Chen Vincent L, Oliveri Antonino, Raut Chinmay, Chen Yanhua, Cushing-Damm Kelly C, Speliotes Elizabeth K
Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA .
Am J Gastroenterol. 2024 Oct 30. doi: 10.14309/ajg.0000000000003169.
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.
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.
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.
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.
TM6SF2基因（rs58542926 -T）与肝硬化发病率增加以及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）和肝脏相关事件（LRE）的相对影响尚不清楚。
我们使用了英国生物银行，这是一个具有遗传和住院诊断数据的前瞻性队列。主要预测因素是TM6SF2基因（rs58542926）的基因型，主要结局是MACE和LRE。通过Fine - Gray竞争风险分析，将效应报告为亚风险比（sHRs）和10年累积发病率。
超过430,000名个体符合纳入标准。TM6SF2基因（rs58542926）的TT基因型（与CC基因型相比）与LRE发病率较高相关（校正后的sHR为3.16，95%置信区间为1.86 - 5.37），与MACE发病率较低相关（TT基因型与CC基因型相比的校正后sHR为0.76，95%置信区间为0.63 - 0.91）。在纤维化 - 4（FIB4）评分<1.3、1.3 - 2.67和>2.67的个体中，TM6SF2基因（rs58542926）的TT基因型个体与CC基因型个体相比，10年LRE发病率分别为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的相应值分别为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）。除FIB4评分>2.67的所有组中，rs58542926 - TT（与CC相比）基因型导致的MACE绝对降低超过了LRE的绝对增加。TM SF2基因型与LRE/MACE的关联在男性中显著，但在女性中不显著。TM6SF2基因（rs58542926）的T等位基因也与肝脏脂肪变性增加以及磁共振成像校正后的T1时间相关，男性的效应大小大于女性。
TM6SF2基因型对LRE和MACE发病率有相反的影响，除了FIB4评分最高的个体外，对MACE的绝对影响更大。在男性中效应最强。这些发现基于个性化临床风险阐明了TM6SF2基因型的影响。
