Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy
Abstract
:1. Introduction
2. Materials and Methods
2.1. Structural Variability Data
2.2. Bioinformatics Analysis of Gene Expression, Mirna Interactions, and Pharmacogenomics
3. Results and Discussion
3.1. Protein–Protein Interaction Networks of Sars-Cov-2-Interacting Genes
3.2. Expression of ACE2, BSG, and TMPRSS2 in Single Cells
3.3. Snv and Indel Variants of the Tmprss2 Gene
3.4. Frequency of Protein-Changing Allelic Variants of the Tmprss2 Gene in Populations of North Eurasia
3.5. Regulation of Expression of Tmprss2
3.5.1. Eqtls
3.5.2. Mirnas
3.5.3. Pharmacotranscriptomics of Tmprss2
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Variant Type | Maf > 0.01 | Maf < 0.01 |
---|---|---|
3_prime_UTR_variant | 0 | 22 |
5_prime_UTR_variant | 0 | 5 |
frameshift_variant | 0 | 17 |
inframe_deletion | 0 | 1 |
inframe_insertion | 0 | 2 |
intron_variant | 13 | 409 |
missense_variant | 2 | 332 |
splice_acceptor_variant | 0 | 4 |
splice_donor_variant | 0 | 5 |
splice_region_variant | 0 | 54 |
stop_gained | 0 | 13 |
stop_lost | 0 | 1 |
synonymous_variant | 5 | 140 |
Region | N | Frequency % | Copy Number | Gene Name |
---|---|---|---|---|
Chr21:42857241-42863723 | 164 | 1.2195122 | 1 | TMPRSS2 |
Population | N | rs148125094 | rs143597099 | rs12329760 | rs201093031 |
---|---|---|---|---|---|
Easten Europe | 419 | 0.0012 | 0.0012 | 0.2983 | 0.0000 |
Bashkirs Burzyan | 29 | 0.0000 | 0.0000 | 0.1552 | 0.0000 |
Bashkirs Perm | 15 | 0.0000 | 0.0000 | 0.3000 | 0.0000 |
Bashkirs Salavat | 15 | 0.0000 | 0.0000 | 0.3667 | 0.0000 |
Besermians | 16 | 0.0000 | 0.0000 | 0.1563 | 0.0000 |
Chuvash | 26 | 0.0000 | 0.0000 | 0.3077 | 0.0000 |
Karelians | 29 | 0.0172 | 0.0000 | 0.3966 | 0.0000 |
Komi | 30 | 0.0000 | 0.0000 | 0.3333 | 0.0000 |
Mari | 30 | 0.0000 | 0.0000 | 0.2500 | 0.0000 |
Mordvins Erzya | 16 | 0.0000 | 0.0000 | 0.3125 | 0.0000 |
Mordvins Moksha | 30 | 0.0000 | 0.0000 | 0.3000 | 0.0000 |
Mordvins Shoksha | 14 | 0.0000 | 0.0000 | 0.3214 | 0.0000 |
Russians | 33 | 0.0000 | 0.0000 | 0.3333 | 0.0000 |
Tatars Kazan | 30 | 0.0000 | 0.0000 | 0.3000 | 0.0000 |
Udmurts | 30 | 0.0000 | 0.0000 | 0.3000 | 0.0000 |
Udmurts Balezino | 28 | 0.0000 | 0.0000 | 0.3214 | 0.0000 |
Udmurts Sharkan | 18 | 0.0000 | 0.0000 | 0.2500 | 0.0000 |
Veps | 30 | 0.0000 | 0.0167 | 0.3333 | 0.0000 |
North Caucasus (excl. Dagestan) | 274 | 0.0018 | 0.0000 | 0.1989 | 0.0000 |
Abkhaz | 30 | 0.0167 | 0.0000 | 0.3000 | 0.0000 |
Adyghe | 10 | 0.0000 | 0.0000 | 0.1500 | 0.0000 |
Balkars | 50 | 0.0000 | 0.0000 | 0.1800 | 0.0000 |
Chechens | 27 | 0.0000 | 0.0000 | 0.2222 | 0.0000 |
Cherkess | 30 | 0.0000 | 0.0000 | 0.2167 | 0.0000 |
