Genetic Susceptibility to COVID-19 Linked to Hypothyroidism

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A novel study of genome-wide association studies (GWASs) of people with COVID-19 or thyroid disorders shows that having COVID-19, or even just a genetic susceptibility for infection with the virus, increases the risk of developing hypothyroidism in a causative manner.

“To our knowledge, this is the first Mendelian randomization study evaluating the causal relationship between host genetic liability to COVID-19 phenotypes and thyroid-related traits,” the authors write.

Dr Ching-Lung Cheung

The results show that “host genetic susceptibility to SARS-CoV-2 infection is associated with increased risk of overt and subclinical hypothyroidism,” senior author Ching-Lung Cheung, PhD, an associate professor in the Department of Pharmacology and Pharmacy, the University of Hong Kong, Pokfulam, Hong Kong, told Medscape Medical News.

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

“It may be beneficial if clinicians are aware of the possibility that host genetic liability to SARS-CoV-2 infection may increase the lifelong risk of overt and subclinical hypothyroidism,” he said.

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

Without a control group of patients with other (non-SARS-CoV-2) infections, “the authors are not able to evaluate whether the observed associations between COVID-19 and the thyroid are more or less common than patients recovering from other virus infections,” Brix told Medscape Medical News.

Largest Available GWAS Meta-Analyses

For the study, published July 19 in Thyroid, Cheung, first author Gloria Hoi-Yee Li, and colleagues evaluated data from the largest available meta-analyses of GWASs, which included about 1.3 million patients with COVID-19. Of those patients, about 1.5 million were hospitalized with the illness, and about 1 million had severe COVID-19.

GWASs also included 51,823 patients with hyperthyroidism, 53,423 patients with hypothyroidism, 755,406 patients with autoimmune thyroid disease, 54,288 whose thyroid stimulating hormone (TSH) level was in the normal reference range, 49,269 patients whose FT4 was in the reference range, and 119,715 with TSH in the full range.

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

Sensitivity analyses of the association showed similar results, with ORs ranging from 1.296 to 1.712. Because hypothyroidism was defined as TSH levels in the reference range, the increased risk includes mild subclinical and overt hypothyroidism.

“Assuming the incidence rate of hypothyroidism among people without COVID-19 is similar to the rate in the European population prior to the COVID-19 pandemic of 226.2 per 100,000 person-years, the absolute risk of hypothyroidism among those with COVID-19 is increased by 75.8 incident cases per 100,000 person-years, compared with those without infection, if the prevalence of SARS-CoV-2 infection is doubled,” the authors report.

The risk applies to genetic susceptibility to COVID-19, so it is increased even if patients do not actually become infected, Cheung noted.

“The current study showed the association of host genetic liability to SARS-CoV-2 infection with hypothyroidism per se, without accounting for the actual host response to the infection,” he said. “Thus, there could be a separate risk from genetic liability.”

The evidence was insufficient to suggest a link between the genetic susceptibility to more severe COVID-19 or being hospitalized with the disease and hypothyroidism.

No Link Between COVID-19 and Hyperthyroidism; No Reverse Causation

The GWASs showed no association between the genetic disposition for COVID-19 and hyperthyroidism. However, the authors note that those results should be interpreted with caution, inasmuch as the statistical power for that association was “the lowest among all other analyses in the current study, due to small numbers, and an outcome dataset that was only of medium size.”

No reverse association was seen regarding a genetic predisposition for hypo- or hyperthyroidism being linked to an increased risk of COVID-19 or its degree of severity.

Possible Mechanisms

Key mechanisms that have been suggested to explain the link 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 since ACE2 is highly expressed in thyroid tissue, the thyroid is considered to be vulnerable to SARS-CoV-2 infection.

COVID-19 may also indirectly cause thyroid gland inflammation by triggering abnormal immune-inflammatory responses and cytokine storm, the authors note.

It is known that subacute thyroiditis often originates from any kind of viral infection. Thus, it is prevalent among patients with COVID-19, and subclinical or overt hypothyroidism after SARS-CoV-2 infection has been reported in various studies.

Collectively, the results show that “both the genetic predisposition, suggested by our study, and the actual infection, demonstrated by the observational studies, may increase the risk of hypothyroidism,” Cheung said.

Regarding clinical implications, it may be too costly to genotype individual patients to assess genetic susceptibility to SARS-CoV-2 infection. Those who do become infected should be considered at higher risk, Cheung said.

“Clinicians should be aware of the possibility of subclinical and overt hypothyroidism among those patients who are susceptible to SARS-CoV-2 infection, eg, those with SARS-CoV-2 infection or even repeated SARS-CoV-2 infection.

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

In further comments, Brix noted that, with the understanding that subacute thyroiditis and hypothyroidism are related to prior viral infection, a link between COVID-19 and hypothyroidism “is not surprising.”

However, the lack of adjustment for various confounders is relevant.

“This is perhaps the most important shortcoming of the paper,” he said. “Thyroid disease and COVID-19 share common exposures, such as smoking, cardiovascular disease, diabetes, chronic lung disease (smoking again), and mental illness,” Brix explained. “The authors have not taken any of these confounders into account in their analysis.”

Importantly, “in almost all former studies investigating the association between thyroid dysfunction and prognosis of COVID-19 infection, the unadjusted analyses showed a significant association, which vanished after adjustment for relevant confounders,” he said.

In a population-based, case-control, cohort study using data from a large Danish COVID-19 cohort, which was published in The Lancet in 2021, Brix and his colleagues found no association between hypo- or hyperthyroidism and the development of COVID-19.