L‐thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer: Effect of a novel UGT1 marker, rs11563250A > G

Tables of Links

TARGETS http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=2768
Enzymes http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1135
Deiodinase, iodothyronine, type I http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1138 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1138

LIGANDS
T4 http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=3726

These tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 1 and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 2.

We reported in this journal 3 that UGT1A haplotypes (denoted HapBr) comprising UGT1A1 rs8175347, UGT1A3 rs3806596 and UGT1A3 rs1983023 associate with the dose of levothyroxine (T₄; 3,5,3′,5′‐triiodo‐l‐thyronine) required for suppression of thyrotropin (TSH) secretion in patients with differentiated thyroid cancer (DTC). This association was attributed to reduced UGT1A1 expression and T₄ glucuronidation in the liver of carriers of low expression UGT1A1 rs8175347 alleles 3.

A novel polymorphism (rs11563250 A > G), located in the intergenic region downstream of UGT1 has been identified recently 4. Carriers of the minor rs11563250G allele exhibited decreased total bilirubin and reduced risk of irinotecan‐induced neutropenia, compared to carriers of the AA genotype. These findings led to the suggestion that the rs11563250G allele may be associated with elevated UGT1A1 activity and thereby ‘potentially affect the overall conjugation capacity of UGT1A‐targetted substrates’ 4. Prompted by this suggestion, we examined the impact of rs11563250 A > G on the dose requirement of T₄, a UGT1A substrate, in our cohort of DTC patients (n = 262).

A TaqMan allele discrimination assay (C__32051792_10; Applied Biosystems, Foster City, CA, USA) revealed that the minor allele (rs11563250G) frequency in the study cohort was 0.10 (95% CI: 0.07–0.13); no deviation from Hardy–Weinberg equilibrium was observed (χ² test P = 0.74). Because of the small number of patients with the variant homozygous genotype (GG, n = 2), the cohort was divided into carriers (genotypes AG + GG, n = 48) and non‐carriers (AA genotype, n = 214) of the rs11563250G allele. A two‐step (univariate followed by multivariate) regression modelling was used to assess the association of rs11563250 with daily T₄ dose, adjusted to body weight. Body weight was previously shown to be a major determinant of T₄ dose requirement in this cohort of DTC patients 3.

Initially, we assessed the independent effect of rs11563250G carriage and observed that the T₄ dose was, on average 5.2% higher in rs11563250G carriers (2.08 μg/kg, 95% CI 1.97–2.19) compared to non‐carriers (1.97 μg/kg, 1.91–2.03; P = 0.13, Student t‐test; Figure 1A). The direction of this effect was consistent with augmented UGT1A1 activity in rs11563250G carriers, as proposed by Chen et al. 4. Led by these authors’ findings, we repeated the association assessment in two sub‐sets. First, only patients with the UGT1A1 *1 /*1 genotype, where a considerably larger effect of the rs11563250 A > G SNP was seen: the T₄ dose was, on average, 12.5% higher in carriers (2.24 μg/kg; 2.08–2.40) than non‐carriers of the rs11563250G allele (1.98 μg/kg; 1.89–2.08; P = 0.025; Figure 1B). Second, in carriers vs. non‐carriers of the haplotype III described by Chen et al. 4, composed by the rs11563250G allele and the wild type allele for UGT1A1 rs8175347. The T₄ dose was, on average, 12.3% higher in carriers (2.20 μg/kg, 95% CI 2.03–2.37) compared to non‐carriers (1.96 μg/kg, 1.90–2.02; P = 0.023; Figure 1C).

Figure 1.

Distribution of weight‐adjusted T₄ daily dose according to rs11563250 genotype in the overall cohort (A) and in patients homozygous for the UGT1A1*1 allele (B), and in carriers vs. non‐carriers of the haplotype III, composed by the rs11563250G allele and the wild type allele for UGT1A1 rs8175347. The number of patients in each group is indicated

Next we performed a multivariable regression analysis, adding the rs11563250 genotype and the number of copies of haplotype III to the variables which were previously shown to associate with daily T₄ dose in DTC patients 3. The final regression model retained only UGT1A HapBr (P = 0.03) and age (P < 0.0001) as covariates significantly associated with the body weight‐adjusted T₄ dose. The final model accounted for 9.7% of the inter‐individual variation in T₄ dose requirement in our DTC cohort.

In conclusion, our results showed a trend towards higher T₄ dosage in DTC patients who are carriers of the rs11563250G allele per se or in combination with the wild‐type UGT1A1 rs8175347 allele. This is consistent with the notion of augmented UGT1A activity in rs11563250G carriers 4, leading to increased UGT1A‐mediated T₄ glucuronidation in liver. However, rs11563250G carriage was not retained as a covariate associated with T₄ daily dose in a multivariate regression analysis. We conclude that knowledge of the rs11563250 A > G genotype does not alter our previous proposal 3 that UGT1A haplotypes associate with T₄ dosage in DTC patients, but the effect accounts for a minor fraction of inter‐individual dose variability and recommendation of UGT1A genotyping is not warranted.

Competing Interests

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear to have influenced the submitted work.

Research in GS‐K′s lab is supported by grants from CNPq, Faperj and DECIT/Ministry of Health, Brazil.

Santoro, A. B. , Struchiner, C. J. , and Suarez‐Kurtz, G. (2016) L‐thyroxine doses required for TSH suppression in patients with differentiated thyroid cancer: Effect of a novel UGT1 marker, rs11563250A > G. Br J Clin Pharmacol, 82: 1402–1403. doi: 10.1111/bcp.13064.