Liu Siyuan, Mu Zhuosong, Chen Xinyi, Xu Yingying
The Third Clinical Medical College of Zhejiang, University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China.
Jiangnan Hospital Affiliated to Zhejiang, Chinese Medical University (Hangzhou Xiaoshan Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, China.
Diabetol Metab Syndr. 2024 Sep 3;16(1):215. doi: 10.1186/s13098-024-01443-4.
Observational studies have found associations between sex hormones and metabolic syndrome(Mets), but the causal relationships remains unclear. This study utilizes univariable and multivariable Mendelian randomization (MR) to elucidate the associations between sex hormones (including sex hormone-binding globulin(SHBG), estradiol(E2), testosterone(T)) and Mets and its subtypes (including waist circumference(WC), fasting blood glucose(FBG), high blood pressure(HBP), high-density lipoprotein(HDL-C), triglycerides(TG)).
We utilized summary data from large-scale genome-wide association studies. Univariable Mendelian randomization (UMVMR) analysis was primarily conducted using the inverse variance weighted method (IVW), with secondary analyses employing the weighted median, MR-Egger regression, simple mode method, and weighted mode method. Subsequently, multivariable Mendelian randomization (MVMR) was employed to assess the causal relationships between SHBG, T, E2, and MetS and its components: WC, FPG, HBP, HDL-C, and TG. Sensitivity analyses were conducted to assess result reliability.
Genetically predicted SHBG was significantly negatively associated with MetS (UMVMR: β=-0.72; 95% CI = 0.41 to 0.57; P = 1.28e-17; MVMR: β=-0.60; 95% CI=-0.83 to -0.38; P < 0.001). Positive causal relationships were observed between SHBG and WC(MVMR: β = 0.10; 95% CI = 0.03 to 0.17; P = 0.01) and HDL-C (MVMR: β = 0.41; 95% CI = 0.21 to 0.60; P < 0.001), while negative causal relationships were found between SHBG and HBP (MVMR: β=-0.02; 95% CI=-0.04 to -0.00; P = 0.02), TG (MVMR: β=-0.48; 95% CI=-0.70 to -0.26; P < 0.001). Genetically predicted E2 exhibited a negative association with TG (MVMR: β=-1.49; 95% CI=-2.48 to -0.50; P = 0.003). Genetically predicted T was negatively associated with TG (MVMR: β=-0.36; 95% CI=-0.71 to -0.00; P = 0.049) and WC (MVMR: β=-0.13; 95% CI=-0.24 to -0.02; P = 0.02), with inconsistent sensitivity analyses. Additionally, No other causal associations were found.
Our study indicates that SHBG is a protective factor for MetS, potentially delaying its onset and progression through improvements in HBP and TG. Furthermore, T and E2 may improve TG levels, with T also reducing WC levels. Importantly, our study provides new insights for the prevention and treatment of MetS.
观察性研究发现性激素与代谢综合征（Mets）之间存在关联，但因果关系仍不明确。本研究采用单变量和多变量孟德尔随机化（MR）方法，以阐明性激素（包括性激素结合球蛋白（SHBG）、雌二醇（E2）、睾酮（T））与Mets及其亚型（包括腰围（WC）、空腹血糖（FBG）、高血压（HBP）、高密度脂蛋白（HDL-C）、甘油三酯（TG））之间的关联。
我们利用了大规模全基因组关联研究的汇总数据。单变量孟德尔随机化（UMVMR）分析主要采用逆方差加权法（IVW）进行，二级分析采用加权中位数、MR-Egger回归、简单模式法和加权模式法。随后，采用多变量孟德尔随机化（MVMR）来评估SHBG、T、E2与Mets及其组成部分（WC、FPG、HBP、HDL-C和TG）之间的因果关系。进行敏感性分析以评估结果的可靠性。
基因预测的SHBG与Mets显著负相关（UMVMR：β=-0.72；95%CI=0.41至0.57；P=1.28e-17；MVMR：β=-0.60；95%CI=-0.83至-0.38；P<0.001）。在SHBG与WC（MVMR：β=0.10；95%CI=0.03至0.17；P=0.01）和HDL-C（MVMR：β=0.41；95%CI=0.21至0.60；P<0.001）之间观察到正因果关系，而在SHBG与HBP（MVMR：β=-0.02；95%CI=-0.04至-0.00；P=0.02）、TG（MVMR：β=-0.48；95%CI=-0.70至-0.26；P<0.001）之间发现负因果关系。基因预测的E2与TG呈负相关（MVMR：β=-1.49；95%CI=-2.48至-0.50；P=0.003）。基因预测的T与TG（MVMR：β=-0.36；95%CI=-0.71至-0.00；P=0.049）和WC（MVMR：β=-0.13；95%CI=-0.24至-0.02；P=0.02）呈负相关，敏感性分析结果不一致。此外，未发现其他因果关联。
我们的研究表明，SHBG是Mets的保护因素，可能通过改善HBP和TG来延迟其发病和进展。此外，T和E2可能改善TG水平，T还可降低WC水平。重要的是，我们的研究为Mets的预防和治疗提供了新的见解。
