OBJECTIVES: COVID-19 caused a global pandemic with millions of deaths. Fat mass and obesity-associated gene (FTO) (alias m6A RNA demethylase) and its functional rs17817449 polymorphism are candidates to influence COVID-19-associated mortality since methylation status of viral nucleic acids is an important factor influencing viral viability. METHODS: We tested a population-based cohort of 5233 subjects (aged 63-87 years in 2020) where 70 persons died from COVID-19 and 394 from other causes during the pandemic period. RESULTS: The frequency of GG homozygotes was higher among those who died from COVID-19 (34%) than among survivors (19%) or deaths from other causes (20%), P <0.005. After multiple adjustments, GG homozygotes had a higher risk of death from COVID-19 with odds ratio = 2.01 (95% confidence interval; 1.19-3.41, P <0.01) compared with carriers of at least one T allele. The FTO polymorphism was not associated with mortality from other causes. CONCLUSIONS: Our results suggest that FTO variability is a significant predictor of COVID-19-associated mortality in Caucasians.

Institute of Clinical and Experimental Medicine Experimental Medicine Centre Prague Czech Republic; Charles University 3rd Department of Internal Medicine 1st Faculty of Medicine Prague Czech Republic

National Institute of Public Health Prague Czech Republic

University College London Institute of Epidemiology and Health Care London United Kingdom; Masaryk University RECETOX Faculty of Science Brno Czech Republic

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Tuček M, Vaněček V. COVID-19 in the Czech Republic 2020 and 2021: comparative analysis of probable work-related transmission of the coronavirus SARS-CoV-2. Cent Eur J Public Health. 2022;30:201–204. doi: 10.21101/cejph.a7610. PubMed DOI

Chams N, Chams S, Badran R, Shams A, Araji A, Raad M, et al. COVID-19: a multidisciplinary review. Front Public Health. 2020;8:383. doi: 10.3389/fpubh.2020.00383. PubMed DOI PMC

Dessie ZG, Zewotir T. Mortality-related risk factors of COVID-19: a systematic review and meta-analysis of 42 studies and 423,117 patients. BMC Infect Dis. 2021;21:855. doi: 10.1186/s12879-021-06536-3. PubMed DOI PMC

Hubacek JA. Effects of selected inherited factors on susceptibility to SARS-CoV-2 infection and COVID-19 progression. Physiol Res. 2021;70:S125–S134. doi: 10.33549/physiolres.934730. PubMed DOI PMC

Gupta K, Kaur G, Pathak T, Banerjee I. Systematic review and meta-analysis of human genetic variants contributing to COVID-19 susceptibility and severity. Gene. 2022;844 doi: 10.1016/j.gene.2022.146790. PubMed DOI PMC

Delanghe JR, Speeckaert MM. host. Host polymorphisms and COVID-19 infection. Adv Clin Chem. 2022;107:41–77. doi: 10.1016/bs.acc.2021.07.002. PubMed DOI PMC

Zhang Q, Bastard P, Human Genetic Effort COVID, Cobat A, Casanova JL. Human genetic and immunological determinants of critical COVID-19 pneumonia. Nature. 2022;603:587–598. doi: 10.1038/s41586-022-04447-0. PubMed DOI PMC

Dina C, Meyre D, Gallina S, Durand E, Körner A, Jacobson P, et al. Variation in FTO contributes to childhood obesity and severe adult obesity. Nat Genet. 2007;39:724–726. doi: 10.1038/ng2048. PubMed DOI

Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007;316:889–894. doi: 10.1126/science.1141634. PubMed DOI PMC

Scott LJ, Mohlke KL, Bonnycastle LL, Willer CJ, Li Y, Duren WL, et al. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007;316:1341–1345. doi: 10.1126/science.1142382. PubMed DOI PMC

Hubacek JA, Viklicky O, Dlouha D, Bloudickova S, Kubinova R, Peasey A, et al. The FTO gene polymorphism is associated with end-stage renal disease: two large independent case-control studies in a general population. Nephrol Dial Transplant. 2012;27:1030–1035. doi: 10.1093/ndt/gfr418. PubMed DOI PMC

Lappalainen T, Kolehmainen M, Schwab US, Tolppanen AM, Stančáková A, Lindström J, et al. Association of the FTO gene variant (rs9939609) with cardiovascular disease in men with abnormal glucose metabolism–the Finnish Diabetes Prevention Study. Nutr Metab Cardiovasc Dis. 2011;21:691–698. doi: 10.1016/j.numecd.2010.01.006. PubMed DOI

Lan N, Lu Y, Zhang Y, Pu S, Xi H, Nie X, et al. FTO - A common genetic basis for obesity and cancer. Front Genet. 2020;11 doi: 10.3389/fgene.2020.559138. PubMed DOI PMC

Usategui-Martín R, Pérez-Castrillón JL, Briongos-Figuero L, Abadía-Otero J, Lara-Hernandez F, García-Sorribes S, et al. Genetic variants in obesity-related genes and the risk of osteoporotic fracture. The Hortega follow-up study. Front Biosci (Landmark Ed) 2022;27:32. doi: 10.31083/j.fbl2701032. PubMed DOI

Gerken T, Girard CA, Tung Y-CL, Webby CJ, Saudek V, Hewitson KS, et al. The obesity-associated FTO gene encodes a 2-oxoglutarate-dependent nucleic acid demethylase. Science. 2007;318:1469–1472. doi: 10.1126/science.1151710. PubMed DOI PMC

Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7:885–887. doi: 10.1038/nchembio.687. Erratum in: Nat Chem Biol 2012;8:1008. PubMed DOI PMC

Zannella C, Rinaldi L, Boccia G, Chianese A, Sasso FC, De Caro F, et al. Regulation of m6A methylation as a new therapeutic option against COVID-19. Pharmaceuticals (Basel) 2021;14:1135. doi: 10.3390/ph14111135. PubMed DOI PMC

Moon JS, Lee W, Cho YH, Kim Y, Kim GW. The significance of N6-methyladenosine RNA methylation in regulating the hepatitis B virus life cycle. J Microbiol Biotechnol. 2024;34:233–239. doi: 10.4014/jmb.2309.09013. PubMed DOI PMC

Horlacher M, Oleshko S, Hu Y, Ghanbari M, Cantini G, Schinke P, et al. A computational map of the human-SARS-CoV-2 protein-RNA interactome predicted at single-nucleotide resolution. NAR Genom Bioinform. 2023;5:lqad010. doi: 10.1093/nargab/lqad010. PubMed DOI PMC

Feng Y, Wang F, Pan H, Qiu S, Lü J, Wu L, et al. Obesity-associated gene FTO rs9939609 polymorphism in relation to the risk of tuberculosis. BMC Infect Dis. 2014;14:592. doi: 10.1186/s12879-014-0592-2. PubMed DOI PMC

Peasey A, Bobak M, Kubinova R, Malyutina S, Pajak A, Tamosiunas A, et al. Determinants of cardiovascular disease and other non-communicable diseases in Central and Eastern Europe: rationale and design of the HAPIEE study. BMC Public Health. 2006;6:255. doi: 10.1186/1471-2458-6-255. PubMed DOI PMC

Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215. doi: 10.1093/nar/16.3.1215. PubMed DOI PMC

Hubacek JA, Bohuslavova R, Kuthanova L, Kubinova R, Peasey A, Pikhart H, et al. The FTO gene and obesity in a large Eastern European population sample: the HAPIEE study. Obesity (Silver Spring) 2008;16:2764–2766. doi: 10.1038/oby.2008.421. PubMed DOI

Hubáček JA, Pikhart H, Peasey A, Kubínová R, Bobák M. Nobody is perfect: comparison of the accuracy of PCR-RFLP and KASP™ method for genotyping. ADH1B and FTO polymorphisms as examples. Folia Biol (Praha) 2015;61:156–160. doi: 10.14712/fb2015061040156. PubMed DOI

Molinie B, Wang J, Lim KS, Hillebrand R, Lu ZX, Van Wittenberghe N, et al. m(6)A-LAIC-seq reveals the census and complexity of the m(6)A epitranscriptome. Nat Methods. 2016;13:692–698. doi: 10.1038/nmeth.3898. PubMed DOI PMC

Chen Y, Wang W, Zhang W, He M, Li Y, Qu G, et al. Emerging roles of biological m6A proteins in regulating virus infection: a review. Int J Biol Macromol. 2023;253 doi: 10.1016/j.ijbiomac.2023.126934. PubMed DOI

Zhou Y, Kong Y, Fan W, Tao T, Xiao Q, Li N, et al. Principles of RNA methylation and their implications for biology and medicine. Biomed Pharmacother. 2020;131 doi: 10.1016/j.biopha.2020.110731. PubMed DOI

Liu J, Xu YP, Li K, Ye Q, Zhou HY, Sun H, et al. The m6A methylome of SARS-CoV-2 in host cells. Cell Res. 2021;31:404–414. doi: 10.1038/s41422-020-00465-7. PubMed DOI PMC

Zhang X, Hao H, Ma L, Zhang Y, Hu X, Chen Z, et al. Methyltransferase-like 3 modulates severe acute respiratory syndrome coronavirus-2 RNA N6-methyladenosine modification and replication. mBio. 2021;12 doi: 10.1128/mBio.01067-21. PubMed DOI PMC

Doaei S, Kalantari N, Keshavarz Mohammadi N, Izadi P, Gholamalizadeh M, Eini-Zinab H, et al. The role of FTO genotype in the association between FTO gene expression and anthropometric measures in obese and overweight adolescent boys. Am J Mens Health. 2019;13 doi: 10.1177/1557988318808119. PubMed DOI PMC

COVID Mapping the human genetic architecture of COVID-19. Nature. 2021;600:472–477. doi: 10.1038/s41586-021-03767-x. PubMed DOI PMC

Pairo-Castineira E, Rawlik K, Bretherick AD, Qi T, Wu Y, Nassiri I, et al. GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19. Nature 2023;617:764–8. 10.1038/s41586-023-06034-3. Erratum in: Nature 2023;619:E61. 10.1038/s41586-023-06383-z. PubMed DOI PMC

Kousathanas A, Pairo-Castineira E, Rawlik K, Stuckey A, Odhams CA, Walker S, et al. Whole-genome sequencing reveals host factors underlying critical COVID-19. Nature. 2022;607:97–103. doi: 10.1038/s41586-022-04576-6. PubMed DOI PMC

Zimmermann E, Kring SII, Berentzen TL, Holst C, Pers TH, Hansen T, et al. Fatness-associated FTO gene variant increases mortality independent of fatness - in cohorts of Danish men. PLoS One. 2009;4:e4428. doi: 10.1371/journal.pone.0004428. PubMed DOI PMC