Human Molecular Genetics

Human Molecular Genetics Advance Access originally published online on August 27, 2003

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Human Molecular Genetics, 2003, Vol. 12, No. 20 2679-2692
DOI: 10.1093/hmg/ddg294
© 2003 Oxford University Press

A comprehensive haplotype analysis of CYP19 and breast cancer risk: the Multiethnic Cohort

Christopher A. Haiman^1,*, Daniel O. Stram¹, Malcolm C. Pike¹, Laurence N. Kolonel², Noel P. Burtt³, David Altshuler^3,4,5,6, Joel Hirschhorn^3,6,7 and Brian E. Henderson¹

¹Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA, ²Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, HI 96813, USA, ³Whitehead/MIT Center for Genome Research, Cambridge, MA 02139, USA, ⁴Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, ⁵Department of Molecular Biology and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA, ⁶Department of Genetics, Harvard Medical School, Boston, MA 02115, USA and ⁷Division of Endocrinology, Children's Hospital and Department of Pediatrics, Boston, MA 02115, USA

Received June 18, 2003; Accepted August 16, 2003

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 single-nucleotide polymorphisms (SNPs) (one 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 to 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=1355; controls, n=2580). 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.

^* To whom correspondence should be addressed at: Department of Preventive Medicine, University of Southern California, USC/Norris Comprehensive Cancer Center, 1441 Eastlake Ave, Rm 4441, Los Angeles, CA 90089-9175, USA. Tel: +1 3238650429; Fax: +1 3238650127; Email: haiman{at}usc.edu

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