背景:本研究的目的是探讨通过垂体-甲状腺/肾上腺/性腺轴调节的激素对发生静脉血栓栓塞(VTE)的风险的遗传效应,并探讨它们之间的潜在因果关系。
方法:采用双样本孟德尔随机化(MR)设计。用作各种激素和激素介导的疾病的工具变量的单核苷酸多态性(SNP)来自已发表的全基因组关联研究(GWAS)。从UKBiobank和FinnGen联盟获得了发生VTE(包括深静脉血栓形成[DVT]和肺栓塞[PE])风险的汇总统计数据。采用逆方差加权(IVW)作为分析因果关联的主要方法。其他MR方法用于补充估计和敏感性分析。
结果:游离甲状腺素(FT4)浓度较高的遗传易感性与发生DVT的风险较大相关(OR=1.0007,95CI[1.0001-1.0013],p=0.0174)和VTE(OR=1.0008,95CI[1.0002-1.0013],p=0.0123)。遗传预测的甲状腺功能亢进与发生DVT的风险增加显著相关(OR=1.0685,95CI[1.0139-1.1261],p=0.0134)和VTE(OR=1.0740,95CI[1.0165-1.1348],p=0.0110)。根据最初的MR分析,睾酮浓度与发生VTE的风险呈正相关(OR=1.0038,95CI[1.004-1.0072],p=0.0285)。性别分层后,雌二醇浓度与发生DVT的风险呈正相关(OR=1.0143,95CI[1.0020-1.0267],p=0.0226)和VTE(OR=1.0156,95CI[1.0029-1.0285],p=0.0158)在女性中,而睾酮和VTE之间的显著关系并不持续。SHBGrs858518被确定为唯一与发生VTE风险增加相关的SNP。由雌二醇介导,在女性。
结论:遗传预测的甲状腺功能亢进和FT4浓度升高与发生VTE的风险呈正相关。遗传预测的性激素对发生VTE的风险的影响在男性和女性之间有所不同。更高的遗传预测雌二醇浓度与女性发生VTE的风险增加有关。而SHBGrs858518变异可能成为女性VTE的潜在预防和治疗靶点。
BACKGROUND: The aim of this study was to explore the genetic effects of hormones modulated through the pituitary-thyroid/adrenal/gonadal axis on the risk of developing venous thromboembolism (VTE) and to investigate the potentially causal relationships between them.
METHODS: A two-sample Mendelian randomization (MR) design was used. The single-nucleotide polymorphisms (SNPs) used as instrumental variables for various hormones and hormone-mediated diseases were derived from published genome-wide association studies (GWASs). Summary statistics for the risk of developing VTE (including deep venous thrombosis [DVT] and pulmonary embolism [PE]) were obtained from the UK Biobank and the FinnGen consortium. Inverse-variance weighting (IVW) was applied as the primary method to analyse causal associations. Other MR methods were used for supplementary estimates and sensitivity analysis.
RESULTS: A genetic predisposition to greater free thyroxine (FT4) concentrations was associated with a greater risk of developing DVT (OR = 1.0007, 95%CI [1.0001-1.0013], p = 0.0174) and VTE (OR = 1.0008, 95%CI [1.0002-1.0013], p = 0.0123). Genetically predicted hyperthyroidism was significantly associated with an increased risk of developing DVT (OR = 1.0685, 95%CI [1.0139-1.1261], p = 0.0134) and VTE (OR = 1.0740, 95%CI [1.0165-1.1348], p = 0.0110). According to the initial MR analysis, testosterone concentrations were positively associated with the risk of developing VTE (OR = 1.0038, 95%CI [1.004-1.0072], p = 0.0285). After sex stratification, estradiol concentrations were positively associated with the risk of developing DVT (OR = 1.0143, 95%CI [1.0020-1.0267], p = 0.0226) and VTE (OR = 1.0156, 95%CI [1.0029-1.0285], p = 0.0158) in females, while the significant relationship between testosterone and VTE did not persist. SHBG rs858518 was identified as the only SNP that was associated with an increased risk of developing VTE, mediated by estradiol, in females.
CONCLUSIONS: Genetically predicted hyperthyroidism and increased FT4 concentrations were positively associated with the risk of developing VTE. The effects of genetically predicted sex hormones on the risk of developing VTE differed between males and females. Greater genetically predicted estradiol concentrations were associated with an increased risk of developing VTE in females, while the SHBG rs858518 variant may become a potential prevention and treatment target for female VTE.