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Keywords:

  • Drug metabolism;
  • UDP-glucuronosyltransferase 1A1;
  • UDP-glucuronosyltransferase 1A7;
  • haplotype diversity;
  • allele frequency;
  • population structure;
  • UGT1A gene complex;
  • bilirubin

Summary

Variation of a short (TA)n repeat sequence (rs8175347) covering the TATA box of UGT1A1 (UDP-glucuronosyltransferase1A1) is associated with hyperbilirubinaemia (Gilbert's syndrome) and adverse drug reactions, and is used for dosage advice for irinotecan. Several reports indicate that the low-activity (risk) alleles ((TA)7 and (TA)8)) are very frequent in Africans but the patterns of association with other variants in the UGT1A gene complex that may modulate these responses are not well known. rs8175347 and two other clinically relevant UGT1A variants (rs11692021 and rs10929302) were assayed in 2616 people from Europe and Africa. Low-activity (TA)n alleles frequencies were highest in equatorial Africa, (TA)7, being the most common in Cameroon, Ghana, southern Sudan, and in Ethiopian Anuak. Haplotypic diversity was also greatest in equatorial Africa, but in Ethiopia was very variable across ethnic groups. Resequencing of the promoter of a sample subset revealed no novel variations, but rs34547608 and rs887829 were typed and shown to be tightly associated with (TA)n. Our results illustrate the need for investigation of the effect of UGT1A variants other than (TA)n on the risk of irinotecan toxicity, as well as hyperbilirubinaemia due to hemolytic anaemia or human immunodeficiency virus protease inhibitors, so that appropriate pharmacogenetic advice can be given.