Thompson Deborah J, Healey Catherine S, Baynes Caroline, Kalmyrzaev Bolot, Ahmed Shahana, Dowsett Mitch, Folkerd Elizabeth, Luben Robert N, Cox David, Ballinger Dennis, Pharoah Paul D P, Ponder Bruce A J, Dunning Alison M, Easton Douglas F
Cambridge University, Strangeways Research Laboratories, Worts Causeway, Cambridge CB1 8RN, United Kingdom.
Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3490-8. doi: 10.1158/1055-9965.EPI-08-0734.
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.
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.
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).
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.
绝经后女性中，性激素结合球蛋白（SHBG）的循环水平与乳腺癌风险呈负相关。据报道，SHBG基因内的三种多态性会影响SHBG水平，但尚未有系统的研究来确定其他此类变异。
我们研究了1134名健康绝经后女性的SHBG水平与SHBG基因内或其周围的11个标签单核苷酸多态性（SNP）之间的关联。在多达6622例绝经后乳腺癌病例和6784例对照中测试了SHBG SNP与乳腺癌之间的关联。
SHBG基因内或其附近的10个SNP以及（TAAAA）（n）多态性与SHBG水平显著相关。rs6259、rs858521和rs727428与体重指数、腰围、臀围、年龄和吸烟状况的最佳拟合组合解释了SHBG水平（自然对数转换）变异的24%。单倍型分析表明，rs858518、rs727428或与其处于连锁不平衡的一个变异会降低SHBG水平，但这种效应被rs6259（D356N）中和。rs1799941会增加SHBG水平，但先前报道的与（TAAAA）（n）重复长度的关联似乎是与这些SNP连锁不平衡的结果。另一个SHBG SNP与乳腺癌显著相关（rs6257，每等位基因优势比为0.88；95%置信区间为0.82 - 0.95；P = 0.002）。
至少3个SNP与SHBG水平的关联高度显著，但效应大小相对较小。rs6257是一个潜在的乳腺癌易感变异，但SHBG水平的遗传决定因素与乳腺癌之间的关系很复杂。