Ingush | 30 | 0.0000 | 0.0000 | 0.1500 | 0.0000 |
Karachays | 22 | 0.0000 | 0.0000 | 0.2045 | 0.0000 |
Mingrelians | 28 | 0.0000 | 0.0000 | 0.1607 | 0.0000 |
North Ossetians | 30 | 0.0000 | 0.0000 | 0.1833 | 0.0000 |
South Ossetians | 17 | 0.0000 | 0.0000 | 0.2059 | 0.0000 |
Dagestan | 538 | 0.0000 | 0.0000 | 0.2309 | 0.0000 |
Aghuls | 24 | 0.0000 | 0.0000 | 0.2292 | 0.0000 |
Akhvakhs | 24 | 0.0000 | 0.0000 | 0.3125 | 0.0000 |
Andis | 17 | 0.0000 | 0.0000 | 0.2353 | 0.0000 |
Archins | 24 | 0.0000 | 0.0000 | 0.3333 | 0.0000 |
Avars | 24 | 0.0000 | 0.0000 | 0.1875 | 0.0000 |
Bagulals | 23 | 0.0000 | 0.0000 | 0.3261 | 0.0000 |
Bezhtins | 22 | 0.0000 | 0.0000 | 0.2273 | 0.0000 |
Botlikhs | 16 | 0.0000 | 0.0000 | 0.1250 | 0.0000 |
Chamalals | 24 | 0.0000 | 0.0000 | 0.2083 | 0.0000 |
Dargins | 28 | 0.0000 | 0.0000 | 0.2321 | 0.0000 |
Ginukhs | 19 | 0.0000 | 0.0000 | 0.0000 | 0.0000 |
Gunzibians | 17 | 0.0000 | 0.0000 | 0.0294 | 0.0000 |
Karanogais | 19 | 0.0000 | 0.0000 | 0.2368 | 0.0000 |
Karatins | 24 | 0.0000 | 0.0000 | 0.3333 | 0.0000 |
Khvarshins | 15 | 0.0000 | 0.0000 | 0.1000 | 0.0000 |
Kumyks | 37 | 0.0000 | 0.0000 | 0.2703 | 0.0000 |
Laks | 24 | 0.0000 | 0.0000 | 0.3125 | 0.0000 |
Lezgins | 28 | 0.0000 | 0.0000 | 0.2037 | 0.0000 |
Nogais | 20 | 0.0000 | 0.0000 | 0.2750 | 0.0000 |
Rutuls | 22 | 0.0000 | 0.0000 | 0.1818 | 0.0000 |
Tabasarans | 21 | 0.0000 | 0.0000 | 0.2619 | 0.0000 |
Tindins | 18 | 0.0000 | 0.0000 | 0.2222 | 0.0000 |
Tsakhurs | 24 | 0.0000 | 0.0000 | 0.2292 | 0.0000 |
Tsez | 24 | 0.0000 | 0.0000 | 0.2708 | 0.0000 |
Central Asia | 128 | 0.0000 | 0.0000 | 0.3565 | 0.0000 |
Dungans | 23 | 0.0000 | 0.0000 | 0.4130 | 0.0000 |
Kazakh Junior Horde | 29 | 0.0000 | 0.0000 | 0.2931 | 0.0000 |
Kazakh Great Horde | 26 | 0.0000 | 0.0000 | 0.4423 | 0.0000 |
Kyrgyz | 28 | 0.0000 | 0.0000 | 0.3704 | 0.0000 |
Uzbeks | 22 | 0.0000 | 0.0000 | 0.2619 | 0.0000 |
Siberia | 404 | 0.0000 | 0.0000 | 0.3540 | 0.0013 |
Altaians Maymalar | 24 | 0.0000 | 0.0000 | 0.3958 | 0.0000 |
Altaians Kizhi | 25 | 0.0000 | 0.0000 | 0.3600 | 0.0000 |
Buryats Aginskoe | 23 | 0.0000 | 0.0000 | 0.4130 | 0.0000 |
Buryats Kurumkan | 28 | 0.0000 | 0.0000 | 0.3929 | 0.0000 |
Chulyms | 22 | 0.0000 | 0.0000 | 0.3636 | 0.0000 |
Evenks Yakutia | 28 | 0.0000 | 0.0000 | 0.2857 | 0.0000 |
Evenks Zabaykalsky Krai | 25 | 0.0000 | 0.0000 | 0.3200 | 0.0000 |
Kalmyks | 29 | 0.0000 | 0.0000 | 0.3103 | 0.0000 |
Kets | 15 | 0.0000 | 0.0000 | 0.3333 | 0.0000 |
Khakas Kachins | 26 | 0.0000 | 0.0000 | 0.4423 | 0.0000 |
Khakas Sagays | 29 | 0.0000 | 0.0000 | 0.6379 | 0.0000 |
Khanty Kazym | 30 | 0.0000 | 0.0000 | 0.1333 | 0.0000 |
Khanty Russkinskie | 26 | 0.0000 | 0.0000 | 0.2500 | 0.0000 |
