Wattacheril Julia, Kleinstein Sarah E, Shea Patrick R, Wilson Laura A, Subramanian G Mani, Myers Robert P, Lefkowitch Jay, Behling Cynthia, Xanthakos Stavra A, Goldstein David B
Columbia University Vagelos College of Physicians and Surgeons, Department of Medicine, Center for Liver Disease and Transplantation, New York Presbyterian Hospital.
Columbia University Vagelos College of Physicians and Surgeons, Institute for Genomic Medicine.
medRxiv. 2024 Mar 4:2024.03.02.24303632. doi: 10.1101/2024.03.02.24303632.
Nonalcoholic Fatty Liver Disease (NAFLD) is a complex human disease. Common genetic variation in the patatin-like phospholipase domain containing 3 () and transmembrane 6 superfamily member 2 () genes have been associated with an increased risk of developing NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis in adults. The role of rare genetic variants in the development and progression of NAFLD in children is not well known. We aimed to explore the role of rare genetic variants in pediatric patients with advanced fibrosis.
Whole exome sequencing data was generated for 229 pediatric patients diagnosed with NAFLD recruited from the NASH Clinical Research Network (NASH CRN). Case-control single variant and gene-based collapsing analyses were used to test for rare variants that were enriched or depleted within the pediatric NAFLD cohort specifically for advanced fibrosis (cases) versus those without fibrosis (controls) or six other histologic characteristics. Exome data from non-NAFLD population controls were also used for additional analyses. All results were adjusted for multiple testing using a Bonferroni correction.
No genome-wide significant associations were found between rare variation and presence of advanced fibrosis or NASH, nor the severity of steatosis, inflammation, or hepatocellular ballooning. Significantly, no enrichment of rare variants in or was observed across phenotypes.
In a cohort of children with histologically proven NAFLD, no genome-wide significant associations were found between rare genetic variation and advanced fibrosis or six other histologic features. Of particular interest was the lack of association with genes of interest in adults: and , though limitations in sample size may reduce the ability to detect associations, particularly with rare variation.
非酒精性脂肪性肝病（NAFLD）是一种复杂的人类疾病。含patatin样磷脂酶结构域3（PNPLA3）和跨膜6超家族成员2（TM6SF2）基因的常见基因变异与成人患NAFLD、非酒精性脂肪性肝炎（NASH）及肝纤维化的风险增加有关。罕见基因变异在儿童NAFLD发生发展中的作用尚不清楚。我们旨在探讨罕见基因变异在患有晚期肝纤维化的儿科患者中的作用。
对从NASH临床研究网络（NASH CRN）招募的229例诊断为NAFLD的儿科患者进行全外显子组测序。采用病例对照单变异和基于基因的合并分析，检测在儿科NAFLD队列中，特别是晚期肝纤维化患者（病例组）与无肝纤维化患者（对照组）或其他六种组织学特征相比，富集或缺失情况的罕见变异。非NAFLD人群对照的外显子组数据也用于进一步分析。所有结果均使用Bonferroni校正进行多重检验校正。
未发现罕见变异与晚期肝纤维化或NASH的存在、脂肪变性、炎症或肝细胞气球样变的严重程度之间存在全基因组显著关联。值得注意的是，在各表型中均未观察到PNPLA3或TM6SF2中罕见变异的富集。
在一组经组织学证实患有NAFLD的儿童中，未发现罕见基因变异与晚期肝纤维化或其他六种组织学特征之间存在全基因组显著关联。特别令人感兴趣的是，与成人中相关基因（PNPLA3和TM6SF2）缺乏关联，尽管样本量的限制可能会降低检测关联的能力，尤其是对于罕见变异。
