–29
24. Wambier CG, Goren A, Vaño-Galván S, Ramos PM, Ossimetha A, Nau G, et al Androgen sensitivity gateway to COVID-19 disease severity Drug Development Research. 2020;81:771–6
25. Bennett CL, Price DK, Kim S, Liu D, Jovanovic BD, Nathan D, et al Racial variation in CAG repeat lengths within the androgen receptor gene among prostate cancer patients of lower socioeconomic status J Clin Oncol. 2002;20:3599–604
26. Taneja V. Sex hormones determine immune response Front Immunol. 2018;9:1931 doi:10.3389/fimmu. 2018.01931
27. Choudhury A, Mukherjee S. In silico studies on the comparative characterization of the interactions of SARS-CoV-2 spike glycoprotein with ACE-2 receptor homologs and human TLRs J Med Virol. 2020;92:2105–13
28. Onofrio L, Caraglia M, Facchini G, Margherita V, Placido SD, Buonerba C. Toll-like receptors and COVID-19:A two-faced story with an exciting ending Future Sci OA. 2020;6:FSO605
29. Conti P, Younes A. Coronavirus COV-19/SARS-CoV-2 affects women less than men:Clinical response to viral infection J Biol Regul Homeost Agents. 2020;34:339–43
30. Klein SL, Flanagan KL. Sex differences in immune responses Nat Rev Immunol. 2016;16:626–38
31. Moradi F, Enjezab B, Ghadiri-Anari A. The role of androgens in COVID-19 Diabetes Metab Syndr. 2020;14:2003–6
32. Salem ML. Estrogen, a double-edged sword:Modulation of TH1- and TH2-mediated inflammations by differential regulation of TH1/TH2 cytokine production Curr Drug Targets Inflamm Allergy. 2004;3:97–104
33. Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation J Clin Invest. 2002;109:1625–33
34. Patil A, Tripathy JP, Deshmukh V, Sontakke B, Tripathi SC. SeXX and COVID-19:Tussle between the two Monaldi Arch Chest Dis. 2020;90 doi:10.4081/monaldi. 2020.1461
35. Dufailu OA, Afriyie-Asante A, Gyan B, Kwabena DA, Yeboah H, Ntiakoh F, et al COVID-19 in Africa:An ovarian victory? J Ovarian Res. 2021;14:70
36. Brooks WH. X chromosome inactivation and autoimmunity Clin Rev Allergy Immunol. 2010;39:20–9
37. Klein SL. Sex influences immune responses to viruses, and efficacy of prophylaxis and therapeutic treatments for viral diseases Bioessays. 2012;34:1050–9
38. Schurz H, Salie M, Tromp G, Hoal EG, Kinnear CJ, Möller M. The X chromosome and sex-specific effects in infectious disease susceptibility Human Genomics. 2019;13:2
39. Salvati L, Biagioni B, Vivarelli E, Parronchi P. A gendered magnifying glass on COVID-19 Clin Mol Allergy. 2020;18:14
40. van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, et al Presence of genetic variants among young men with severe COVID-19 JAMA. 2020;324:663–73
41. Pinheiro I, Dejager L, Libert C. X-chromosome-located microRNAs in immunity:Might they explain male/female differences?The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females Bioessays. 2011;33:791–802
42. Li Y, Jerkic M, Slutsky AS, Zhang H. Molecular mechanisms of sex bias differences in COVID-19 mortality Crit Care. 2020;24:405
43. Ramteke S, Tikkas R, Goel M, Mandraha S, Shrivastava J. Paediatric COVID-19:Milder presentation—A silver lining in dark cloud J Trop Pediatr. 2020;67:fmaa106 doi:10.1093/tropej/fmaa106
44. Macias-Parra M, Fortes-Gutierrez S, Aguilar-Gomez N, Diaz-Garcia L, Otero-Mendoza F, Arias de la Garza E, et al Clinical and epidemiological characteristics of paediatric patients diagnosed with COVID-19 in a tertiary hospital in Mexico City J Trop Pediatr. 2021;67:fmab025
