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Identification of common variants in the SHBG gene affecting sex hormone-binding globulin levels and breast cancer risk in postmenopausal women.

AbstractBACKGROUND:
Circulating levels of sex hormone-binding globulin (SHBG) are inversely associated with breast cancer risk in postmenopausal women. Three polymorphisms within the SHBG gene have been reported to affect SHBG levels, but there has been no systematic attempt to identify other such variants.
METHODS:
We looked for associations between SHBG levels in 1,134 healthy, postmenopausal women and 11 tagging single nucleotide polymorphisms (SNP) in or around the SHBG gene. Associations between SHBG SNPs and breast cancer were tested in up to 6,622 postmenopausal breast cancer cases and 6,784 controls.
RESULTS:
Ten SNPs within or close to the SHBG gene were significantly associated with SHBG levels as was the (TAAAA)(n) polymorphism. The best-fitting combination of rs6259, rs858521, and rs727428 and body mass index, waist, hip, age, and smoking status accounted for 24% of the variance in SHBG levels (natural logarithm transformed). Haplotype analysis suggested that rs858518, rs727428, or a variant in linkage disequilibrium with them acts to decrease SHBG levels but that this effect is neutralized by rs6259 (D356N). rs1799941 increases SHBG levels, but the previously reported association with (TAAAA)(n) repeat length appears to be a consequence of linkage disequilibrium with these SNPs. One further SHBG SNP was significantly associated with breast cancer (rs6257, per-allele odds ratio, 0.88; 95% confidence interval, 0.82-0.95; P = 0.002).
CONCLUSION:
At least 3 SNPs showed associations with SHBG levels that were highly significant but relatively small in magnitude. rs6257 is a potential breast cancer susceptibility variant, but relationships between the genetic determinants of SHBG levels and breast cancer are complex.
AuthorsDeborah J Thompson, Catherine S Healey, Caroline Baynes, Bolot Kalmyrzaev, Shahana Ahmed, Mitch Dowsett, Elizabeth Folkerd, Robert N Luben, David Cox, Dennis Ballinger, Paul D P Pharoah, Bruce A J Ponder, Alison M Dunning, Douglas F Easton, Studies in Epidemiology and Risks of Cancer Heredity Team
JournalCancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology (Cancer Epidemiol Biomarkers Prev) Vol. 17 Issue 12 Pg. 3490-8 (Dec 2008) ISSN: 1055-9965 [Print] United States
PMID19064566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Sex Hormone-Binding Globulin
Topics
  • Aged
  • Breast Neoplasms (genetics)
  • Case-Control Studies
  • Female
  • Genetic Variation
  • Genotype
  • Haplotypes
  • Humans
  • Linear Models
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Postmenopause
  • Risk
  • Sex Hormone-Binding Globulin (genetics)

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