title: Frequency of the thiopurine S-methyltransferase alleles in the ancient genetic population isolate of Sardinia.
abstract: BACKGROUND
  Thiopurine S-methyltransferase (TPMT) is an enzyme involved in the normal metabolic inactivation of thiopurine drugs. Patients with intermediate or no TPMT activity are at risk of toxicity after receiving standard doses of thiopurine drugs and it was shown that inter-individual differences in response to these drugs is largely determined by genetic variation at the TPMT locus.
  
  
  OBJECTIVE
  This study was designed to investigate in the Sardinian population the frequency distribution of four of the most common variants accounting for TPMT deficiency and to conduct comparative analyses with other populations in order to obtain insights into the main factors that have shaped diversity at the TPMT locus in Sardinia.
  
  
  METHODS
  DNA was extracted in 259 Sardinians and the frequencies of allelic variants of TPMT were determined using polymerase chain reaction-restriction fragment length polymorphism technique.
  
  
  RESULTS
  Among the 259 Sardinians genotyped, 6.95% were found to be heterozygous for one of four TPMT variants screened; for each variant the frequency estimate was 1.74%, 0.58%, 0.39% and 0.77% for TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C respectively.
  
  
  CONCLUSIONS
  Although Sardinia does not show reduced diversity at the TPMT locus, the spectrum of TPMT allele frequencies affords evidence of remarkable influence of genetic drift and founder effects throughout its population history. In the broad context of the European TPMT diversity, the Sardinians come out as outliers, an observation consistent with previous genetic inferences that Sardinia has features of a genetic isolate.
authors.affiliation: Dipartimento Di Scienze Biomediche e Biotecnologie, Università Di Cagliari, and Ospedale Microcitemico, Cagliari, Italy. rossino1@libero.it
authors.forename: R
authors.initials: R
authors.lastname: Rossino
authors.forename: C
authors.initials: C
authors.lastname: Vincis
authors.forename: S
authors.initials: S
authors.lastname: Alves
authors.forename: M J
authors.initials: MJ
authors.lastname: Prata
authors.forename: M D
authors.initials: MD
authors.lastname: Macis
authors.forename: A L
authors.initials: AL
authors.lastname: Nucaro
authors.forename: E
authors.initials: E
authors.lastname: Schirru
authors.forename: M
authors.initials: M
authors.lastname: Congia
mesh_terms: D000328:Adult; D000483:Alleles; D004247:DNA / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008780:Methyltransferases / Q000235:genetics*; D008875:Middle Aged; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004247:DNA; D008780:Methyltransferases; C022745:thiopurine methyltransferase