Association between DIO2 Thr92Ala polymorphism and hypertension in patients with hypothyroidism: Korean Genome and Epidemiology Study

Abstract

Background/aims: Recent evidence has identified the significance of type 2 iodothyronine deiodinase (DIO2) in various diseases. However, the role of DIO2 polymorphism in metabolic parameters in patients with hypothyroidism is not fully understood.

Methods: We assessed the polymorphism of the DIO2 gene and various clinical parameters in 118 patients who were diagnosed with hypothyroidism from the Ansan-Anseong cohort of the Korean Genome and Epidemiology Study. Furthermore, we systematically analyzed Genotype-Tissue Expression (GTEx) data.

Results: A total of 118 participants with hypothyroidism were recruited; 32 (27.1%) were homozygous for the Thr allele, 86 (73.9%) were homozygous for the Ala allele or heterozygous. Patients with hypothyroidism with DIO2 polymorphism without hypertension at baseline had higher incidence of hypertension compared to patients without DIO2 polymorphism. Analysis of the GTEx database revealed that elevation of DIO2 expression is associated with enhancement of genes involved in blood vessel regulation and angiogenesis.

Conclusion: Commonly inherited variation in the DIO2 gene is associated with high blood pressure and prevalence of hypertension in patients with hypothyroidism. Our results suggest that genetic variation in the hypothalamic-pituitary-thyroid pathway in influencing susceptibility to hypertension.

Keywords: Blood pressure; Hypertension; Hypothyroidism; Iodothyronine deiodinase type II.

Figure 1

Upregulation of physiological pathways in artery-aorta with high expression of type 2 iodothyronine deiodinase (DIO2) in the Genotype-Tissue Expression database. (A) DIO2 expression levels in 432 human artery-aorta samples in the University of California Santa Cruz (UCSC) database. (B) Volcano plot of differentially expressed gene (DEG) between DIO2 top 25% group and DIO2 bottom 25% group. (C) Numbers of DEGs in a comparison of the samples in the highest quartile for DIO2 expression and those in the lowest quartile. (D) Upregulated biological processes in the Gene Ontology (GO) annotation associated with increased DIO2 expression. (E) Down-regulated biological processes in the GO annotation associated with increased DIO2 expression. TPM, transcripts per million; GO-BP, GO-Biological Process; MAPK, mitogen-activated protein kinase; cAMP, cyclic adenosine monophosphate; ER, endoplasmic reticulum; ATP, adenosine triphosphate; NADH, nicotinamide adenine dinucleotide hydrogen; CoA, coenzyme A.

Figure 2

Upregulation of physiological pathways in left ventricle with high expression of type 2 iodothyronine deiodinase (DIO2) in the Genotype-Tissue Expression database. (A) DIO2 expression levels in 432 human left ventricle samples in the University of California Santa Cruz (UCSC) database. (B) Volcano plot of differentially expressed gene (DEG) between DIO2 top 25% group and DIO2 bottom 25% group. (C) Numbers of differentially expressed genes in a comparison of the samples in the highest quartile for DIO2 expression and those in the lowest quartile. (D) Upregulated biological processes in the Gene Ontology (GO) annotation associated with increased DIO2 expression. (E) Downregulated biological processes in the GO annotation associated with increased DIO2 expression. TPM, transcripts per million; GO-BP, GO-Biological Process; cAMP, cyclic adenosine monophosphate; MAPK, mitogen-activated protein kinase; ATP, adenosine triphosphate; NADH, nicotinamide adenine dinucleotide hydrogen; CoA, coenzyme A.