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Genetic Susceptibility to COVID-19 Linked to Hypothyroidism

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Editor’s note: Find the latest news and guidance about COVID-19 at the Medscape Coronavirus Resource Center.

A new genome-wide association study (GWAS) study of people with COVID-19 or thyroid disease shows that having COVID-19, or even just being genetically predisposed to contracting the virus, increases the risk of developing hypothyroidism in a causal manner. .

“To our knowledge, this is the first Mendelian randomized trial that evaluates the causal relationship between host genetic predisposition to COVID-19 phenotypes and thyroid-related traits,” the authors write.

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Dr. Ching-Lung Cheng

The results indicate that “host genetic predisposition to SARS-CoV-2 infection is associated with an increased risk of overt and subclinical hypothyroidism,” says senior author Ching-Lung Chung, Ph.D., assistant professor of pharmacology and pharmacy at the State University of New York. Hong Kong, Pokfulam, Hong Kong, Medscape Medical News reported.

Conversely, there was no evidence that a genetic predisposition to thyroid-related traits could alter susceptibility to SARS-CoV-2 infection and outcomes, Cheng noted.

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“It may be helpful if clinicians are aware of the possibility that a host’s genetic predisposition to SARS-CoV-2 infection may increase the lifetime risk of overt and subclinical hypothyroidism,” he said.

The study is not without some key caveats, said Thomas H. Brix, MD, from the Department of Endocrinology at Odense University Hospital, Denmark.

Without a control group of patients with other (non-SARS-CoV-2) infections, “the authors cannot assess whether the observed associations between COVID-19 and the thyroid are more or less common than in patients recovering from other viral infections. ,” Brix said in an interview with Medscape Medical News.

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Largest GWAS meta-analyses available

For the study, published July 19 in the journal Thyroid, Cheung, first author Gloria Hoi-Yi Lee and colleagues evaluated data from the largest GWAS meta-analyses available, which included about 1.3 million patients with COVID-19. Of these patients, about 1.5 million were hospitalized with the disease, and about 1 million had severe COVID-19.

The GWAS also included 51,823 patients with hyperthyroidism, 53,423 patients with hypothyroidism, 755,406 patients with autoimmune thyroid disease, 54,288 patients with normal thyroid-stimulating hormone (TSH), 49,269 patients with FT4 within the normal range, and 119,715 patients with TSH. in full range.

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Using two-sample Mendelian randomization to detect genetic correlation, the authors found that genetic predisposition to SARS-CoV-2 infection increases the risk of hypothyroidism with an odds ratio (OR) of 1.335 in the main analysis (P = 2.4 x 10-5).

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Association sensitivity analysis showed similar results with an OR ranging from 1.296 to 1.712. Because hypothyroidism was defined as a TSH level in the reference range, increased risk includes mild subclinical and overt hypothyroidism.

“Assuming that the incidence of hypothyroidism among people without COVID-19 is similar to the pre-COVID-19 European population of 226.2 per 100,000 person-years, the absolute risk of hypothyroidism among people with COVID-19 increases. by 75.8 cases per 100,000 person-years compared to those without infection if the prevalence of SARS-CoV-2 infection doubles,” the authors report.

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The risk relates to a genetic predisposition to COVID-19, so it increases even if patients don’t actually become infected, Cheng noted.

“The current study has shown an association of a host’s genetic predisposition to SARS-CoV-2 infection with hypothyroidism per se, without taking into account the host’s actual response to the infection,” he said. “So there could be a separate risk from genetic liability.”

Evidence was insufficient to suggest an association between a genetic predisposition to more severe forms of COVID-19 or hospitalization with the disease and hypothyroidism.

No link between COVID-19 and hyperthyroidism; No reverse causality

GWAS found no association between genetic predisposition to COVID-19 and hyperthyroidism. However, the authors note that these results should be interpreted with caution, as the statistical power of this association was “the lowest among all other analyzes in the current study due to the small number and the initial data set, which was only of medium size.” .”

No inverse relationship was seen regarding genetic predisposition to hypo- or hyperthyroidism associated with an increased risk of COVID-19 or its severity.

Possible Mechanisms

Key mechanisms that have been proposed to explain the association between COVID-19 and hypothyroidism include the fact that SARS-CoV-2 is known to enter human cells via the angiotensin-converting enzyme 2 (ACE2) receptor, and because ACE2 is highly expressed in the thyroid gland. tissue, the thyroid gland is considered vulnerable to SARS-CoV-2 infection.

The authors note that COVID-19 can also indirectly induce thyroid inflammation by causing abnormal immune-inflammatory responses and a cytokine storm.

It is known that subacute thyroiditis often occurs against the background of a viral infection. As such, it is common among COVID-19 patients, and subclinical or overt hypothyroidism has been reported in various studies following SARS-CoV-2 infection.

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Taken together, the results suggest that “both the genetic predisposition suggested by our study and the actual infection demonstrated by observational studies may increase the risk of hypothyroidism,” Cheng said.

In terms of clinical implications, genotyping individual patients to assess genetic predisposition to SARS-CoV-2 infection may be too costly. Those who become infected should be seen as a high-risk group, Cheng said.

“Physicians should be aware of the possibility of subclinical and overt hypothyroidism in those patients who are susceptible to SARS-CoV-2 infection, such as patients with SARS-CoV-2 infection or even SARS-CoV-2 reinfection.

“Monitoring of thyroid function and timely treatment can be arranged for individuals previously infected with SARS-CoV-2,” he said. “This may reduce the risk of undiagnosed hypothyroidism.”

In further comments, Briks noted that with the understanding that subacute thyroiditis and hypothyroidism are associated with prior viral infection, the association between COVID-19 and hypothyroidism is “not surprising.”

However, the lack of adjustment for various confounding factors is significant.

“This is perhaps the main drawback of the newspaper,” he said. “Thyroid disease and COVID-19 share common risk factors such as smoking, cardiovascular disease, diabetes, chronic lung disease (smoking again) and mental illness,” Brix explained. “The authors did not take into account any of these confounding factors in their analysis.”

Importantly, “in almost all previous studies examining the association between thyroid dysfunction and COVID-19 infection prognosis, unadjusted analyzes showed a significant association that disappeared after adjusting for relevant factors,” he said.

In a population-based case-control cohort study using data from a large cohort of Danish patients with COVID-19, which was published in The Lancet in 2021, Briks and colleagues did not find an association between hypo- or hyperthyroidism and the development of COVID-19. 19.

The authors and Brix have not disclosed any relevant financial relationship.

Thyroid. Published July 19, 2022 Full text

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