Heterozygote Advantage of the Type II Deiodinase Thr92Ala Polymorphism on Intrahospital Mortality of COVID-19

Abstract

Introduction The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and pulmonary fibrosis. Methods Here we conducted an observational, longitudinal, and prospective cohort study to investigate a possible association between the Thr92Ala-DIO2 polymorphism and intra-hospital mortality from COVID-19 in adult patients admitted between June and August 2020. Blood biochemistry, thyroid function tests, length of stay, comorbidities, complications, and severity scores were also studied according to Thr92Ala-DIO2 polymorphism. Results 220 consecutive patients [median age: 62 (48–74) years] were stratified into three subgroups: Thr/Thr (n=79), Thr/Ala (n=119) and Ala/Ala (n=23). While the overall mortality was 17.3%, the lethality was lower in Ala/Thr patients (12.6%) when compared to Thr/Thr patients (21.7%) or Ala/Ala patients (23%). The heterozygous genotype (Thr/Ala) was associated with a 47% reduced risk of intra-hospital mortality whereas the univariate and multivariate logistic regression adjusted for multiple covariates, revealed a reduction that ranged from 51-66%. The association of the Thr/Ala genotype with better clinical outcomes was confirmed in a metanalysis of 5 studies, including the present one. Conclusion Here we provide evidence for a protective role played by the Thr92Ala-DIO2 heterozygosity in patients with COVID-19. This protective effect follows an inheritance model known as overdominance, in which the phenotype of the heterozygote lies outside the phenotypical range of both homozygous.

The Physiological Functions and Polymorphisms of Type II Deiodinase

“…In Graves’ disease (GD) patients, the polymorphic inheritance (CC+CT genotype) of DIO2 rs225014 was associated with less body weight variation after GD treatment than in patients with the wild-type TT genotype, suggesting that DIO2 rs225014 genotyping might have an auxiliary role in predicting the posttreatment weight behavior of GD patients [ 92 ]. de Lima Beltrao et al [ 93 ] investigated a possible association between the Thr92Ala- DIO2 polymorphism and in-hospital mortality from COVID-19 in adult patients admitted between June and August 2020, and the results showed lower lethality in people with the heterozygous genotype (Thr/Ala) than in those with homozygous genotypes (Thr/Thr and Ala/Ala), implying a protective role of Thr92Ala- DIO2 heterozygosity. An Ala92- Dio2 polymorphism-carrying mouse exhibited unfolded protein response and hypothyroidism in distinct brain areas, and the polymorphism-containing mice refrained from physical activity, slept more, and required additional time to memorize objects; however, LT3 treatment enhanced T3 signaling in the brain and improved cognition [ 94 ].…”

COVID-19 and thyroid function: What do we know so far?

“…The protective role of Thr92Ala’s heterozygous advantage was supported in a meta-analysis of 21 studies on thousands of cases with different diseases, such as ischemic stroke, myocardial infarction, and left ventricular hypertrophy. This protection could be explained by the gene Thr92Ala-DIO2 expression association with endoplasmic reticulum stress, inflammation, oxidative stress, apoptosis, and mitochondrial dysfunction that are mechanisms also related to the pathophysiology of COVID-19 ( 101 ).…”

Variation in Thyroid Hormone Metabolism May Affect COVID-19 Outcome

“…The study by de Lima Beltrão and colleagues ( 1 ) indicates a protective role by the heterozygous state of the DIO2 polymorphic variant (Thr92Ala; rs225014) on the outcome of COVID-19 disease. Heterozygous patients would be protected 47% by intrahospital mortality.…”

“…The authors allude to a possible effect of Thr92Ala variation on endoplasmic reticulum stress, and the latter would play a relevant role in the inflammatory response and lung inflammatory diseases. In previous studies, the authors documented the association 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 exclusive 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, indicates 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 plausible protective role of the DIO2 heterozygosity against severe disease outcomes.…”