Genetic Study Finds Hypothyroidism May Increase PAH Risk

Hypothyroidism has been newly associated with greater risk of developing pulmonary arterial hypertension (PAH), in a study that used inverse variance weighting (IVW), MR-Egger regression (MR-Egger), and weighted median (WM) methods to reach this conclusion.1

The research published in International Journal of Cardiology: Heart & Vasculature sought to connect 5 subtypes of thyroid dysfunction—free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), hypothyroidism, and hyperthyroidism—but found only hypothyroidism was connected to PAH. There was an approximately 49% greater risk of PAH in the presence of hypothyroidism (OR, 1.485; 95% CI, 1.051-2.100; P = .025).

With hypothyroidism, the thyroid gland—which serves to regulate metabolism, growth, and development through hormone production—underdelivers; it is considered in an underactive state and can lead to bouts of fatigue and weight gain from a metabolism that has been greatly slowed.2 PAH is typically defined through right ventricular dysfunction, demonstrated by a mean pulmonary arterial pressure above 22 mm Hg,1 and symptom onset of dyspnea, syncope, lower extremity edema, abdominal distention, and angina.3

This new study incorporated and evaluated summary data from the Genome-wide Association Studies (GWAS) of the European Ancestry Cohort for instrumental variables for thyroid dysfunction and PAH, and GWAS data on OAH were gleaned from the IEU OpenGWAS project. The authors evaluated single nucleotide polymorphisms (SNPs) for heterogeneity using Cochran’s Q test, ultimately selecting 30, 59, 161, 68, and 41 SNPs, respectively, for FT3, FT4, TSH, hypothyroidism, and hyperthyroidism.

IVW produced the aforementioned 49% greater risk of PAH in the presence of hypothyroidism. MR-Egger (OR, 2.123; 95% CI, 1.011-4.459; P = .051) and the WM method (OR, 1.003; 95% CI, 0.578-1.739; P = .991) did not find similar associations, “but because the [β] values of each method were in the same direction (all greater than 0), we still consider that hypothyroidism can increase the risk of PAH,” the study authors noted. These β values were 0.753 for MR-Egger, 0.003 for the WM method, and 0.396 for IVW.

In contrast, the β values for MR-Egger were negative for FT3, FT4, and TSH but positive for hyperthyroidism; for the WM method, negative for all; and for IVW, positive for FT3 and hyperthyroidism but negative for FT4 and TSH. Also, heterogeneity and horizontal pleiotropy were not seen among these findings (P > .05).

PAH is typically defined through right ventricular dysfunction, demonstrated by a mean pulmonary arterial pressure above 22 mm Hg and symptom onset of dyspnea, syncope, lower extremity edema, abdominal distention, and angina. | Image Credit: Kiattisak-stock.adobe.com

Drilling down, the following results were seen for heterogeneity using Cochran’s Q test:

• FT3: MR-Egger, 31.553 (P = .293); IVW, 31.636 (P = .336)
• FT4: MR-Egger, 51.351 (P = .539); IVW, 51.406 (P = .575)
• TSH: MR-Egger, 170.939 (P = .245); IVW, 170.959 (P = .262)
• Hypothyroidism: MR-Egger, 69.464 (P = .362); IVW, 70.662 (P = .356)
• Hyperthyroidism: MR-Egger, 53.735 (P = .058); IVW, 53.760 (P = .072)

These were the authors’ findings on horizontal pleiotropy:

• FT3: 0.022 (P = .788)
• FT4: –0.009 (P = .816)
• TSH: –0.003 (P = .892)
• Hypothyroidism: –0.042 (P = .297)
• Hyperthyroidism: –0.010 (P = .07)

They also did not find evidence of reverse causal association between PAH and thyroid dysfunction.

“Thyroid dysfunction is often combined with various autoimmune abnormalities, which induce systemic vascular inflammation,” the study authors wrote. “In addition, hypothyroidism is strongly associated with venous thromboembolic events.”

Strengths of their findings are that they reflect the results of previous studies—prospective and retrospective analyses—showing elevated rates of hypothyroidism in children with PAH4 and the presence of thyroid disease in patients with pulmonary hypertension, with the highest prevalence in the setting of PAH.5

However, limitations were noted, too. Because their data were from a solely European population, the findings may not apply to other populations. Also, the data they used were summary data, so they could not account for the potential influence of medications to treat PAH that may have precipitated thyroid dysfunction.

The authors underscore that further investigation is needed to validate their findings.

References

1. Pang G, Wang X, Zhao R, et al. Thyroid dysfunction and pulmonary arterial hypertension: a bidirectional mendelian randomization study. Int J Cardiol Heart Vasc. 2025:60:101747. doi:10.1016/j.ijcha.2025.101747
2. Hypothyroidism (underactive thyroid). Cleveland Clinic. Accessed July 25, 2025. https://my.clevelandclinic.org/health/diseases/12120-hypothyroidism
3. PAH diagnostic criteria. PAH Initiative. Accessed July 25, 2025. https://www.pahinitiative.com/hcp/pah-overview/diagnosing-pah-criteria
4. Kwiatkowska J, Zuk M, Migdal A, et al. Children and adolescents with pulmonary arterial hypertension: baseline and follow-up data from the Polish registry of pulmonary hypertension (BNP-PL). J Clin Med. 2020;9(6):1717. doi:10.3390/jcm9061717
5. Li JH, Safford RE, Aduen JF, Heckman MG, Crook JE, Burger CD. Pulmonary hypertension and thyroid disease. Chest. 2007;132(3):793-797. doi:10.1378/chest.07-0366