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Cited by 61Genetic Associations and EpidemiologyEstrogen and related hormone effectsBRCA gene mutations in cancer

Identification of Common Variants in the SHBG Gene Affecting Sex Hormone-Binding Globulin Levels and Breast Cancer Risk in Postmenopausal Women

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Thompson, Deborah J., Healey, Catherine S., Baynes, Caroline, Kalmyrzaev, Bolot, Ahmed, Shahana, Dowsett, Mitch, Folkerd, Elizabeth, Luben, Robert N. +7 more·2008·Cancer Epidemiology, Biomarkers & Prevention
DOI 10.1158/1055-9965.epi-08-0734PMC PMC2660245
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Abstract

Background: 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. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3490–8)

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  • For rs727428, the T allele accounted for a decrease in both SHBG and T levels, without affecting calculated free T.

    “For a third SNP in the SHBG locus, rs727428, the T allele accounted for a decrease in both SHBG and T levels, without affecting calculated free T [66, 68].”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [68]

    The Results section (page unavailable) associates rs727428 with lower SHBG levels, and the Discussion identifies the associated allele as the minor allele. The copy does not establish that this is the T allele or report that rs727428 lowers testosterone while leaving calculated free testosterone unchanged. (LLM, conf=0.85)

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Authors
Thompson, D. J., Healey, C. S., Baynes, C., Kalmyrzaev, B., Ahmed, S., Dowsett, M., Folkerd, E., Luben, R. N., Cox, D., Ballinger, D., Pharoah, P. D. P., Ponder, B. A. J., Dunning, A. M., Easton, D. F., & The Studies in Epidemiology and Risks of Cancer Heredity Team
Affiliations
  • Cancer Research UK (GB)
  • 2Department of Oncology, and
  • Royal Marsden Hospital (GB)
  • University of Cambridge (GB)
  • Perlegen (United States) (US)
ORCID
Venue
Cancer Epidemiology, Biomarkers & Prevention
Publisher
American Association for Cancer Research (AACR)
Published
2008-12-01
Volume
17
Issue
12
Pages
3490-3498
ISSN
  • 1055-9965 (ISSN-L)
  • 1538-7755
DOI
10.1158/1055-9965.epi-08-0734
PMC
PMC2660245
OpenAlex
W2126545533
Cited by
61
References
2
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 2 · 2017: 7 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 5 · 2012: 8
FWCI
2.09
Type
journal article
Language
en
Open access
Locations
  • Cancer Epidemiology Biomarkers & Prevention (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Wellcome Trust (999998)
  • Cancer Research UK (A10118, 10118)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
Keywords
sex hormone-binding globulin, SHBG gene, single nucleotide polymorphisms, breast cancer risk, postmenopausal women, genetic susceptibility, haplotype analysis, linkage disequilibrium, body mass index
MeSH terms
Aged, Breast Neoplasms, Female, Genotype, Haplotypes, Humans, Middle Aged, Risk, Sex Hormone-Binding Globulin, Genetic Variation, Linear Models, Case-Control Studies, Postmenopause, Polymorphism, Single Nucleotide

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