INTRODUCTION TM6SF2 -rs58542926-T is associated with increased cirrhosis and modestly decreased coronary artery disease prevalence. However, relative effects of TM6SF2 genotype on major adverse cardiovascular events (MACE) vs liver-related events (LRE) are not known. METHODS We used the UK Biobank, a prospective cohort with genetic and inpatient diagnosis data. The primary predictor was TM6SF2 -rs58542926 genotype, and the primary outcomes were MACE and LRE. Effects were reported as subhazard ratios (sHRs) and 10-year cumulative incidence by Fine-Gray competing risk analyses. RESULTS More than 430,000 individuals met inclusion criteria. TM6SF2 -rs58542926-TT genotype (vs CC) was associated with higher incidence of LRE (adjusted sHR 3.16, 95% confidence interval 1.86-5.37) and lower incidence of MACE (adjusted sHR for TT vs CC genotype 0.76, 95% confidence interval 0.63-0.91). In individuals with fibrosis-4 (FIB4) < 1.3, 1.3-2.67, and > 2.67, 10-year LRE incidence in TM6SF2 -rs58542926-TT vs CC individuals was 0.08% vs 0.06% ( P > 0.05), 0.81% vs 0.20% ( P < 0.0001), and 10.5% vs 3.4% ( P = 0.00094), respectively. The corresponding values for MACE were 3.8% vs 5.1% ( P = 0.032), 6.4% vs 8.2% ( P = 0.040), and 17.1% vs 12.4% ( P > 0.05). The absolute decrease in MACE with rs58542926-TT (vs CC) genotype exceeded the absolute increase in LRE in all groups but FIB4 > 2.67. Associations of TM6SF2 genotype with LRE/MACE were significant in men but not women. TM6SF2 -rs58542926-T allele was also associated with increased hepatic steatosis and corrected T1 time by magnetic resonance imaging, with greater effect sizes in men than women. DISCUSSION TM6SF2 genotype has opposite effects on LRE vs MACE incidence, and absolute effects on MACE were greater except in those with highest FIB4 scores. Effects were strongest in men. These findings clarify implications of TM6SF2 genotype based on personalized clinical risk.

中文翻译：

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TM6SF2 -rs58542926 基因型对社区队列中肝脏和心脏事件的发生率具有相反的影响。


引言 TM6SF2 -rs58542926-T 与肝硬化增加和冠状动脉疾病患病率适度降低有关。然而，TM6SF2 基因型对主要不良心血管事件 （MACE） 与肝脏相关事件 （LRE） 的相对影响尚不清楚。方法 我们使用了英国生物样本库，这是一个具有遗传和住院诊断数据的前瞻性队列。主要预测因子为 TM6SF2 -rs58542926 基因型，主要结局为 MACE 和 LRE。通过 Fine-Gray 竞争风险分析，以亚风险比 （sHRs） 和 10 年累积发生率的形式报告效果。结果 超过 430,000 人符合纳入标准。TM6SF2 -rs58542926-TT 基因型 （vs CC） 与 LRE 发生率较高 （调整后的 sHR 3.16,95% 置信区间 1.86-5.37） 和 MACE 的发生率较低 （TT 与 CC 基因型的调整 sHR 0.76,95% 置信区间 0.63-0.91） 相关。在纤维化 4 （FIB4） < 1.3、1.3-2.67 和 > 2.67 个体中，TM6SF2 -rs58542926-TT 与 CC 个体的 10 年 LRE 发生率分别为 0.08% 对 0.06% （P > 0.05）、0.81% 对 0.20% （P < 0.0001） 和 10.5% 对 3.4% （P = 0.00094）。MACE 的相应值为 3.8% 对 5.1% （P = 0.032）、6.4% 对 8.2% （P = 0.040） 和 17.1% 对 12.4% （P > 0.05）。rs58542926-TT （vs CC） 基因型的 MACE 绝对减少超过了除 FIB4 > 2.67 外所有组 LRE 的绝对增加。TM6SF2 基因型与 LRE/MACE 的相关性在男性中显著，但在女性中不显著。TM6SF2 -rs58542926-T 等位基因也与肝脂肪变性增加和磁共振成像校正 T1 时间相关，男性的效应量大于女性。 讨论 TM6SF2 基因型对 LRE 与 MACE 发生率的影响相反，除了 FIB4 评分最高的人外，对 MACE 的绝对影响更大。男性的影响最强。这些发现阐明了基于个性化临床风险的 TM6SF2 基因型的含义。