Ou Ya-Nan, Yang Liu, Wu Bang-Sheng, Tan Lan, Yu Jin-Tai
Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China.
Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
Ann Transl Med. 2022 Oct;10(19):1054. doi: 10.21037/atm-22-1156.
Extensive observational studies have suggested an association between serum sex-hormone binding globulin (SHBG) and Alzheimer's disease (AD); however, causality remains unclear. Furthermore, the effects on other neurodegenerative diseases have been poorly investigated. We aimed to explore the causal effects of genetically predicted SHBG serum levels on common neurodegenerative diseases.
A two-sample Mendelian randomization (MR) approach was used. Genetic variants of SHBG levels in the serum, detected using the chemiluminescent two-step sandwich immunoassay method, were identified from a genome-wide association meta-analysis from the UK Biobank (N=363,228). Summary-level data for AD, and other common neurodegenerative diseases including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD) were adopted from the corresponding large genome-wide association studies of individuals of European ancestry, which were either clinically or autopsy-diagnosed. Causal estimates were calculated using the inverse-variance weighted (IVW) method and several sensitivity methods (MR-Egger, weighted median, and weighted mode). Egger intercept, MR-PRESSO, and leave-one-out analyses were used to identify potential violations.
Genetically determined serum SHBG levels [odds ratio (OR) =1.113, 95% CI: 1.019-1.215, P=0.017] were associated with an increased risk of ALS. This causal effect was confirmed using sensitivity analyses, including the MR-Egger (OR =1.229, 95% CI: 1.049-1.441, P=0.012), weighted median (OR =1.231, 95% CI: 1.077-1.406, P=0.002), and weighted mode (OR =1.235, 95% CI: 1.067-1.431, P=0.005) methods. No notable heterogeneity or directional pleiotropy was observed. However, leave-one-out analysis showed that rs9892297 drove the observed effects. There was no evidence that genetically predicted serum SHBG levels affect other neurodegenerative diseases, including AD, PD, MS, DLB, and FTD (all P>0.05).
This MR analysis found that genetically determined serum SHBG was associated with an increased risk of ALS rather than AD, which is inconsistent with previous observational studies. This novel finding highlights the potential of SHBG in peripheral serum for ALS prevention. Further research into the effects of SHBG on other neurodegenerative diseases is required, especially because of the increased utilization of hormone therapy.
大量观察性研究表明血清性激素结合球蛋白（SHBG）与阿尔茨海默病（AD）之间存在关联；然而，因果关系仍不明确。此外，对其他神经退行性疾病的影响研究较少。我们旨在探讨基因预测的SHBG血清水平对常见神经退行性疾病的因果效应。
采用两样本孟德尔随机化（MR）方法。使用化学发光两步夹心免疫测定法检测血清中SHBG水平的基因变异，这些变异来自英国生物银行（N = 363,228）的全基因组关联荟萃分析。AD以及其他常见神经退行性疾病的汇总数据，包括帕金森病（PD）、肌萎缩侧索硬化症（ALS）、多发性硬化症（MS）、路易体痴呆（DLB）和额颞叶痴呆（FTD），均来自相应的针对欧洲血统个体的大型全基因组关联研究，这些研究通过临床或尸检诊断。使用逆方差加权（IVW）方法和几种敏感性方法（MR-Egger、加权中位数和加权模式）计算因果估计值。使用Egger截距、MR-PRESSO和留一法分析来识别潜在的违反情况。
基因决定的血清SHBG水平[比值比（OR）= 1.113，95%置信区间：1.019 - 1.215，P = 0.017]与ALS风险增加相关。使用敏感性分析（包括MR-Egger（OR = 1.229，95%置信区间：1.049 - 1.441，P = 0.012）、加权中位数（OR = 1.231，95%置信区间：1.077 - 1.406，P = 0.002）和加权模式（OR = 1.235，95%置信区间：1.067 - 1.431，P = 0.005）方法）证实了这种因果效应。未观察到明显的异质性或方向性多效性。然而，留一法分析表明rs9892297驱动了观察到的效应。没有证据表明基因预测的血清SHBG水平会影响其他神经退行性疾病，包括AD、PD、MS、DLB和FTD（所有P>0.05）。
这项MR分析发现，基因决定的血清SHBG与ALS风险增加相关，而非AD，这与先前的观察性研究不一致。这一新发现凸显了外周血清中SHBG在预防ALS方面的潜力。需要进一步研究SHBG对其他神经退行性疾病的影响，尤其是考虑到激素疗法的使用增加。
