title: Pharmacogenetic risk for adverse reactions to irinotecan in the major ethnic populations of Singapore: regulatory evaluation by the health sciences authority.
abstract: BACKGROUND
  For genetic polymorphisms known to alter drug effect or safety, regulatory authorities can tap into population genomic databases and other sources of allele and genotype distribution data to make a more informed decision about the anticipated impact of such variants on the main ethnic groups in a country's population.
  
  
  OBJECTIVE
  The aim of this short communication is to describe how the Singapore Health Sciences Authority (HSA) made use of allele and genotype distributions in the main ethnic groups in Singapore (Chinese, Malay, Indian) and population genetic tools to compare with North American Caucasians and Japanese.
  
  
  METHODS
  Published papers and publicly accessible genomic databases were searched up to August 2009 to obtain allele and genotype frequencies for UGT1A1*6 and *28, two common variants of UGT1A1, a gene that encodes for a key enzyme in the pathway of irinotecan metabolism. These variants are associated with greater risk of serious toxicity.
  
  
  RESULTS
  In Singapore, the combined prevalence of three high-risk genotypes, UGT1A1*6/*6, *6/*28 and *28/*28, is 9.7% in Chinese, 5.0% in Malays and 18.7% in Indians, compared with 11.5% in North American Caucasians and 8.1% in Japanese. Indians are at an elevated risk of irinotecan-induced neutropenia associated with UGT1A1*28 compared with Chinese and Japanese, and at an even higher risk compared with North American Caucasians. On the other hand, Chinese and Japanese are at an elevated risk of irinotecan-induced neutropenia associated with UGT1A1*6 relative to Indians in Singapore or North American Caucasians. Population genotype data were the basis for the HSA to request revision of the package insert from manufacturers of irinotecan products. Moreover, the data provided the impetus for the HSA to publicize the availability of UGT1A1 genetic testing at the National Cancer Centre.
  
  
  CONCLUSIONS
  With the growing volume of genomic data and pharmacogenomic associations, a regulatory authority is now able to more readily utilize population genetic information and tools to supplement evaluations of drug products pertinent to the country's ethnic demography.
authors.affiliation: Health Products Regulation Group, Health Sciences Authority, Singapore. cynthia_sung@hsa.gov.sg
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sung
authors.forename: Pui Ling
authors.initials: PL
authors.lastname: Lee
authors.forename: Liesbet L
authors.initials: LL
authors.lastname: Tan
authors.forename: Dorothy S L
authors.initials: DS
authors.lastname: Toh
mesh_terms: D000483:Alleles; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives*; D005006:Ethnicity / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D009503:Neutropenia / Q000139:chemically induced*; D010597:Pharmacogenetics; D012307:Risk Factors; D012846:Singapore / Q000453:epidemiology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin
references.citation: Genet Med. 2009 Jan;11(1):21-34
references.pmid: 19125129
references.citation: Cancer Chemother Pharmacol. 2011 Aug;68(2):279-84
references.pmid: 20957480
references.citation: Jpn J Clin Oncol. 2011 May;41(5):617-23
references.pmid: 21310730
references.citation: J Clin Oncol. 2009 Jun 1;27(16):2604-14
references.pmid: 19349540
references.citation: Pharmacogenomics. 2010 Aug;11(8):1077-94
references.pmid: 20712526
references.citation: Pharmacogenet Genomics. 2006 Sep;16(9):683-91
references.pmid: 16906022
references.citation: Int J Clin Oncol. 2009 Apr;14(2):136-42
references.pmid: 19390945
references.citation: J Clin Oncol. 2009 May 20;27(15):2457-65
references.pmid: 19364970
references.citation: Clin Cancer Res. 2010 Aug 1;16(15):3832-42
references.pmid: 20562211
references.citation: Genet Epidemiol. 2010 Jan;34(1):34-41
references.pmid: 19479748
references.citation: Clin Cancer Res. 2004 Aug 1;10(15):5151-9
references.pmid: 15297419
references.citation: Pharmacogenet Genomics. 2007 Jul;17(7):497-504
references.pmid: 17558305
references.citation: Pharmacogenetics. 1998 Aug;8(4):357-60
references.pmid: 9731723
references.citation: J Clin Pharmacol. 2007 Jan;47(1):78-86
references.pmid: 17192505
references.citation: Cancer Sci. 2006 Nov;97(11):1255-9
references.pmid: 16965601
references.citation: Genome Res. 2009 Nov;19(11):2154-62
references.pmid: 19700652
references.citation: Cancer. 2009 Sep 1;115(17):3858-67
references.pmid: 19517472
references.citation: Clin Cancer Res. 2005 Feb 1;11(3):1226-36
references.pmid: 15709193
references.citation: Leuk Res. 1999 Nov;23(11):1061-70
references.pmid: 10576512
references.citation: J Natl Cancer Inst. 2007 Sep 5;99(17):1290-5
references.pmid: 17728214
references.citation: N Engl J Med. 1995 Nov 2;333(18):1171-5
references.pmid: 7565971
references.citation: Genet Med. 2009 Jan;11(1):15-20
references.pmid: 19125128
references.citation: Cancer. 2006 Mar 1;106(5):1007-16
references.pmid: 16456808
references.citation: Eur J Cancer. 2010 Jul;46(10):1856-65
references.pmid: 20335017
references.citation: Pharmacogenomics J. 2008 Aug;8(4):278-88
references.pmid: 17549067
references.citation: J Clin Oncol. 2006 May 20;24(15):2237-44
references.pmid: 16636344
references.citation: Clin Cancer Res. 2010 Jan 15;16(2):736-42
references.pmid: 20068078
references.citation: Cancer. 2008 May 1;112(9):1932-40
references.pmid: 18300238
references.citation: Cancer Sci. 2007 Sep;98(9):1461-7
references.pmid: 17627617
references.citation: Pharmacogenomics J. 2008 Jun;8(3):174-85
references.pmid: 17700594
references.citation: J Clin Oncol. 2004 Apr 15;22(8):1382-8
references.pmid: 15007088
references.citation: Neonatology. 2009;96(3):150-5
references.pmid: 19325249
references.citation: Br J Cancer. 2004 Aug 16;91(4):678-82
references.pmid: 15280927
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8170-4
references.pmid: 9653159
references.citation: Br J Cancer. 2008 Jul 22;99(2):275-82
references.pmid: 18594531