Type 2 Deiodinase Thr92Ala Polymorphism Is Associated with a Reduction in Bone Mineral Density: A Community-Based Korean Genome and Epidemiology Study

Abstract

Background: Type 2 deiodinase (DIO2)-mediated thyroid hormone synthesis stimulates osteoblast activity and increases the expression of osteoblast differentiation markers. Moreover, recent clinical studies identified a significant relationship between bone mineral density and thyroid hormone level in humans, but these studies had limitations that may have influenced their results, including small sample size, gender bias and enrollment of participants with specific diseases. Therefore, large cohort studies to identify the role of the DIO2 polymorphism in bone mineral density in humans are needed to provide additional information. Methods: To investigate the hypothesis that individuals with the DIO2 gene polymorphism are susceptible to osteoporosis, we assessed the polymorphism of the DIO2 gene in 7,524 Koreans drawn from the large-scale Ansan-Anseong cohort of the Korean Genome and Epidemiology Study (KoGES). Participants who were prescribed drugs that influence bone mineral density, those who provided insufficient information, and those with other diseases associated with osteoporosis were excluded from the study. All of the participants underwent genotyping of the DIO2 Thr92Ala polymorphism. We estimated the association of the DIO2 gene polymorphism with bone mineral density and other diverse clinical parameters using the chi-square test and ANOVA, and the risk of osteoporosis was determined using Cox regression analysis. Findings: A total of 6,022 participants were recruited; 1,991 (33.0%) were homozygous for the Thr allele, 2,967 (49.3%) were heterozygous (Thr/Ala), and 1,064 (17.7%) were homozygous for the Ala allele. The effects of the DIO2 Thr92Ala polymorphism on axial speed of sound (SOS) and the T-score in the tibia and radius were assessed, with age, gender, estrogen status, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, and parathyroid hormone (PTH) included as covariables. Subjects carrying the DIO2 Thr92Ala polymorphism had consistently lower SOS and T-scores than heterozygous subjects. Additionally, female patients carrying the DIO2 Thr92Ala polymorphism had significantly lower SOS and T-scores than heterozygous participants. Cox regression analysis revealed a significant relationship between the DIO2 polymorphism and diagnosis of osteoporosis in female participants. Interpretation: We conclude that the DIO2 Thr92Ala polymorphism is associated with decreased SOS and T-scores in the tibia independent of other clinical parameters, where this indicates a potential functional role of DIO2 in the maintenance of bone mineral density. Funding Statement: This study was conducted with bioresources from the National Biobank of Korea, the Centers for Disease Control and Prevention, Republic of Korea (2018-022). This work was supported by the Korean Endocrine Society of New Faculty Research Award, 2018. Hyon-Seung Yi was also supported by the Basic Science Research Program, National Research Foundation, Ministry of Science and ICT, Future Planning, Korea (NRF-2018R1C1B6004439). Young Mi Kang and Yea Eun Kang were supported by the Basic Science Research Program, National Research Foundation, Ministry of Science and ICT, Future Planning, Korea (NRF2017R1D1A1B03027820). Declaration of Interests: All other authors declare no competing interests. Ethics Approval Statement: All subjects participated voluntarily and the study procedures were in accordance with our institutional guidelines and were approved by the Institutional Review Committee of the Korean National Institute of Health (CNUH-2018-03-028)