Phenotypic variability in expressivity and deleterious capability of the homozygous UGT1A1*28 genotype

Author(s): Raquel Rodríguez-López, Jorge Ferriz Vivancos, Ana Cristina Requena Piedrabuena, Irene Ferrer Bolufer, Carola Guzmán Luján, Otilia Zomeño Alcalá, Joan Más Lloret, Jennifer Valero García, Ana de Blas Zapata, Mireia Gil Raga, Ana Vallejo Antolín, Mercedes Latorre Sánchez, Mª José Safont Aguilera

Background :

The UGT1A1*28 polymorphism (rs3064744) is responsible for Gilbert's Syndrome (GS) and is characterized by allelic variability based on TA repeats in the TATA sequence of the UGT1A1 gene promoter, whose alleles 7TA and 8TA are associated with elevated bilirubin, as well as an increased risk of certain neoplasms and adverse reactions to the chemotherapy Irinotecan. In contrast, the existence of hyperbilirubinemia has been considered a preventive factor for certain cardiovascular and oncological pathologies. We analyzed the allelic distribution of the UGT1A1 allele in the Valencian population with hyperbilirubinemia and Valencian patients diagnosed with digestive neoplasms; we studied their biochemical profiles, specifically comparing individuals with the UGT1A1*28 genotype in homozygosis of both groups.

Methods :

We collected a sample of 1,358 individuals: 621 patients with suspected GS (cases) and 737 individuals affected by one oncological disease (possible reference population). After extracting DNA, samples were analyzed the number of TA repeats by both Sanger sequencing and fragment analysis technique. In addition, the clinical history and set of analytical parameters of 242 patients carrying the genotype UGT1A1*28 in homozygosis were reviewed, with special attention to the consecutive measurement of bilirubin levels.

Results :

The differences in the distribution of the UGT1A1*28 genotypes in both groups, heterozygous and homozygous, were statistically significant; the homozygous UGT1A1*28 genotype reached 55.4% among patients with suspected GS. Severe H-W E deviations were observed in this group (OR: 45.37), while in cancer patients they were distributed according to the H-W E balance. Bilirubin levels in the group of homozygous UGT1A1*28 individuals among oncology patients were lower, showing a higher risk (OR: 2.86) in males.