title: Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L-thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer.
abstract: OBJECTIVE
  To evaluate the impact of genetic polymorphisms in uridine 5'-glucuronosylytansferases UGT1A1 and UGT1A3 and iodothyronine-deiodinases types 1 and 2 on levothyroxine (T4 ; 3,5,3',5'-triiodo-L-thyronine) dose requirement for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC).
  
  
  METHODS
  Patients (n = 268) submitted to total thyroidectomy and ablation by (131) I, under T4 therapy for at least 6 months were recruited in three public institutions in Brazil. Multivariate regression modelling was applied to assess the association of T4 dosing with polymorphisms in UGT1A1 (rs8175347), UGT1A3 (rs3806596 and rs1983023), DIO1 (rs11206244 and rs2235544) and DIO2 (rs225014 and rs12885300), demographic and clinical variables.
  
  
  RESULTS
  A regression model including UGT1A haplotypes, age, gender, body weight and serum TSH concentration accounted for 39% of the inter-individual variation in the T4 dosage. The association of T4 dose with UGT1A haplotype is attributed to reduced UGT1A1 expression and T4 glucuronidation in liver of carriers of low expression UGT1A1 rs8175347 alleles. The DIO1 and DIO2 genotypes had no influence of T4 dosage.
  
  
  CONCLUSIONS
  UGT1A haplotypes associate with T4 dosage in DTC patients, but the effect accounts for only 2% of the total variability and recommendation of pre-emptive UGT1A genotyping is not warranted.
authors.affiliation: Divisão de Farmacologia, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: Ana B
authors.initials: AB
authors.lastname: Santoro
authors.forename: Daniela D
authors.initials: DD
authors.lastname: Vargens
authors.forename: Mateus de Camargo
authors.initials: Mde C
authors.lastname: Barros Filho
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bulzico
authors.forename: Luiz Paulo
authors.initials: LP
authors.lastname: Kowalski
authors.forename: Ricardo M R
authors.initials: RM
authors.lastname: Meirelles
authors.forename: Daniela P
authors.initials: DP
authors.lastname: Paula
authors.forename: Ronaldo R S
authors.initials: RR
authors.lastname: Neves
authors.forename: Cencita N
authors.initials: CN
authors.lastname: Pessoa
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Struchine
authors.forename: Guilherme
authors.initials: G
authors.lastname: Suarez-Kurtz
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D002277:Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002291:Carcinoma, Papillary; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012044:Regression Analysis; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013972:Thyrotropin / Q000037:antagonists & inhibitors* / Q000097:blood; D013974:Thyroxine / Q000008:administration & dosage* / Q000627:therapeutic use; D000097564:Iodothyronine Deiodinase Type II; D000099148:UGT1A1 Enzyme
chemical_list: D014453:Glucuronosyltransferase; D007453:Iodide Peroxidase; D013972:Thyrotropin; D013974:Thyroxine; D000097564:Iodothyronine Deiodinase Type II; D000099148:UGT1A1 Enzyme; C109812:iodothyronine deiodinase type I; C122075:UDP-glucuronosyltransferase, UGT1A3
keywords: Brazilian population; L-thyroxine; differentiated thyroid cancer; iodothyronine-deiodinases; pharmacogenomics; uridine glucuronyltransferases