The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density

Abstract

The role of type 2 deiodinase (D2) in the human skeleton remains unclear. The D2 polymorphism Thr92Ala has been associated with lower enzymatic activity, which could result in lower local triiodothyronine (T 3 ) availability in bone. We therefore hypothesized that the D2 Thr92Ala polymorphism may influence bone mineral density (BMD) and bone turnover. We studied 154 patients (29 men, 125 women: 79 estrogen-replete, 46 estrogen-deficient) with cured differentiated thyroid carcinoma. BMD and bone turnover markers [bone-specific alkaline phosphatase (BAP), cross-linking terminal C-telopeptide of type I collagen (CTX), procollagen type 1 aminoterminal propeptide (P1NP), and cross-linked N-telopeptide of type I collagen (NTX)] were measured. Effects of the D2 Thr92Ala polymorphism on BMD and bone turnover markers were assessed by a linear regression model, with age, gender, estrogen state, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and free triiodothyroxine (T 4 ) as covariables. Sixty patients were wild type (Thr/Thr), 66 were heterozygous (Thr/Ala), and 28 were homozygous (Ala/Ala) for the D2 polymorphism. There were no significant differences in any covariables between the three genotypes. Subjects carrying the D2 Thr92Ala polymorphism had consistently lower femoral neck and total hip densities than wild-type subjects ( p ¼ .028), and this was accompanied by significantly higher serum P1NP and CTX and urinary NTX/creatinine levels. We conclude that in patients with cured differentiated thyroid carcinoma, the D2 Thr92Ala polymorphism is associated with a decreased femoral neck BMD and higher bone turnover independent of serum thyroid hormone levels, which points to a potential functional role for D2 in bone. ß

Thyroid hormone status within the physiological range affects bone mass and density in healthy men at the age of peak bone mass

“…We found associations only between FT 3 and BMD or BMC, but not with FT 4 , which is in agreement with the premise that most actions of thyroid hormone in the body are mediated by the active form of thyroid hormone, T 3 . More specifically in bone, remodeling is considered to be predominantly mediated by via TRa (25).…”

Physiological role and regulation of iodothyronine deiodinases: A 2011 update

“…The same polymorphism is in linkage disequilibrium with the susceptibility to generalized osteoarthritis (127), decreased femoral neck bone mineral density and higher bone turnover independently of serum thyroid hormones (59). In addition, this SNP is associated with higher serum TSH but not thyroid hormone levels in healthy individuals (128) and with lower T3 release after TRH infusion (129).…”

“…Thus the absence of D2 would preclude compensation in overt hypo or hyperthyroidism, resulting in increased susceptibility to fracture in both conditions. From a clinical point of view, in a recent study, patients carrying a missense polymorphism in the human DIO2 gene (Thr92Ala), which is associated with lower D2 expression in several tissues (58), display reduced bone mineral density in association with alterations in markers of bone turnover and remodeling (59).…”

Heredity and lifestyle in the determination of between-subject variation in thyroid hormone levels in euthyroid men

“…In recent years, several of the genes involved in this regulation have been identified, with common genetic variation in phosphodiesterase 8B (PDE8B), TSH receptor (TSHR), deiodinase 1 (DIO1), and capping protein muscle Z-line beta (CAPZB) being associated with circulating THs (12,13,14,15,16,17,18,19,20,21,22). Besides, some of these single-nucleotide polymorphisms (SNPs) in the TH pathway have also been associated with clinical characteristics such as lean mass, bone density, hypertension, and insulin resistance (23,24,25,26,27,28). Nevertheless, most of the heritability remains unexplained, suggesting that many more regulatory genes remain to be identified and/or that rare genetic variants may be important (6).…”