Effect of UGT1A1, UGT1A3, DIO1 and DIO2 polymorphisms on L‐thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer

Abstract

AIMTo 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). METHODSPatients (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. RESULTSA 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. CONCLUSIONUGT1A 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Inter-individual variation in L-thyroxine (T4) doses required for suppression of thyrotropin (TSH) in patients with differentiated thyroid cancer (DTC) is considerable and multifactorial. Age, gender and body weight explain part of this variability.• To exert its inhibitory control of TSH secretion, T4 must be deiodinated to T3 (3,5,3′-triiodo-L-thyronine) by iodothyronine-deiodinases types 1 (D1) and 2 (D2). Genetic polymorphisms in D1 and D2 have been associated with circulating levels of T3 and T4 and/or TSH, with controversial results. • T4 is metabolized in human liver by UDP-glucuronyltransferases, especially UGT1A1 and UGT1A3 and readily excreted into bile as thyroxine glucuronide. A common polymorphism in UGT1A1 (-53(TA)n, rs8175347) has been associated with the T4 dose required for TSH suppression in DTC patients. WHAT THIS STUDY ADDS• Multivariate regression modelling was applied to assess the association of T4 dosing in 268 Brazilian DTC patients with polymorphisms in DIO1 (rs11206244 and rs2235544), DIO2 (rs225014 and rs12885300), UGT1A1 (rs8175347) and UGT1A3 (rs3806596 and rs1983023), in addition to demographic and clinical variables. • 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.• UGT1A haplotypes associate with T4 dosage in DTC patients, but the ef...

Genetic abnormalities in thyroid hormone deiodinases

“…In addition, the fact that serum FT4 and FT3 levels were not different between the genotype groups in this study did not fully support an altered pituitary setpoint in these patients either [29]. Hence, it seems more likely that any additive effect of low thyroid hormone levels with D2 deiodinase genotype occurs at the level of local T 3 generation in parts of the brain separate from the HPT axis control.…”

“…An inadequate TSH response arising from this variant to borderline thyroid function may, however, not be part of the mechanism of action as recent data indicated that the Thr92Ala substitution and variation at rs12885300 were not associated with higher T4 doses to achieve TSH suppression in thyroid cancer in a modestly powered study (N ¼ 285) [29]. This is not in keeping with earlier studies (N ¼ 191) which showed that individuals homozygous for the Thr92Ala substitution required higher doses of levothyroxine to achieve target TSH levels post-thyroidectomy for thyroid cancer [30].…”

New insights into thyroid hormone action

“…Polymorphisms in FOXE1 are also associated with congenital hypothyroidism (Carre et al, 2014). Some polymorphisms have little to no effect in patient care such as the type 1 deiodinase (DIO1), which does not change the dose of T4 required for TSH suppression in thyroidectimized patients (Santoro et al, 2014). Recently, hypothyroidism has been asociated with both neurological disease and a longer life span.…”

Pharmacogenomics research and clinical implementation in Brazil

“…The CPIC guideline for atazanavir considers several polymorphisms in UGT1A1 , including a variable dinucleotide (TA) repeat within the gene promoter region (rs8175347, alleles UGT1A1*28, *36 and *37 ), and the SNPs rs4148323 ( UGT1A1*6 ) and rs887829 ( UGT1A1*80 ). The distribution of the rs8175347 variants and of the rs887829 SNP does not differ across the Brazilian race/colour groups, whereas the UGT1A1*6 allele, common in Asian populations, was not detected in the REFARGEN cohorts (Table ).…”