45. Jat KR, Sankar J, Das RR, Ratageri VH, Choudhary B, Bhat JI, et al Clinical profile and risk factors for severe disease in 402 children hospitalized with SARS-CoV-2 from India:Collaborative Indian pediatric COVID study group J Trop Pediatr. 2021;67:fmab048
46. Sinaei R, Pezeshki S, Parvaresh S, Sinaei R. Why COVID-19 is less frequent and severe in children:A narrative review World J Pediatr. 2020;17:10–20
47. Kammoun R, Masmoudi K. Paediatric aspects of COVID-19:An update Respir Med Res. 2020;78:100765 doi:10.1016/j.resmer. 2020.100765
48. Nussbaum C, Gloning A, Pruenster M, Frommhold D, Bierschenk S, Genzel-Boroviczény O, et al Neutrophil and endothelial adhesive function during human fetal ontogeny J Leukoc Biol. 2013;93:175–84
49. Förster-Waldl E, Sadeghi K, Tamandl D, Gerhold B, Hallwirth U, Rohrmeister K, et al Monocyte toll-like receptor 4 expression and LPS-induced cytokine production increase during gestational aging Pediatr Res. 2005;58:121–4
50. Zimmermann P, Curtis N. Why is COVID-19 less severe in children?A review of the proposed mechanisms underlying the age-related difference in severity of SARS-CoV-2 infections Arch Dis Child. 2020 doi:10.1136/archdischild-2020-320338
51. Wollina U, Karadağ AS, Rowland-Payne C, Chiriac A, Lotti T. Cutaneous signs in COVID-19 patients:A review Dermatol Ther. 2020;33:e13549
52. Soriano V, Barreiro P. Why such excess of mortality for COVID-19 in Spain? Ther Adv Infect Dis. 2020;7:2049936120932755 doi:10.1177/2049936120932755
53. McManus JM, Sabharwal N, Bazeley P, Sharifi N. A common androgen synthesis variant is associated with COVID susceptibility [Internet] 2020 Sep [cited 2021 Aug 19] p. 2020.08.27.20183004 Available from: https://www.medrxiv.org/content/10.1101/2020.08.27.20183004v1
54. Hu J, Li C, Wang S, Li T, Zhang H. Genetic variants are identified to increase risk of COVID-19 related mortality from UK Biobank data medRxiv. 2020 2020.11.05.20226761
55. Li X, Ma X. Acute respiratory failure in COVID-19:Is it “typical”ARDS? Crit Care. 2020;24:198
56. Pasek RC, Berbari NF, Lewis WR, Kesterson RA, Yoder BK. Mammalian Clusterin associated protein 1 is an evolutionarily conserved protein required for ciliogenesis Cilia. 2012;1:20
57. Kuek LE, Lee RJ. First contact:The role of respiratory cilia in host-pathogen interactions in the airways Am J Physiol Lung Cell Mol Physiol. 2020;319:L603–19
58. Li W, Li M, Ou G. COVID-19, cilia, and smell FEBS J. 2020;287:3672–6
59. Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, et al Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19) JAMA Cardiol. 2020;5:811–8
60. Brodehl A, Gaertner-Rommel A, Milting H. Molecular insights into cardiomyopathies associated with desmin (DES) mutations Biophys Rev. 2018;10:983–1006
61. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al COVID-19 and thrombotic or thromboembolic disease:Implications for prevention, antithrombotic therapy, and follow-up J Am Coll Cardiol. 2020;75:2950–73
62. Zhu Q, Yamakuchi M, Ture S, de la Luz Garcia-Hernandez M, Ko KA, Modjeski KL, et al Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion J Clin Invest. 2014;124:4503–16
63. Nara H, Onoda T, Rahman M, Araki A, Juliana FM, Tanaka N, et al WSB-1, a novel IL-21 receptor binding molecule, enhances the maturation of IL-21 receptor Cell Immunol. 2011;269:54–9
64. Zanella I, Zacchi E, Piva S, Filosto M, Beligni G, Alaverdian D, et al C9orf72 intermediate repeats confer genetic risk for severe COVID-19 pneumonia independently of age Int J Mol Sci. 2021;22:6991
65. Group TSC-19 G. . Genomewide association study of severe Covid-19 with respiratory failure N Engl J Med. 2020;383:1522–34 Available from: https://www.nejm.org/doi/100.1056/NEJMoa2020283Last accessed on 2021 Jul 6
66. Shelton JF, Shastri AJ, Ye C, Weldon CH, Filshtein-Sonmez T, Coker D, et al Trans-ancestry analysis reveals genetic and nongenetic associations with COVID-19 susceptibility and severity Nat Genet. 2021;53:801–8
67. Boutin S, Hildebrand D, Boulant S, Kreuter M, Rüter J, Pallerla SR, et al Host factors facilitating SARS-CoV-2 virus infection and replication in the lungs Cell Mol Life Sci. 2021 doi:10.1007/s00018-021-03889-5
68. Narang K, Enninga EA, Gunaratne MD, Ibirogba ER, Trad AT, Elrefaei A, et al SARS-CoV-2 Infection and COVID-19 during pregnancy:A multidisciplinary review Mayo Clin Proc. 2020;95:1750–65
69. Wastnedge EA, Reynolds RM, van Boeckel SR, Stock SJ, Denison FC, Maybin JA, et al Pregnancy and COVID-19 Physiol Rev. 2021;101:303–18
70. Arcavi L, Benowitz NL. Cigarette smoking and infection Arch Intern Med. 2004;164:2206–16
71. Shastri MD, Shukla SD, Chong WC, Kc R, Dua K, Patel RP, et al Smoking and COVID-19:What we know so far Respir Med. 2020;176:106237 doi:10.1016/j.rmed. 2020.106237
72. Benzano D, Ornell F, Schuch JB, Pechansky F, Sordi AO, von Diemen L, et al Clinical vulnerability for severity and mortality by COVID-19 among users of alcohol and other substances Psychiatry Res. 2021;300:113915 doi:10.1016/j.psychres. 2021.113915
73. van Zyl-Smit RN, Richards G, Leone FT. Tobacco smoking and COVID-19 infection Lancet Respir Med. 2020;8:664–5
74. Maggi F, Rosellini A, Spezia PG, Focosi D, Macera L, Lai M, et al Nicotine upregulates ACE2 expression and increases competence for SARS-CoV-2 in human pneumocytes ERJ Open Res. 2021;7 doi:10.1183/23120541.00713-2020
75. Purohit B, Panda AK. Smoking habits correlate with the defense against SARS-CoV-2 infection in the Indian population Hum Cell. 2021;34:1282–4
76. Chick J. Alcohol and COVID-19 Alcohol Alcohol. 2020;55:341–2
77. Saurabh S, Verma MK, Gautam V, Kumar N, Jain V, Goel AD, et al Tobacco, alcohol use and other risk factors for developing symptomatic COVID-19 vs asymptomatic SARS-CoV-2 infection:A case–control study from western Rajasthan, India Trans R Soc Trop Med Hyg. 2021;115:820–31
78. Dubey MJ, Ghosh R, Chatterjee S, Biswas P, Chatterjee S, Dubey S. COVID-19 and addiction Diabetes Metab Syndr. 2020;14:817–23
79. Wang QQ, Kaelber DC, Xu R, Volkow ND. COVID-19 risk and outcomes in patients with substance use disorders:Analyses from electronic health records in the United States Mol Psychiatry. 2021;26:30–9
80. Althobaiti YS, Alzahrani MA, Alsharif NA, Alrobaie NS, Alsaab HO, Uddin MN. The possible relationship between the abuse of tobacco, opioid, or alcohol with COVID-19 Healthcare (Basel). 2020;9:2
Keywords:

ACE-2; androgen; COVID-19; host genetic factors; SARS-CoV-2

© 2021 Journal of Family Medicine and Primary Care | Published by Wolters Kluwer – Medknow