Hakim Aaron, Lin Kung-Hung, Schwantes-An Tae-Hwi, Abreu Marco, Tan Jingyi, Guo Xiuqing, Yates Katherine P, Lotta Luca, Verweij Niek, Loomba Rohit, Kleiner David E, Schwimmer Jeffrey B, Rotter Jerome I, Chalasani Naga P
Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Hepatol Commun. 2025 May 29;9(6). doi: 10.1097/HC9.0000000000000728. eCollection 2025 Jun 1.
There is a substantial heritable component to metabolic dysfunction-associated steatotic liver disease (MASLD), and several genetic variants that promote MASLD development or associate with its severity have been reported. These associations vary in terms of their effect size and degree of replication.
We developed a framework to classify previously identified MASLD genetic polymorphisms into 4 tiers based on effect size and extent of replication in the literature. We tested the association between "tier 1" single-nucleotide polymorphisms (OR ≥1.5, replicated in >2 independent studies) and biopsy measures of MASLD severity in a large, well-characterized histologic cohort of MASLD patients (n=3094).
Across 19 "tier 1" variants reflecting 11 genetic loci, only those in the PNPLA3-SAMM50-PARVB locus showed significant associations with biopsy-proven fibrosis severity and NAFLD activity score; the highest risk was for the rs738409 p.I148M variant in PNPLA3. A genetic risk score based on "tier 1" variants, as well as a previously developed genetic risk score based on variants in PNPLA3, TM6SF2, and HSD17B13, were both associated with fibrosis and NAFLD activity score, but these results were driven entirely by PNPLA3 rs738409.
Our study provides a framework to prioritize evaluation of genetic polymorphisms for future replication efforts and demonstrates that in a large case-only cohort, histologic severity of MASLD is only robustly associated with the presence of variation in PNPLA3 among known candidate genes. These findings may have implications for patient risk stratification based on the presence of PNPLA3 rs738409.
代谢功能障碍相关脂肪性肝病（MASLD）存在显著的遗传因素，已有多项促进MASLD发展或与其严重程度相关的基因变异被报道。这些关联在效应大小和复制程度方面存在差异。
我们开发了一个框架，根据文献中的效应大小和复制程度，将先前鉴定的MASLD基因多态性分为4个层级。我们在一个大型、特征明确的MASLD患者组织学队列（n = 3094）中，测试了“1级”单核苷酸多态性（比值比≥1.5，在>2项独立研究中得到复制）与MASLD严重程度的活检指标之间的关联。
在反映11个基因位点的19个“1级”变异中，只有PNPLA3 - SAMM50 - PARVB位点的变异与活检证实的纤维化严重程度和非酒精性脂肪性肝病活动评分有显著关联；风险最高的是PNPLA3中的rs738409 p.I148M变异。基于“1级”变异的遗传风险评分，以及先前基于PNPLA3、TM6SF2和HSD17B13变异开发的遗传风险评分，均与纤维化和非酒精性脂肪性肝病活动评分相关，但这些结果完全由PNPLA3 rs738409驱动。
我们的研究提供了一个框架，用于优先评估基因多态性以便未来进行复制研究，并表明在一个仅包含病例的大型队列中，MASLD的组织学严重程度仅与已知候选基因中PNPLA3的变异存在显著关联。这些发现可能对基于PNPLA3 rs738409的存在进行患者风险分层有启示意义
