Several genetic discoveries robustly implicate five single-nucleotide variants in the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis and fibrosis (NASH-fibrosis), including a recently identified variant in MTARC1. To better understand these variants as potential therapeutic targets, we aimed to characterize their impact on metabolism using comprehensive metabolomics data from two population-based studies. A total of 9135 participants from the Fenland study and 9902 participants from the EPIC-Norfolk cohort were included in the study. We identified individuals with risk alleles associated with NASH-fibrosis: rs738409C>G in PNPLA3, rs58542926C>T in TM6SF2, rs641738C>T near MBOAT7, rs72613567TA>T in HSD17B13 and rs2642438A>G in MTARC1. Circulating levels of 1449 metabolites were measured using targeted and untargeted metabolomics. Associations between NASH-fibrosis variants and metabolites were assessed using linear regression. The specificity of variant-metabolite associations were compared to metabolite associations with ultrasound-defined steatosis, gene variants linked to liver fat (in GCKR, PPP1R3B and LYPLAL1) and gene variants linked to cirrhosis (in HFE and SERPINA1). Each NASH-fibrosis variant demonstrated a specific metabolite profile with little overlap (8/97 metabolites) comprising diverse aspects of lipid metabolism. Risk alleles in PNPLA3 and HSD17B13 were both associated with higher 3-methylglutarylcarnitine and three variants were associated with lower lysophosphatidylcholine C14:0. The risk allele in MTARC1 was associated with higher levels of sphingomyelins. There was no overlap with metabolites that associated with HFE or SERPINA1 variants. Our results suggest a link between the NASH-protective variant in MTARC1 to the metabolism of sphingomyelins and identify distinct molecular patterns associated with each of the NASH-fibrosis variants under investigation.

中文翻译：

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从代谢物分析中洞察与 NASH 纤维化相关的遗传变异。


多项基因发现有力地表明五种单核苷酸变异与非酒精性脂肪肝疾病进展为非酒精性脂肪性肝炎和纤维化（NASH-纤维化）有关，其中包括最近发现的MTARC1变异。为了更好地理解这些变异作为潜在的治疗靶点，我们旨在利用两项基于人群的研究的综合代谢组学数据来表征它们对代谢的影响。该研究共纳入了来自 Fenland 研究的 9135 名参与者和来自 EPIC-Norfolk 队列的 9902 名参与者。我们确定了具有与NASH纤维化相关的风险等位基因的个体： PNPLA3中的rs738409C>G、 TM6SF2中的rs58542926C>T、 MBOAT7附近的rs641738C>T、 HSD17B13中的rs72613567TA>T和MTARC1中的rs2642438A>G。使用靶向和非靶向代谢组学测量了 1449 种代谢物的循环水平。使用线性回归评估 NASH 纤维化变异与代谢物之间的关联。将变异代谢物关联的特异性与超声定义的脂肪变性的代谢物关联、与肝脏脂肪相关的基因变异（在GCKR 、 PPP1R3B和LYPLAL1中）以及与肝硬化相关的基因变异（在HFE和SERPINA1中）进行比较。每种 NASH 纤维化变异都表现出特定的代谢物谱，几乎没有重叠（8/97 代谢物），包括脂质代谢的不同方面。 PNPLA3和HSD17B13中的风险等位基因均与较高的 3-甲基戊二酰肉碱相关，并且三个变体与较低的溶血磷脂酰胆碱 C14:0 相关。 MTARC1中的风险等位基因与较高水平的鞘磷脂相关。与HFE或SERPINA1变异相关的代谢物没有重叠。我们的结果表明MTARC1中的 NASH 保护性变异与鞘磷脂代谢之间存在联系，并确定了与所研究的每种 NASH 纤维化变异相关的不同分子模式。