CYP3A4-V and prostate cancer in African Americans: causal or confounding association because of population stratification?
CYP3A4-V, an A to G promoter variant associated with prostate cancer in African Americans, exhibits large differences in allele frequency between populations. Given that the African American population is genetically heterogeneous because of its African ancestry and subsequent admixture with European Americans, case-control studies with African Americans are highly susceptible to spurious associations. To test for association with prostate cancer, we genotyped CYP3A4-V in 1376 (2 N) chromosomes from prostate cancer patients and age- and ethnicity-matched controls representing African Americans, Nigerians, and European Americans. To detect population stratification among the African American samples, 10 unlinked genetic markers were genotyped. To correct for the stratification, the uncorrected association statistic was divided by the average of association statistics across the 10 unlinked markers. Sharp differences in CYP3A4-V frequencies were observed between Nigerian and European American controls (0.87 and 0.10, respectively; P<0.0001). African Americans were intermediate (0.66). An association uncorrected for stratification was observed between CYP3A4-V and prostate cancer in African Americans (P=0.007). A nominal association was also observed among European Americans (P=0.02) but not Nigerians. In addition, the unlinked genetic marker test provided strong evidence of population stratification among African Americans. Because of the high level of stratification, the corrected P-value was not significant (P=0.25). Follow-up studies on a larger dataset will be needed to confirm whether the association is indeed spurious; however, these results reveal the potential for confounding of association studies by using African Americans and the need for study designs that take into account substructure caused by differences in ancestral proportions between cases and controls.
Kittles
Rick A
RA
National Human Genome Center, Howard University, Washington, DC 20060, USA. rkittles@howard.edu
Chen
Weidong
W
Panguluri
Ramesh K
RK
Ahaghotu
Chiledum
C
Jackson
Aaron
A
Adebamowo
Clement A
CA
Griffin
Robin
R
Williams
Tyisha
T
Ukoli
Flora
F
Adams-Campbell
Lucile
L
Kwagyan
John
J
Isaacs
William
W
Freeman
Vincent
V
Dunston
Georgia M
GM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D001483:Base Sequence; D044383:Black People / Q000235:genetics*; D016022:Case-Control Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D005787:Gene Frequency; D005819:Genetic Markers; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics*; D009549:Nigeria; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics*; D014481:United States; D044465:White People / Q000235:genetics; D001741:Black or African American
D004273:DNA, Neoplasm; D005819:Genetic Markers; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human