Sex hormone-binding globulin and risk of type 2 diabetes in women and men.
Sex hormone-binding globulin and risk of type 2 diabetes in women and men.
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性激素结合球蛋白和男性2型糖尿病的风险。
DOI：
10.1056/nejmoa0804381
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发表时间：
2009-09-17
期刊：
影响因子：
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通讯作者：
Liu S
中科院分区：
文献类型：
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作者：
Ding EL;Song Y;Manson JE;Hunter DJ;Lee CC;Rifai N;Buring JE;Gaziano JM;Liu S
循环中的性激素结合球蛋白水平与胰岛素抵抗呈负相关，但这些水平是否能预测发生2型糖尿病的风险尚不确定。我们对妇女健康研究中未使用激素治疗的绝经后妇女进行了巢式病例对照研究（359例新诊断的2型糖尿病患者和359例对照）。测量性激素结合球蛋白的血浆水平;对编码性激素结合球蛋白（SHBG）的基因的两种多态性进行基因分型，并应用于孟德尔随机化分析。然后，我们对来自医生健康研究II的独立男性队列（170名新诊断的2型糖尿病患者和170名对照）进行了重复研究。在女性中，较高的血浆性激素结合球蛋白水平与较低的2型糖尿病风险具有前瞻性相关性：多变量比值比为1.00的第一（最低）四分位数的血浆水平，0.16（95%置信区间[CI]，0.08 - 0.33），第二四分位数，0.04第三四分位数为0.09（95%CI，0.03 - 0.21）（趋势P<0.001）。这些前瞻性关联在男性中得到了复制（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）。与相应野生型等位基因的纯合子相比，SHBG单核苷酸多态性（SNP）rs6259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），rs6257变异携带者的血浆水平降低10（P = 0.004）;两种SNPs的变异也与2型糖尿病的风险相关，方向对应于其相关的性激素结合球蛋白水平。在孟德尔随机化分析中，血浆性激素结合球蛋白水平每增加一个标准差，2型糖尿病的预测比值比为0.28（95% CI，0.13至0.58），女性为0.29（95%CI，0.15至0.58），这一发现表明，性激素结合球蛋白可能在2型糖尿病的风险中起因果作用。低循环水平的性激素结合球蛋白是女性和男性2型糖尿病风险的强有力预测因素。SHBG基因型和血浆水平在2型糖尿病风险分层和干预中的临床应用值得进一步研究。
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. 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). 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. 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.