title: Variability in CYP2C9 allele frequency: a pilot study of its predicted impact on warfarin response among healthy South and North Indians.
abstract: BACKGROUND
  Wide variability exists in the frequency of pharmacogeneticmarkers for anticoagulant response in different populations. There is insufficient data on the prevalence of these variant genotypes in the Indian population. This study aims to determine the frequency of various genotype combinations of CYP2C9*2, *3 and VKORC1-1639G>A polymorphisms in the South and North Indians.
  
  
  METHODS
  Genotyping was carried out by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) technique in 209 North Indians (NI) and 82 South Indians (SI). Warfarin maintenance dose was predicted for all subjects based on FDA approved genotype-based dose estimates from revised COUMADIN medication guide. Fisher exact test and Χ2 test were applied to compare categorical data among the SI and NI groups.
  
  
  RESULTS
  In SI and NI, the allele frequency of CYP2C9*2 was 0.006 and 0.05 (significant variation; p<0.001); of CYP2C9*3 was 0.09 and 0.11; and of VKORC1-1639A was 0.14 and 0.19 (not significant), respectively. The variation in the frequency of combined CYP2C9/ VKORC1 genotypes revealed plausible difference in warfarin response among SI and NI. Based on the FDA approved revised dosing guidelines, significantly higher percentage of NI were likely to require intermediate dose (3-4 mg/day; p=0.015, RR=2.16) and were also predicted to have an increased risk of bleeding episodes and over anticoagulation (p=0.012, RR=1.93).
  
  
  CONCLUSIONS
  Genotype frequency of CYP2C9 and VKORC1 SNPs is variable among the two ethno-geographically distinct Indian populations. This could translate into diverse warfarin response among the Indian population.
authors.affiliation: Centre of Medical Genetics, Sir Ganga Ram Hospital, Rajinder Nagar-110060, New Delhi, India. rishanahar@gmail.com
authors.forename: Risha
authors.initials: R
authors.lastname: Nahar
authors.forename: Roumi
authors.initials: R
authors.lastname: Deb
authors.forename: Renu
authors.initials: R
authors.lastname: Saxena
authors.forename: Ratna Dua
authors.initials: RD
authors.lastname: Puri
authors.forename: Ishwar Chander
authors.initials: IC
authors.lastname: Verma
mesh_terms: D000328:Adult; D000483:Alleles; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007194:India; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010597:Pharmacogenetics; D010865:Pilot Projects; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases