Human Molecular Genetics

Human Molecular Genetics Advance Access published online on August 27, 2003
Human Molecular Genetics, doi:10.1093/hmg/ddg294
© 2003 by Oxford University Press

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©2003 Oxford University Press

Article

A Comprehensive Haplotype Analysis of CYP19 and Breast Cancer Risk: The Multiethnic Cohort

Christopher A. Haiman ^1*, Daniel O. Stram ², Malcolm C. Pike ², Laurence N. Kolonel ³, Noel P. Burtt ⁴, David Altshuler ⁵, Joel Hirschhorn ⁶, and Brian E. Henderson ²

¹ Department of Preventive Medicine, Keck School of Medicine, University of Southern California, USC/Norris Comprehensive Cancer Center, 1441 Eastlake Ave., Rm. 4441, Los Angeles, California 90089-9175, USA
² Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089
³ Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii 96813
⁴ Whitehead/MIT Center for Genome Research, Cambridge, Massachusetts 02139
⁵ Whitehead/MIT Center for Genome Research, Cambridge, Massachusetts 02139; Department of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts 02115, Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02114
⁶ Whitehead/MIT Center for Genome Research, Cambridge, Massachusetts 02139; Division of Endocrinology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115

^* To whom correspondence should be addressed. E-mail: haiman{at}usc.edu.

	Abstract

The CYP19 gene encodes for aromatase (P450arom), a key steroidogenic enzyme that catalyzes the final step of estrogen biosynthesis. Apart from rare mutations in CYP19 which result in severe phenotypes associated with estrogen insufficiency, little is known about whether common variation in CYP19 is associated with risk of hormone-related diseases. In this study, we employed a haplotype-based approach to search for common disease-associated variants in this candidate breast cancer susceptibility gene among African-American, Hawaiian, Japanese, Latina and White women in the Multiethnic Cohort Study (MEC). We utilized 74 densely spaced SNPs (1 every 2.6 kb) spanning 189.4 kb of the CYP19 locus to characterize linkage disequilibrium (LD) and haplotype patterns among 69-70 individuals from each ethnic population. We detected four regions of strong LD (blocks 1-4) that were quite closely conserved across populations. Within each block there was a limited diversity of common haplotypes (5-10 with a frequency 5%) and most haplotypes were observed to be shared across populations. Twenty-five haplotype-tagging SNPs (htSNPs) were selected to predict the common haplotypes with high probability (average R_h² = 0.92) and genotyped in a breast cancer case-control study in the MEC (cases, n = 1,355; controls, n = 2,580). We first performed global tests for differences in risk according to the common haplotypes and observed significant haplotype-effects in block 2 (P = 0.01; haplotypes 2b (OR = 1.23; 95% CI, 1.07-1.40), 2d (OR = 1.28; 95% CI, 1.01-1.62)). We also found a common long-range haplotype comprised of block-specific haplotypes 2b and 3c to be associated with increased risk of breast cancer (haplotype 2b-3c: OR = 1.31; 95% CI, 1.11-1.54)). Our findings suggest the hypothesis that women with the long-range CYP19 haplotype 2b-3c may be carriers of a predisposing breast cancer susceptibility allele.

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