Department of Health Management, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
J Transl Med. 2024 Jul 12;22(1):650. doi: 10.1186/s12967-024-05478-z.
Although the inherited risk factors associated with fatty liver disease are well understood, little is known about the genetic background of metabolic dysfunction-associated steatotic liver disease (MASLD) and its related health impacts. Compared to non-alcoholic fatty liver disease (NAFLD), MASLD presents significantly distinct diagnostic criteria, and epidemiological and clinical features, but the related genetic variants are yet to be investigated. Therefore, we conducted this study to assess the genetic background of MASLD and interactions between MASLD-related genetic variants and metabolism-related outcomes.
Participants from the UK Biobank were grouped into discovery and replication cohorts for an MASLD genome-wide association study (GWAS), and base and target cohorts for polygenic risk score (PRS) analysis. Autosomal genetic variants associated with NAFLD were compared with the MASLD GWAS results. Kaplan-Meier and Cox regression analyses were used to assess associations between MASLD and metabolism-related outcomes.
Sixteen single-nucleotide polymorphisms (SNPs) were identified at genome-wide significance levels for MASLD and duplicated in the replication cohort. Differences were found after comparing these SNPs with the results of NAFLD-related genetic variants. MASLD cases with high PRS had a multivariate-adjusted hazard ratio of 3.15 (95% confidence interval, 2.54-3.90) for severe liver disease (SLD), and 2.81 (2.60-3.03) for type 2 diabetes mellitus. The high PRS amplified the impact of MASLD on SLD and extrahepatic outcomes.
High PRS of MASLD GWAS amplified the impact of MASLD on SLD and metabolism-related outcomes, thereby refining the process of identification of individuals at high risk of MASLD. Supplementation of this process with relevant genetic backgrounds may lead to more effective MASLD prevention and management.
尽管人们已经充分了解与脂肪肝相关的遗传风险因素，但代谢相关脂肪性肝病（MASLD）的遗传背景及其相关健康影响却知之甚少。与非酒精性脂肪性肝病（NAFLD）相比，MASLD 具有明显不同的诊断标准、流行病学和临床特征，但相关的遗传变异尚未得到研究。因此，我们开展了这项研究，旨在评估 MASLD 的遗传背景，以及 MASLD 相关遗传变异与代谢相关结局之间的相互作用。
英国生物库中的参与者被分为发现和复制队列，以进行 MASLD 全基因组关联研究（GWAS），以及基础和目标队列，以进行多基因风险评分（PRS）分析。将与 NAFLD 相关的全基因组遗传变异与 MASLD GWAS 结果进行比较。采用 Kaplan-Meier 和 Cox 回归分析评估 MASLD 与代谢相关结局之间的关联。
共鉴定出 16 个单核苷酸多态性（SNP），在全基因组水平上达到 MASLD 显著性水平，并在复制队列中得到重复。将这些 SNP 与与 NAFLD 相关的遗传变异结果进行比较后，发现了差异。MASLD 病例中，PRS 较高者发生严重肝病（SLD）的多变量校正风险比为 3.15（95%置信区间，2.54-3.90），发生 2 型糖尿病的风险比为 2.81（2.60-3.03）。高 PRS 放大了 MASLD 对 SLD 和肝外结局的影响。
MASLD GWAS 的高 PRS 放大了 MASLD 对 SLD 和代谢相关结局的影响，从而提高了 MASLD 高危个体的识别效率。在此过程中补充相关的遗传背景可能会导致更有效的 MASLD 预防和管理。