Tomsk Tatas | 20 | 0.0000 | 0.0000 | 0.3250 | 0.0000 |
Tuvans | 28 | 0.0000 | 0.0000 | 0.3036 | 0.0185 |
Yakuts | 26 | 0.0000 | 0.0000 | 0.4038 | 0.0000 |
North East Asia | 73 | 0.0000 | 0.0000 | 0.2671 | 0.0284 |
Chukchi | 25 | 0.0000 | 0.0000 | 0.3000 | 0.0000 |
Koryaks | 20 | 0.0000 | 0.0000 | 0.3500 | 0.0000 |
Nivkhs | 13 | 0.0000 | 0.0000 | 0.1538 | 0.0769 |
Udege | 15 | 0.0000 | 0.0000 | 0.2000 | 0.0714 |
rs148125094 | rs12329760 | rs201093031 | ||||
---|---|---|---|---|---|---|
Population | N | Frequency | N | Frequency | N | Frequency |
European | 77147 | 0.0014 | 76846 | 0.2549 | 77117 | 0.0000 |
Finnish | 12560 | 0.0016 | 12544 | 0.3725 | 12561 | 0.0000 |
Estonian | 2416 | 0.0060 | 2394 | 0.3074 | 2406 | 0.0000 |
Southern European | 5805 | 0.0013 | 5778 | 0.1748 | 5802 | 0.0000 |
North-western European | 25402 | 0.0012 | 25348 | 0.2212 | 25391 | 0.0000 |
Other non-Finnish European | 16562 | 0.0012 | 16439 | 0.2286 | 16557 | 0.0000 |
Swedish | 13067 | 0.0010 | 13013 | 0.2722 | 13066 | 0.0000 |
Bulgarian | 1335 | 0.0007 | 1330 | 0.1970 | 1334 | 0.0000 |
South Asian | 15308 | 0.0007 | 15298 | 0.2477 | 15303 | 0.0000 |
Latino | 17718 | 0.0003 | 17705 | 0.1533 | 17697 | 0.0000 |
African | 12480 | 0.0002 | 12448 | 0.2918 | 12480 | 0.0000 |
Ashkenazi Jewish | 5185 | 0.0000 | 5163 | 0.1352 | 5179 | 0.0000 |
East Asian | 9196 | 0.0000 | 9188 | 0.3810 | 9193 | 0.0024 |
Japanese | 76 | 0.0000 | 76 | 0.4013 | 76 | 0.0000 |
Korean | 1909 | 0.0000 | 1909 | 0.3675 | 1909 | 0.0018 |
Other East Asian | 7211 | 0.0000 | 7203 | 0.3844 | 7208 | 0.0026 |
N SNP | Average Maf | Average Slope | |
---|---|---|---|
down | 60 | 0.3722896 | −0.09795966 |
up | 76 | 0.4537386 | 0.09709619 |
miRNA | Cell Ontology |
---|---|
hsa-miR-4476 | B cell |
hsa-miR-5187-3p | myeloid leukocyte |
hsa-miR-5187-3p | hematopoietic cell |
hsa-miR-7849-3p | endothelial cell |
hsa-miR-7849-3p | blood vessel endothelial cell |
hsa-miR-7849-3p | endothelial cell of vascular tree |
hsa-miR-7849-3p | neutrophil |
Drug | Drug Groups | Change | References |
---|---|---|---|
Acetaminophen | Approved | downregulated | 21420995 |
Acyline | Investigational | downregulated | 17510436 |
Stanolone | Illicit Investigational | downregulated | 12711008 |
Stanolone | Illicit Investigational | upregulated | 20601956, 23708653 |
Estradiol | Approved Investigational Vet Approved | downregulated | 24758408 |
Estradiol | Approved Investigational Vet Approved | upregulated | 19619570 |
Curcumin | Approved Experimental Investigational | downregulated | 18719366, 22258452 |
Cyclosporine | Approved Investigational Vet Approved | downregulated | 20106945 |
Calcitriol | Approved Nutraceutical | upregulated | 21592394, 26485663 |
