PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：尽管与脂肪肝疾病相关的遗传危险因素已经很清楚，对代谢功能障碍相关脂肪变性肝病(MASLD)的遗传背景及其相关健康影响知之甚少.与非酒精性脂肪性肝病（NAFLD）相比，MASLD提出了明显不同的诊断标准，以及流行病学和临床特征，但是相关的遗传变异还有待研究。因此,本研究旨在评估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.
方法：来自英国生物库的参与者被分为发现和复制队列，用于MASLD全基因组关联研究（GWAS）。以及多基因风险评分(PRS)分析的基础和目标队列。与NAFLD相关的常染色体遗传变异与MASLDGWAS结果进行比较。Kaplan-Meier和Cox回归分析用于评估MASLD和代谢相关结果之间的关联。
结果：在MASLD的全基因组显著性水平上鉴定出16种单核苷酸多态性（SNP），并在复制队列中重复。在将这些SNP与NAFLD相关遗传变异的结果进行比较后发现差异。具有高PRS的MASLD病例的多变量校正风险比为3.15(95%置信区间,2.54-3.90）用于严重肝病（SLD），2型糖尿病为2.81（2.60-3.03）。高PRS放大了MASLD对SLD和肝外结果的影响。
结论：MASLDGWAS的高PRS放大了MASLD对SLD和代谢相关结局的影响，从而完善MASLD高风险个体的识别过程。用相关的遗传背景补充这一过程可能会导致更有效的MASLD预防和管理。
方法：来自英国生物库的参与者被分为发现和复制队列，用于MASLD全基因组关联研究（GWAS）。以及多基因风险评分(PRS)分析的基础和目标队列。与NAFLD相关的常染色体遗传变异与MASLDGWAS结果进行比较。Kaplan-Meier和Cox回归分析用于评估MASLD和代谢相关结果之间的关联。
结果：在MASLD的全基因组显著性水平上鉴定出16种单核苷酸多态性（SNP），并在复制队列中重复。在将这些SNP与NAFLD相关遗传变异的结果进行比较后发现差异。具有高PRS的MASLD病例的多变量校正风险比为3.15(95%置信区间,2.54-3.90）用于严重肝病（SLD），2型糖尿病为2.81（2.60-3.03）。高PRS放大了MASLD对SLD和肝外结果的影响。
结论：MASLDGWAS的高PRS放大了MASLD对SLD和代谢相关结局的影响，从而完善MASLD高风险个体的识别过程。用相关的遗传背景补充这一过程可能会导致更有效的MASLD预防和管理。
