Dissecting genetics in hypothyroidism as an independent risk factor in atherosclerotic disease
Authors: Rand S , Haunsoe S , Olesen M S , Ghouse J 
Published: October 2022

Abstract

Background
Thyroid disease comprises a joint group of diseases estimated to affect 10% of the general adult population [1]. Hypothyroidism is characterized by high Thyroid-Stimulating Hormone (TSH) production and low concentrations of Thyroxine (T4). This is known to increase overall mortality and risk of cardiovascular disease (CVD), including heart failure (HF), dyslipidemia, stroke, and coronary artery disease (CAD) [2,3]. Still, the association between CVD and hypothyroidism seems independent of conventional CVD risk factors. This highlights that possible genetic underlying mechanisms remain uncovered and could support CVD monitoring and treatment in patients with hypothyroidism [3]. This study aimed to dichotomize independent genetic mechanisms involved in the increased risk of atherosclerotic disease in patients with hypothyroidism.

Methods
We conducted the largest ever genome-wide association study (GWAS) meta-analysis of hypothyroidism from three European cohorts, which amounted to 71,590 cases and 848,581 controls.
Using Linkage Disequilibrium Regression Score, we highlight novel cardiovascular disease correlations in hypothyroidism. With Mendelian Randomization, we dissected which hypothyroidism-associated Single Nucleotide Polymorphisms (SNPs) infer atherosclerotic disease risk.

Results
We identified 79 novel disease loci in hypothyroidism, and tested 12 correlations which identified novel genetic overlap to CVD (Figure 1). We found five significant correlations to cardiovascular disease and two to cardiometabolic disease. Interestingly, we found overlap to atherosclerotic diseases; CAD (rg=0.16, P=2.12x10–9), HF (rg=0.16, P=1.6x10–5), stroke (rg=0.17, P=1.75x10–3) and aorta aneurysm (rg=0.12, P=3.65x10–3). We also found overlap to triglycerides (rg=0.10, P=1.4x10–5) and a negative correlation to HDL (rg=−0.16, P=8.8x10–11).
Mendelian Randomization suggested hypothyroidism as an independent genetic risk factor with 3% increased risk of CAD (OR=1.03, 95% CI: 1.02–1.04, P=8.1x10–7) and 4% increased risk of myocardial infarction (MI) (OR=1.04, 95% CI: 1.02–1.05, P=3.3x10–6). We identified novel causal SNPs involved in CAD and MI in genes suggesting accelerated atherogenesis, namely; TRIM14 (rs141471464, OR_MI = 1.16 and OR_CAD = 1.10), CTLA4 (rs76749018, OR_MI = 1.10 and OR_CAD = 1.11) (Figure 2).

Conclusions
This analysis highlights novel significant findings between atherosclerotic disease and hypothyroidism. These findings could suggest improving consideration in clinical care for hypothyroid patients at risk of atherosclerotic disease. The genetic findings point towards solid indications, that atherogenesis is frequent and accelerated in this disease. Thus, the usual treatment, monitoring, and prevention strategies, could be reviewed with respect to considering other causal pathways than dyslipidemia for atherosclerotic disease in hypothyroid patients.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): The John and Birthe Meyer FoundationVilladsen Family Foundation