BACKGROUND: Circulating sex hormone-binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain. METHODS: We performed a nested case-control study of postmenopausal women in the Women's Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone-binding globulin were measured; two polymorphisms of the gene encoding sex hormone-binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians' Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls). RESULTS: Among women, higher plasma levels of sex hormone-binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone-binding globulin levels (P=0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P=0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone-binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone-binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone-binding globulin may have a causal role in the risk of type 2 diabetes. CONCLUSIONS: Low circulating levels of sex hormone-binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.
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机译：背景：循环性激素结合球蛋白水平与胰岛素抵抗呈负相关，但是这些水平是否可以预测发展为2型糖尿病的风险尚不确定。方法：我们在《妇女健康研究》中对未使用激素疗法的绝经后妇女进行了嵌套病例对照研究（359名新诊断出的2型糖尿病和359名对照）。测量血浆中性激素结合球蛋白的水平;对与性激素结合球蛋白SHBG编码基因与蛋白质水平密切相关的两个多态性进行基因分型，并应用于孟德尔随机分析中。然后，我们在Physicians's Health Study II（170位新诊断的2型糖尿病和170位对照）的独立队列中进行了一项复制研究。结果：在女性中，血浆性激素结合球蛋白的血浆水平较高与2型糖尿病的风险较低相关：血浆水平的第一个（最低）四分位数的多变量优势比为1.00，为0.16（95％置信区间[CI] ]，第二个四分位数为0.08至0.33，第三个四分位数为0.04（95％CI，0.01至0.12），第四个（最高）四分位数为0.09（95％CI，0.03至0.21）（趋势P <0.001） ）。这些前瞻性关联在男性中重复出现（血浆水平最高四分位数与最低四分位数的比值比为0.10; 95％CI为0.03至0.36;趋势P <0.001）。与各个野生型等位基因的纯合子相比，SHBG单核苷酸多态性（SNP）rs6259的变异等位基因携带者的性激素结合球蛋白水平高10％（P = 0.005），而rs6257变异体的携带者更高血浆水平降低10％（P = 0.004）;两个SNP的变体在与它们相关的性激素结合球蛋白水平相对应的方向上也与2型糖尿病风险相关。在孟德尔随机化分析中，女性血浆中性激素结合球蛋白血浆水平每标准偏差升高的预测2型糖尿病比值比为0.28（95％CI，0.13至0.58），女性为0.29（95％CI，0.15至0.58）。 0.58）在男性中，这一发现表明性激素结合球蛋白可能与2型糖尿病的风险有关。结论：低水平的性激素结合球蛋白的循环水平是女性和男性罹患2型糖尿病风险的有力预测指标。 SHBG基因型和血浆水平在分层和干预2型糖尿病风险中的临床应用值得进一步检查。
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