Integrative genetic and liver transcriptomic analyses identify TRIB1AL as a target for steatotic liver disease.

Background

To identify liver-expressed genes that may represent therapeutic candidates for MASLD.

为了识别可能代表MASLD治疗候选者的肝脏表达基因。

Methods

We conducted a new GWAS meta-analysisincluding 16 532 cases and 1 240 188 controls.

我们进行了一项新的全基因组关联研究荟萃分析，包括16,532例病例和1,240,188名对照。

We also generated RNA sequencing data of liver samples and genome-wide genotyping of 504 individuals of the Quebec Obesity Biobank.

我们还生成了魁北克肥胖生物库504名个体的肝样本RNA测序数据和全基因组基因分型数据。

Results

Using mendelian randomization (MR) and genetic colocalization, we confirm the implication of genes previously linked with MASLD and identified novel ones including AKNA (AT-hook transcription factor), EPHA2 (EPH receptor A2), CHEK2 (encoding checkpoint kinase 2), and PCCB (propionyl-CoA carboxylase subunit β).

利用孟德尔随机化(MR)和遗传共定位，我们确认了先前与MASLD相关的基因，并识别了包括AKNA（AT钩转录因子）、EPHA2（EPH受体A2）、CHEK2（编码检查点激酶2）和PCCB（丙酰辅酶A羧化酶亚基β）在内的新基因。

More specifically, we found a strong and positive effect of long noncoding (lnc)RNA TRIB1AL on MASLD.

更具体地说，我们发现长链非编码RNA TRIB1AL对MASLD有强烈且积极的影响。

The lead genetic variant was not linked with expression levels of the nearby protein-coding gene TRIB1 (Tribbles pseudokinase 1).

主要遗传变异与邻近蛋白编码基因TRIB1（Tribbles伪激酶1）的表达水平无关。

In UK Biobank participants with whole-exome sequencing data available, rare loss-of-function variants in TRIB1 were not associated with liver fat accumulation or plasma triglyceride levels, suggesting that the lncRNA TRIB1AL may carry cardiometabolic effects independently of TRIB1.

在有全外显子组测序数据的英国生物银行参与者中，TRIB1的罕见失功能变异与肝脏脂肪积累或血浆甘油三酯水平无关，这表明长链非编码RNA TRIB1AL可能独立于TRIB1具有心脏代谢效应。

Targeted- and phenome-wide MR also identified lower liver-expressed TRIB1AL as being associated with reduced liver fat accumulation, lower plasma lipoprotein-lipid levels, and decreased atherosclerotic cardiovascular disease risk.

靶向和表型全基因组关联研究还发现，较低的肝脏表达的TRIB1AL与减少的肝脏脂肪积累、较低的血浆脂蛋白-脂质水平以及降低的动脉粥样硬化心血管疾病风险有关。

Conclusions

These results open the door to liver-targeted therapeutics silencing of the noncoding genome for the prevention and treatment of MASLD and cardiometabolic diseases.

这些结果为针对肝脏的靶向治疗，通过沉默非编码基因组来预防和治疗MASLD和心血管代谢疾病开辟了道路。