Variability in the UDP-glucuronosyltransferase 1A1 (UGT1A1) promotor in a HIV-infected Portuguese population

Abstract

Introduction: Dolutegravir is an HIV-1 integrase inhibitor (INI) recently approved for the treatment of HIV infection and is metabolized by UGT1A1 [1]. This protein is responsible for the glucuronidation of many compounds, and some functional polymorphisms in the UGT1A1 gene results in a decrease of enzyme activity [2]. The polymorphism (rs8175347) is associated with thymine-adenine (TA) repeats located in the TATA box in the promoter region of the UGT1A1 gene. The increasing number of TA repeats is inversely associated with UGT1A1 transcription, with 6 repeats (allele*1) being associated with normal UGT1A1 activity phenotype. 7 and 8 TA repeats (alleles *28 and *37, respectively) with low UGT1A1 activity phenotype [1]. Knowledge of the frequency distribution of functional polymorphisms in a HIV-infected population may improve therapeutic options. The present study aims to identify the frequency of UGT1A1 (rs8175347) gene polymorphism in a population of Portuguese HIV-infected patients and compare with other ethnic groups.

Materials and methods: The study includes 74 Portuguese HIV-infected adult patients receiving ARV therapy. The informed consent and the study protocol were approved by ethics committee. Genotyping the (TA) insertion in the TATA box region of UGT1A1 gene was performed by PCR amplification followed by direct sequencing. The allelic and genotype frequencies were tested for Hardy-Weinberg equilibrium by goodness off fit χ² test with a 95% CI, using The R Project for Statistical Computing. Obtained frequencies were then compared with 219 unrelated individuals collected from the database Pharmgkb using a χ² test.

Results: All frequencies in our study group were in Hardy-Weinberg equilibrium (p = 0.4016). In this study the allelic frequencies for UGT1A1 *1, *28 and *37 alleles were 61.49%, 30.41% and 8.11%, respectively, being significantly different from African, Asian and European (p < 0.001) ethnic groups. The genotype frequencies for UGT1A 1*1/*1, *1/*28, *1/*37, *28/*28 and *28/*37 were 32.43%, 44.59%, 13.51%, 6.76% and 2.70%, respectively. In our sample a total of 67.56% patients have UGT1A1*28 or *37 alleles which was significantly associated with lower UGT1A1 activity phenotype.

Discussion and conclusions: Obtained UGT1A1*28 and *37 frequencies were similar to the ones observed in African population and different from those of European and Asian origin. Patients with UGT1A1*28 and *37 alleles in our study may be at risk of dolutegravir therapeutic failure, consequently drug monitoring is recommended to guide dose adjustment. Our study contributes for personalized medicine optimization, indicating the individual differences in genetic characteristics.

Acknowledgements

The authors acknowledge funding from Fundação para a Ciência e Tecnologia, Lisbon, Portugal. This work was supported with Project INTELEGEN PTDC/DTP-FTO/1747/2012.