Thr92Ala-DIO2 heterozygosity is associated with skeletal muscle mass and myosteatosis in patients with COVID-19.

INTRODUCTION: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and COVID-19. OBJECTIVE: To identify a potential association between Thr92Ala-DIO2 polymorphism and body composition (appendicular muscle mass, myosteatosis, and fat distribution) and to determine whether they reflect the severity or mortality associated with the disease. METHODS: In this prospective cohort study (June-August 2020), 181 patients hospitalized with moderate-to-severe COVID-19 underwent a non-contrast-enhanced computed tomography (CT) of the thorax to assess body composition, laboratory tests, and genotyping for the Thr92Ala-DIO2 polymorphism. RESULTS: 181 consecutive patients were stratified into three subgroups according to the genotype: Thr/Thr (n = 64), Thr/Ala (n = 96), and Ala/Ala (n = 21). The prevalence of low muscle area (MA) (< 92 cm²) was 52.5 %. Low MA was less frequent in Ala/Thr patients (44.8%) than in Thr/Thr (60.9%) or Ala/Ala patients (61.9%) (p = 0.027). Multivariate logistic regression analysis confirmed that the Thr/Ala allele was associated with a reduced risk of low MA (41% to 69%) and myosteatosis (62% to 72%) compared with Thr/Thr + Ala/Ala (overdominant model). Kaplan-Meier curves showed that patients with low muscle mass and homozygosity had lower survival rates than the other groups. Notably, the heterozygotes with MA ≥ 92 cm² exhibited the best survival rate. CONCLUSION: Thr92Ala-DIO2 heterozygosity is associated with increased skeletal MA and less myosteatosis in patients with COVID-19. The protective effect of Thr92Ala-DIO2 heterozygosity on COVID-19 mortality is restricted to patients with reduced MA.

MTOR gene variants are associated with severe COVID-19 outcomes: A multicenter study.

BACKGROUND: The worst outcomes linked to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been attributed to the cytokine storm, which contributes significantly to the immunopathogenesis of the disease. The mammalian target of rapamycin (mTOR) pathway is essential for orchestrating innate immune cell defense including cytokine production and is dysregulated in severe Coronavirus Disease 2019 (COVID-19) individuals. The individual genetic background might play a role in the exacerbated immune response. OBJECTIVE: In this study, we aimed to investigate the association between MTOR genetic variants and COVID-19 outcomes. METHODS: This study enrolled groups of individuals with severe (n = 285) and mild (n = 207) COVID-19 from Brazilian states. The MTOR variants, rs1057079 and rs2536, were genotyped. A logistic regression analysis and Kaplan-Meier survival curves were performed. We applied a genotyping risk score to estimate the cumulative contribution of the risk alleles. Tumor necrosis factor (TNF) and interleukin-6 (IL-6) plasma levels were also measured. RESULTS: The T allele of the MTOR rs1057079 variant was associated with a higher likelihood of developing the most severe form of COVID-19. In addition, higher levels of IL-6 and COVID-19 death was linked to the T allele of the rs2536 variant. These variants exhibited a cumulative risk when inherited collectively. CONCLUSIONS: These results show a potential pathogenetic role of MTOR gene variants and may be useful for predicting severe outcomes following COVID-19 infection, resulting in a more effective allocation of health resources.

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

CONTEXT: The type 2 deiodinase and its Thr92Ala-DIO2 polymorphism have been linked to clinical outcomes in acute lung injury and pulmonary fibrosis. OBJECTIVE: Our objectives were to evaluate were cumulative mortality during admission according to Thr92Ala-DIO2 polymorphism. METHODS: Here we conducted an observational, longitudinal, and prospective cohort study to investigate a possible association between the Thr92Ala-DIO2 polymorphism and intrahospital 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: In total, 220 consecutive patients (median age 62; 48-74 years) were stratified into 3 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%) than in Thr/Thr patients (21.7%) or Ala/Ala patients (23%). The heterozygous genotype (Thr/Ala) was associated with a 47% reduced risk of intrahospital mortality whereas univariate and multivariate logistic regression adjusted for multiple covariates revealed a reduction that ranged from 51% to 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 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.