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CYP11A catalyzes the rate-limiting step in the biosynthesis of sex-steroid hormones. In this study, we employed a systematic approach that involved gene resequencing and a haplotype-based analysis to investigate the relationship between common variation in CYP11A and breast cancer risk among African-Americans, Latinas, Japanese-Americans, Native Hawaiians, and Whites in the Multiethnic Cohort Study. Resequencing in a multiethnic panel of 95 advanced breast cancer cases revealed no common missense variant (> or =5% frequency). Common haplotype patterns were assessed by genotyping 36 densely spaced single nucleotide polymorphisms (SNPs) spanning 67 kb of the CYP11A locus in a multiethnic panel of subjects (n = 349; 1 SNP/1.86 kb on average). We identified one to two regions of strong linkage disequilibrium in these populations. Twelve tagging SNPs were selected to predict the common haplotypes (> or =5% frequency) in these regions with high probability (average R(h)(2) = 0.94) and were examined in a breast cancer case-control study in the Multiethnic Cohort Study (1,615 cases and 1,962 controls). A global test for differences in risk according to common haplotypes over the locus was statistically significant (P = 0.006), as were associations with haplotypes in each block (block 1 global test, P = 0.008; haplotype 1D, effect per haplotype copy, odds ratios, 1.23; 95% confidence interval, 1.03-1.48) and block 2 (global test, P = 0.016; haplotype 2F odds ratios, 1.52; 95% confidence interval, 1.15-2.01). These haplotypes were most common in Japanese-Americans and Native Hawaiians, followed by Whites then Latinas, and were rare in African-Americans (<5% frequency); the haplotype effects on risk across each group were homogeneous. Based on these findings, CYP11A deserves further consideration as a candidate breast cancer susceptibility gene.

Objective: To review the evidence that polycystic ovary syndrome is a genetic disease., Design: Review of published literature., Results: The existing literature provides a strong basis for arguing that PCOS clusters in families. However, the mode of inheritance of the disorder is still uncertain, although the majority of studies are consistent with an autosomal dominant pattern, modified perhaps by environmental factors. In addition, studies on PCOS cells (theca, muscle, and adipocytes) in culture have documented a persistent biochemical and molecular phenotype that distinguishes them from normal cells. Although several loci have been proposed as PCOS genes including CYP11A, the insulin gene, and a region near the insulin receptor, the evidence supporting linkage is not overwhelming. The strongest case can be made for the region near the insulin receptor gene, as it has been identified in two separate studies. However, the responsible gene at chromosome 19p13.3 remains to be identified. Association studies have provided a number of potential loci with genetic variants that may create or add to a PCOS phenotype, including Calpain 10, IRS-1 and -2, and SHBG., Conclusions: Collectively, these findings are consistent with the concept that a gene or several genes are linked to PCOS susceptibility. Because the mutations/genotypes associated with PCOS are rare, and their full impact on the phenotype incompletely understood, routine screening of women with PCOS or stigmata of PCOS for these genetic variants is not indicated at this time. Currently the treatment implications for individually identified genetic variants is uncertain and must be addressed on a case by case basis.