title: Impact of population admixture on the distribution of the CYP3A5*3 polymorphism.
abstract: OBJECTIVE
  To compare the effectiveness of self-identified ethnic/color and marker-based biogeographical ancestry classifications in genotyping the CYP3A5*3 polymorphism in the Brazilian population.
  
  
  METHODS
  Individual DNA from 308 healthy Brazilians, self-identified as white, intermediate and black was genotyped for the CYP3A5*3 polymorphism and for a set of insertion-deletion polymorphisms, validated as ancestry informative markers (AIMs). The Structure software was used to analyze the AIMs data and to obtain estimates of the African component of ancestry (ACA). Nonlinear logistic regression modeling was developed to describe the association between the CYP3A5*3 polymorphism and the individual ACA values.
  
  
  RESULTS
  The CYP3A5*3 allele and genotype distribution differed significantly across the self-reported 'color' groups (p < 0.0001, Fisher exact test), with a trend for decreasing frequency of both the CYP3A5*3 allele and the *3/*3 genotype from white to intermediate to black individuals (p < 0.0001, chi(2) test for trend in proportions). When the population sample was proportioned in quartiles according to the individual ACA values, the frequency of the CYP3A5*3 allele and the *3/*3 genotype declined progressively from the lowest (<0.25 ACA) to the highest (>0.75 ACA) quartile. Nonlinear logistic regression showed that the odds of having the CYP3A5*3 allele decreases monotonically (p < 0.0001, Wald statistics) with the increase of the ACA, throughout the ACA range (0.15-0.93) observed in the overall population sample.
  
  
  CONCLUSIONS
  Interethnic admixture is a source of cryptic population structure that may lead to spurious genotype-phenotype associations in pharmacogenetic/-genomic studies. Logistic regression modeling of CYP3A5*3 polymorphism shows that admixture must be dealt with as a continuous variable, rather than proportioned in arbitrary subcategories for the convenience of data quantification and analysis.
authors.affiliation: Instituto Nacional de Câncer, Divisão de Farmacologia, Instituto Nacional de Câncer, Rua André Cavalcanti 37, Rio de Janeiro 21230-050, Brazil. kurtz@inca.gov.br
authors.forename: Guilherme
authors.initials: G
authors.lastname: Suarez-Kurtz
authors.forename: Jamila A
authors.initials: JA
authors.lastname: Perini
authors.forename: Luciana
authors.initials: L
authors.lastname: Bastos-Rodrigues
authors.forename: Sergio D J
authors.initials: SD
authors.lastname: Pena
authors.forename: Cláudio
authors.initials: C
authors.lastname: Struchiner
mesh_terms: D001938:Brazil; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007438:Introns; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D044469:Racial Groups / Q000235:genetics; D012044:Regression Analysis
chemical_list: C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A