Campi I.

Persani L.

English

AIR Universita degli studi di Milano

The Journal of Clinical Endocrinology & Metabolism, 2022, XX, 1–2https://doi.org/10.1210/clinem/dgac152Advance access publication 24 March 2022CommentaryVariation in Thyroid Hormone Metabolism May Affect COVID-19 OutcomeLuca Persani,1,2,  and Irene Campi2,1Department of Medical Biotechnology and Experimental Medicine, University of Milan, 20100 Milan, Italy and 2Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, 20149 Milan, ItalyCorrespondence: Luca Persani, MD, PhD, Department of Endocrine and Metabolic Diseases, San Luca Hospital, Istituto Auxologico Italiano IRCCS, Piazzale Brescia 20, 20149 Milan, Italy. Email: Luca.persani@unimi.it.Key Words: thyroid, type II deiodinase, polymorphism, COVID-19Abbreviations: ACE, angiotensin-converting enzyme; T3, 3,5,3′-triiodothyronine.The study by de Lima Beltrão and colleagues (1) indicates a protective role by the heterozygous state of the DIO2 poly-morphic variant (Thr92Ala; rs225014) on the outcome of COVID-19 disease. Heterozygous patients would be pro-tected 47% by intrahospital mortality. Logistic regression analysis confirmed the association of the Thr/Ala genotype with reduced mortality when compared to Thr/Thr, even after correcting for 14 comorbidities and other covariates. The protective role of the Thr92Ala heterozygosity was then con-firmed in a meta-analysis including 21 studies on thousands of cases with variable disease conditions and controls. In 5 of these studies, the heterozygous DIO2 genotype would pro-vide significant protection against disease severity.Though lacking a conclusive explanation for their findings, the authors suggest the protective role played by the Thr92Ala-DIO2 heterozygosity may be due to overdominance, that is, a heterozygous advantage in which heterozygous indi-viduals have better fitness than homozygous individuals. Overdominance is a well-known selection mechanism by which an allele is actively maintained in the population longer than expected from genetic drift alone (2). By this mech-anism, host-pathogen interactions have shaped genetic vari-ants in populations (3). Indeed, HBB variants responsible for sickle anemia and thalassemia confer protection against mal-aria, variants in the CFTR gene responsible for cystic fibrosis protect against cholera toxin, variants of HEXA involved in Tay-Sachs disease are associated with resistance to tubercu-losis, while single-nucleotide variations in human NPC1 (the gene involved in Niemann-Pick disease type C1) influence the entry into cells of filoviruses, like Ebola and Marburg. Thus, the possible protective effect of the DIO2 genotype against COVID-19 and other diseases is also intriguing in light of other data suggesting a role for DIO2 genotype in human evolution (4).The DIO2 variant rs225014 causes the nonconservative missense replacement of a threonine residue with an alanine at the codon 92 of in exon 2 of the DIO2 gene (Ala92-D2). This change has a high frequency in the general population as the frequency of the T/T (Thr/Thr), C/T (Ala/Thr), C/C (Ala/Ala) genotype is found in 30%, 48% and 22% of samples (see the 1000 Genomes Project).The effect of this variant on the catalytic function of D2 is debated as in vitro studies on HEK-293 and COS cells failed to demonstrate a reduced activity, but the Ala92-D2 variant was less efficient than Thr92-D2 in converting thyroxine into 3,5,3′-triiodothyronine (T3) in an in vivo model of myoblast and pituitary cells from Dio2-null mice (5), indicating the Ala92-D2 is associated with reduced production of bioactive T3 at local sites. Moreover, the residue 92 is located within a 6 amino-acid stretch involved in D2 clearance by ubiqui-tination and electron microscopy studies have identified the ectopic localization of the Ala92-D2 in the Golgi along with altered expression of Golgi markers and endoplasmic re-ticulum stress (6).The whole of these data suggest tissue availability of T3 might play a role in the outcome of COVID-19 and other several other organ-specific conditions. A  recent cross-sectional study (7) found an association between hypothyroidism and reduced SARS-CoV-2 infectivity in a large public data set (UC CORDS). A  total of 11 375 hypothyroid patients were tested for COVID-19, with a statistically significantly lower infection rate compared to those without hypothyroidism in male and female partici-pants. One possible explanation relies on the crosstalk be-tween thyroid hormones and the renin-angiotensin system. Angiotensin-converting enzyme type 2 (ACE2) is a key molecule for SARS-CoV-2 infection mediating the virus entry into the cells, and its activity was shown to be influ-enced by thyroid dysfunction both at the circulating and tissue levels (8). In experimental hypothyroidism, the car-diac ACE2 expression was found to be reduced. Similarly, reduced serum and liver ACE concentrations were reported in neonatal and adult rats with hypothyroidism, whereas hyperthyroid rats and patients showed an increase in serum ACE concentrations directly correlated with thyroid hormone levels. Pulmonary ACE activity in rats is low at Received: 7 March 2022. Editorial Decision: 8 March 2022. Corrected and Typeset: 26 March 2022© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.comDownloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac152/6553344 by guest on 22 April 20222 The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. XX, No. XXbirth and increases with age; this increase is larger in eu-thyroid rats than in congenitally hypothyroid animals (8). Nevertheless, the Ala92-D2 homozygosity was not as pro-tective as the Thr92Ala heterozygous state in this study, thus indicating other effects beyond the D2 enzymatic ac-tivity and the tissue T3 availability. The authors allude to a possible effect of Thr92Ala variation on endoplasmic re-ticulum stress, and the latter would play a relevant role in the inflammatory response and lung inflammatory dis-eases. In previous studies, the authors documented the as-sociation of the heterozygous Ala/Thr-D2 genotype with inflammatory markers, such as CXCR4 and SLC44A that are today known to also play a relevant role in the most severe manifestations of COVID-19 disease (1, 6).The limited sample of COVID-19 patients and the exclu-sive enrollment of intensive care unit patients with severe manifestations are the main weaknesses of this study (1). But the whole of these findings and considerations, including the broad effect on the outcome of several disease conditions, in-dicates the need for a) additional DIO2 genotyping studies on larger cohorts of patients with variable clinical manifestations to confirm the protective role of this DIO2 genotype (and the consequent variation in thyroid hormone metabolism) on COVID-19 outcome; and b) experimental approaches to understand the biological mechanism underlying the plaus-ible protective role of the DIO2 heterozygosity against severe disease outcomes.DisclosuresThe authors have nothing to disclose.Data AvailabilityData sharing is not applicable to this article because no data sets were generated or analyzed during the present study.References 1. de  Lima  Beltrão  FE, de  Almeida  Beltrão  DC, Carvalhal  G, et  al. Heterozygote advantage of the type II deiodinase Thr92Ala polymorphism on intrahospital mortality of COVID-19. J Clin Endocrinol Metab. Published online February 9, 2022. doi:10.1210/clinem/dgac075 2. DeGiorgio  M, Lohmueller  KE, Nielsen  RA. A model-based ap-proach for identifying signatures of ancient balancing selection in genetic data. PLoS Genet. 2014;10(8):e1004561. 3. Abramovs  N, Brass  A, Tassabehji  M. Hardy-Weinberg equilib-rium in the large scale genomic sequencing era. Front Genet. 2020;11:210. 4. Ricci  C, Kakularam  KR, Marzocchi  C, et  al. Thr92Ala poly-morphism in the type 2 deiodinase gene: an evolutionary perspec-tive. J Endocrinol Invest. 2020;43(12):1749-1757. 5. Castagna MG, Dentice M, Cantara S, et al. DIO2 Thr92Ala reduces deiodinase-2 activity and serum-T3 levels in thyroid-deficient pa-tients. J Clin Endocrinol Metab. 2017;102(5):1623-1630. 6. Jo  S, Fonseca  TL, Bocco  BMLC, et  al. Type 2 deiodinase poly-morphism causes ER stress and hypothyroidism in the brain. J Clin Invest. 2019;129(1):230-245. 7. Nguyen  C, Yale  K, Ghigi  A, et  al. SARS-CoV-2 infection in pa-tients with thyroid disease: a cross-sectional study. Ann Thyroid. 2022;6:7. 8. Vargas  F, Rodríguez-Gómez  I, Vargas-Tendero  P, Jimenez  E, Montiel M. The renin-angiotensin system in thyroid disorders and its role in cardiovascular and renal manifestations. J Endocrinol. 2012;213(1):25-36.Downloaded from https://academic.oup.com/jcem/advance-article/doi/10.1210/clinem/dgac152/6553344 by guest on 22 April 2022

Variation in Thyroid Hormone Metabolism May Affect COVID-19 Outcome

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Variation in Thyroid Hormone Metabolism May Affect COVID-19 Outcome

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