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The CYP3A4*1B Variant Is Related to the Onset of Puberty, A Known Risk Factor for the Development of Breast Cancer¹

Divisions of Molecular Epidemiology [F. F. K., C. W., B. L. G., G. T.] and Biometry and Risk Assessment [R. R. D.], National Center for Toxicological Research, Jefferson, Arkansas 72079; St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [J. L., E. S.]; and Departments of Community and Preventive Medicine, Mount Sinai School of Medicine, New York, New York 10029 [G. S. B., M. S. W.]

Breast development, one of the first signs of puberty, is closelyassociated with age at menarche; and early menarche is in turn a well-established risk factor for female breast cancer. We examined the relationships between the onset of puberty and gene variants for certain enzymes that regulate hormone metabolism among 137 healthy nine-year-old girls from two pediatric clinics. High-activity CYP17 alleles, involved in estrogen formation, and high-activity CYP1A2 and CYP1B1 alleles, whose gene products metabolize estradiol, were not associated with pubertal stage. High activity CYP3A4, but not CYP3A5, which primarily metabolizes testosterone, showed a striking association with the onset of puberty (adjusted odds ratio, 3.21; 95% confidence interval, 1.62–6.89 for the genotype 0-1-2 rapid alleles). Of the homozygous CYP3A4*1B/1B girls, 90% had reached puberty; whereas, for the low-activity homozygous CYP3A4*1A/1A individuals, only 40% had done so. In heterozygotes, 56% had reached puberty. CYP1B1, CYP3A4, and CYP3A5 rapid variants were more common in African-American than in Hispanic or Caucasian girls.

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