Entinostat | Investigational | upregulated | 26272509 |
Ethinylestradiol | Approved | downregulated | 18936297 |
Genistein | Investigational | downregulated | 15378649, 26865667 |
Metribolone | Experimental | downregulated | 12711008 |
Metribolone | Experimental | upregulated | 17010675, 21440447 |
Resveratrol | Investigational | downregulated | 18586690 |
Selenium | Approved Investigational Vet Approved | upregulated | 19244175 |
Testosterone | Approved Investigational | upregulated | 21592394 |
Tretinoin | Approved Investigational Nutraceutical | upregulated | 23830798 |
Valproic acid | Approved Investigational | upregulated | 23179753, 24383497, 26272509 |
Zoledronic acid | Approved | upregulated | 24714768 |
Drug | Drug Groups | Change | References |
---|---|---|---|
Amiodarone | Approved Investigational | upregulated | 19774075 |
Arsenic trioxide | Approved Investigational | downregulated | 23232515 |
Estradiol | Approved Investigational Vet Approved | upregulated | 19167446 |
Methotrexate | Approved | downregulated | 25339124 |
Quercetin | Experimental Investigational | upregulated | 21632981 |
Isotretinoin | Approved | downregulated | 20436886 |
Silicon dioxide | Approved | downregulated | 25895662 |
Valproic acid | Approved Investigational | downregulated | 23179753 |
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Zarubin, A.; Stepanov, V.; Markov, A.; Kolesnikov, N.; Marusin, A.; Khitrinskaya, I.; Swarovskaya, M.; Litvinov, S.; Ekomasova, N.; Dzhaubermezov, M.; et al. Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy. Genes 2021, 12, 19. https://doi.org/10.3390/genes12010019
Zarubin A, Stepanov V, Markov A, Kolesnikov N, Marusin A, Khitrinskaya I, Swarovskaya M, Litvinov S, Ekomasova N, Dzhaubermezov M, et al. Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy. Genes. 2021; 12(1):19. https://doi.org/10.3390/genes12010019
Chicago/Turabian StyleZarubin, Aleksei, Vadim Stepanov, Anton Markov, Nikita Kolesnikov, Andrey Marusin, Irina Khitrinskaya, Maria Swarovskaya, Sergey Litvinov, Natalia Ekomasova, Murat Dzhaubermezov, and et al. 2021. "Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy" Genes 12, no. 1: 19. https://doi.org/10.3390/genes12010019
APA StyleZarubin, A., Stepanov, V., Markov, A., Kolesnikov, N., Marusin, A., Khitrinskaya, I., Swarovskaya, M., Litvinov, S., Ekomasova, N., Dzhaubermezov, M., Maksimova, N., Sukhomyasova, A., Shtygasheva, O., Khusnutdinova, E., Radzhabov, M., & Kharkov, V. (2021). Structural Variability, Expression Profile, and Pharmacogenetic Properties of TMPRSS2 Gene as a Potential Target for COVID-19 Therapy. Genes, 12(1), 19. https://doi.org/10.3390/genes12010019