title: No Effect of the Thr92Ala Polymorphism of Deiodinase-2 on Thyroid Hormone Parameters, Health-Related Quality of Life, and Cognitive Functioning in a Large Population-Based Cohort Study.
abstract: The presence of the Thr92Ala polymorphism of deiodinase-2 (D2) has been thought to have several effects. It may influence its enzymatic function, is associated with increased expression of genes involved in oxidative stress in brain tissue, and may predict favorable response to combination levothyroxine (LT4) plus triiodothyronine (T3) therapy. It was hypothesized that homozygous carriers of the D2-92Ala allele have different thyroid hormone parameters, and reduced health-related quality of life (HRQoL) and cognitive functioning.
  
  
  
  In 12,625 participants from the LifeLines cohort study with genome-wide genetic data available, the effects of the Thr92Ala polymorphism (rs225014) were evaluated in the general population and in 364 people treated with thyroid hormone replacement therapy, the latter mainly because of primary hypothyroidism. In addition to evaluating anthropometric data, medication use, and existence of metabolic syndrome, HRQoL was assessed with the RAND 36-Item Health Survey, and the Ruff Figural Fluency Test was used as a sensitive test for executive functioning. Data on thyrotropin, free thyroxine (fT4), and free T3 (fT3) levels were available in a subset of 4479 participants.
  
  
  
  The mean age (±standard deviation) was 53 ± 12 years and the body mass index was 27.0 ± 4.5 kg/m2in the LT4 users compared with 48 ± 11 years and 26.2 ± 4.1 kg/m2in participants from the general population. The Ala/Ala genotype of the D2-Thr92Ala polymorphism was present in 11.3% of LT4 users and in 10.7% of the general population. In total, 3742/4479 subjects with thyroid hormone data available had normal TSH (0.4-4.0 mIU/L), and 88% of LT4 users were females. LT4 users had higher fT4, lower fT3, and a lower fT3/fT4 ratio, and female patients had lower scores on the HRQoL domains of physical functioning, vitality, mental health, social functioning, bodily pain, and general health compared with those not using LT4 (p < 0.005). Executive functioning scores, as part of cognitive functioning, were comparable between female LT4 users and the general population. In both groups, the D2-Thr92Ala polymorphism was not associated with differences in TSH, fT4, fT3, the fT3/fT4 ratio, presence of metabolic syndrome or other comorbidities, use of medication, HRQoL, and cognitive functioning.
  
  
  
  The Thr92Ala polymorphism of D2 was not associated with thyroid parameters, HRQoL, and cognitive functioning in the general population and in participants on thyroid hormone replacement therapy.
authors: 1 Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Hanneke J C M
authors: HJ
authors: Wouters
authors: 1 Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Hannah C M
authors: HC
authors: van Loon
authors: 1 Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Melanie M
authors: MM
authors: van der Klauw
authors: 1 Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Martin F
authors: MF
authors: Elderson
authors: 1 Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Sandra N
authors: SN
authors: Slagter
authors: 2 Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Anneke Muller
authors: AM
authors: Kobold
authors: 2 Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Ido P
authors: IP
authors: Kema
authors: 1 Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Thera P
authors: TP
authors: Links
authors: 1 Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Jana V
authors: JV
authors: van Vliet-Ostaptchouk
authors: 1 Department of Endocrinology and Metabolism, University of Groningen, University Medical Center Groningen , Groningen, Netherlands .
authors: Bruce H R
authors: BH
authors: Wolffenbuttel
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003071:Cognition; D015331:Cohort Studies; D005260:Female; D006304:Health Status; D006801:Humans; D007037:Hypothyroidism / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000523:psychology; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011788:Quality of Life; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood / Q000627:therapeutic use; D014284:Triiodothyronine / Q000097:blood; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D013972:Thyrotropin; D013974:Thyroxine; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II
keywords: TSH; deiodinase-2; executive functioning; free T4; general population; polymorphism; quality of life