VKORC1 polymorphisms in Brazilians: comparison with the Portuguese and Portuguese-speaking Africans and pharmacogenetic implications.
OBJECTIVE
The heterogeneity of the Brazilian population renders the extrapolation of pharmacogenomic data derived from well-defined ethnic groups inappropriate. We investigated the influence of self-reported 'race/color', geographical origin and genetic ancestry on the distribution of four VKORC1 SNPs and haplotypes in Brazilians. Comparative data were obtained from two major ancestral roots of Brazilians: Portuguese and Africans from former Portuguese colonies.


METHODS
A total of 1037 healthy adults Brazilians, recruited at four different geographical regions and self identified as white, brown or black (race/color categories), 89 Portuguese and 216 Africans from Angola and Mozambique were genotyped for the VKORC1 3673G>A (rs9923231), 5808T>G (rs2884737), 6853G>C (rs8050894) and 9041G>A (rs7294) polymorphisms using TaqMan(®) (Applied Biosystems, CA, USA) assays. VKORC1 haplotypes were statistically inferred using the haplo.stats software. We inferred the statistical association between the distribution of the VKORC1 polymorphisms among Brazilians and self-reported color, geographical region and genetic ancestry by fitting multinomial log linear models via neural networks. Individual proportions of European and African ancestry were used to assess the impact of genetic admixture on the frequency distribution of VKORC1 polymorphisms among Brazilians, and for the comparison of Brazilians with Portuguese and Africans.


RESULTS
The frequency distribution of the 3673G>A and 5808T>G polymorphisms, and VKORC1 haplotypes among Brazilians varies across geographical regions, within self-reported color categories and according to the individual proportions of European and African genetic ancestry. Notably, the frequency of the warfarin sensitive VKORC1 3673A allele and the distribution of VKORC1 haplotypes varied continuously as the individual proportion of European ancestry increased in the entire cohort, independently of race/color categorization and geographical origin. Brazilians with more than 80% African ancestry differ significantly from Angolans and Mozambicans in frequency of the 3673G>A, 5808T>G and 6853G>C polymorphisms and haplotype distribution, whereas no such differences are observed between Brazilians with more than 90% European ancestry and Portuguese individuals.


CONCLUSIONS
The diversity of the Brazilian population, evident in the distribution of VKORC1 polymorphisms, must be taken into account in the design of pharmacogenetic clinical trials and dealt with as a continuous variable. Warfarin dosing algorithms that include 'race' terms defined for other populations are clearly not applicable to the heterogeneous and extensively admixed Brazilian population.
Suarez-Kurtz
Guilherme
G
Divisão de Farmacologia, Instituto Nacional do Câncer, Rio de Janeiro, Brazil. kurtz@inca.gov.br
Amorim
António
A
Damasceno
Albertino
A
Hutz
Mara H
MH
de Moraes
Manuel Odorico
MO
Ojopi
Elida B
EB
Pena
Sérgio D J
SD
Perini
Jamila A
JA
Prata
Maria João
MJ
Ribeiro-dos-Santos
Andrea
A
Romano-Silva
Marco A
MA
Teixeira
Daniel
D
Struchiner
Claudio José
CJ
D000328:Adult; D000810:Angola / Q000208:ethnology; D000925:Anticoagulants / Q000008:administration & dosage; D044383:Black People / Q000235:genetics*; D001938:Brazil; D015331:Cohort Studies; D005006:Ethnicity / Q000235:genetics*; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009073:Mozambique / Q000208:ethnology; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011174:Portugal; D044469:Racial Groups; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage; D044465:White People / Q000235:genetics
D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases