title: UGT1A1, UGT1A6 and UGT1A7 genetic analysis: repercussion for irinotecan pharmacogenetics in the São Miguel Island Population (Azores, Portugal).
abstract: BACKGROUND
  Glucuronidation reactions, catalyzed by uridine-diphosphate glucuronosyltransferase (UGT) enzymes, constitute a detoxification process that adds glucuronic acid to endogenous and exogenous compounds, aiding their excretion. UGT1A proteins have been implicated as risk factors for both the development of cancer and adverse drug effects.
  
  
  METHODS
  Here, we assess the genome of 469 individuals from São Miguel Island (Azores, Portugal) in order to determine the frequencies of polymorphisms and haplotypes in UGT1A1, UGT1A6, and UGT1A7, the co-occurrence of reduced enzyme activity UGT1A variants related to irinotecan toxicity, and to calculate the extent of linkage disequilibrium (LD) in the genomic region encompassing these genes.
  
  
  RESULTS
  Allelic analysis disclosed the presence of rare alleles - UGT1A1*36 and UGT1A1*37--only found in individuals of African descent, and UGT1A7*4. These alleles confirm our previous results on the São Miguel Island genetic background. We identified five different genotypes in UGT1A1 and UGT1A6 and nine in UGT1A7. Haplotype analysis showed that three haplotypes constituted approximately 80% of the allelic variants. Interestingly, haplotype 3 (UGT1A1*28-UGT1A6*2-UGT1A7*3), with a frequency of 0.235, gathers the three alleles encoding the low-function UGT isoforms. Additionally, LD indicates a strong interaction between functional polymorphisms related to the alteration of the UGT enzyme activity.
  
  
  CONCLUSIONS
  In summary, the results demonstrate a high variability of alleles and haplotypes, which have important roles in modifying expression and activity of UGTs. The data presented here could improve the understanding of the predisposition to cancers and susceptibility to the adverse effects of irinotecan in the São Miguel Island population.
authors.affiliation: Molecular Genetics and Pathology Unit, Hospital of Divino Espirito Santo of Ponta Delgada, São Miguel Island, Azores, Portugal.
authors.forename: Paula R
authors.initials: PR
authors.lastname: Pacheco
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Brilhante
authors.forename: Cristina
authors.initials: C
authors.lastname: Ballart
authors.forename: Francesc
authors.initials: F
authors.lastname: Sigalat
authors.forename: Helena
authors.initials: H
authors.lastname: Polena
authors.forename: Rita
authors.initials: R
authors.lastname: Cabral
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Branco
authors.forename: Luisa
authors.initials: L
authors.lastname: Mota-Vieira
mesh_terms: D000483:Alleles; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D015810:Linkage Disequilibrium / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic / Q000235:genetics; D000099148:UGT1A1 Enzyme
chemical_list: D000970:Antineoplastic Agents; D002166:Camptothecin; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme; C110655:UDP-glucuronosyltransferase, UGT1A6; C107611:UDP-glucuronosyltransferase, UGT1A7