Abstract
To clarify the role of thyroid function in ischemic heart disease (IHD) we assessed IHD risk and risk factors according to genetically predicted thyroid stimulating hormone (TSH), free thyroxine (FT4) and thyroid peroxidase antibody (TPOAb) positivity. Separate-sample instrumental variable analysis with genetic instruments (Mendelian randomization) was used in an extensively genotyped case (n = 64,374)-control (n = 130,681) study, CARDIoGRAMplusC4D. Associations with lipids, diabetes and adiposity were assessed using the Global Lipids Genetics Consortium Results (n = 196,475), the DIAbetes Genetics Replication And Meta-analysis case (n = 34,380)-control (n = 114,981) study, and the Genetic Investigation of ANthropometric Traits (body mass index in 152,893 men and 171,977 women, waist-hip ratio in 93,480 men and 116,741 women). Genetically predicted thyroid function was not associated with IHD (odds ratio (OR) per standard deviation for TSH 1.05, 95% confidence interval (CI) 0.97 to 1.12; for FT4 1.01, 95% CI 0.91 to 1.12; for TPOAb positivity 1.10, 95% CI 0.83 to 1.46) or after Bonferroni correction with risk factors, except for an inverse association of FT4 with low-density lipoprotein-cholesterol. The associations were generally robust to sensitivity analyses using a weighted median method and MR Egger. This novel study provides little indication that TSH, FT4 or TPOAb positivity affects IHD, despite potential effects on its risk factors.
Highlights
Cardiovascular disease (CVD) is the leading cause of mortality globally[1]
Rs13015993 in IGFBP5 and rs7568039 in IGFBP2 might be associated with coronary artery disease/myocardial infarction (CAD/MI) other than via TSH50 because associations with CAD were suggested by the Mendelian randomization (MR) Catalogue (p value 1.73 × 10−4 for rs13015993; 1.40 × 10−4 for rs7568039)
Rs657152 is in ABO, a gene strongly associated with ischemic heart disease (IHD) for reasons that are not entirely clear but may be unrelated to TSH52
Summary
Cardiovascular disease (CVD) is the leading cause of mortality globally[1]. Despite substantial progress in prevention and control, the etiology of CVD is not completely understood[2], as evidenced by failures of new treatments[3]. Thyroid hormones are involved in testicular development in animals[17] In humans, both overt and subclinical thyroid dysfunction, especially the former, are associated with higher risk of CVD events[18,19,20]. People who are TPOAb-positive have higher TSH and faster carotid intima media thickness (cIMT) progression[32], in another study, cardiovascular risk associated with subclinical hypothyroidism did not differ by TPOAb status[33]. Mendelian randomization (MR) provides a means of assessing genetic validity, by examining whether people with genetically different levels of TSH, FT4 and TPOAb positivity have higher or lower risk of IHD. To clarify the role of thyroid function, we assessed the associations of genetically predicted TSH, FT4 and TPOAb positivity with coronary artery disease/myocardial infarction (CAD/MI) using instrumental variable analysis with genetic instruments, i.e., MR, in large case-control studies with extensive genotyping. We assessed the associations with established CVD risk factors, including lipids, diabetes and adiposity to identify if any associations with IHD were independent of these risk factors
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