目的:非酒精性脂肪肝(NAFL)和脂肪性肝炎(NASH)代表了一种遗传和表型多样化的实体,没有批准的治疗,必须定义有助于其发病机理的途径谱。编码核包膜蛋白的基因中的罕见变异导致脂肪代谢障碍与早发性NAFLD/NASH;我们假设核包膜相关基因中的常见变异也可能导致肝性脂肪变性和NAFLD。
方法:使用肝性脂肪变性作为感兴趣的结果,我们在三个大型发现队列(N>120,000名参与者)中对核包膜相关编码变异进行了关联荟萃分析,随后在大型验证队列(N>600,000)中进行表型关联研究,并对细胞培养物中的最高脂肪变性相关变体进行功能测试。
结果:一种常见的蛋白质编码变体,rs6461378(SUN1H118Y),在我们的关联荟萃分析中,是脂肪变性相关的最高变异(P<0.001)。在祖先不同的验证队列中,rs6461378与组织学NAFLD和NAFLD相关的代谢性状相关,包括血清脂肪酸增加,2型糖尿病,高血压,心血管疾病,减少HDL。与野生型SUN1相比,SUN1H118Y在细胞中的蛋白酶体降解增加,表达SUN1H118Y的细胞表现出胰岛素抵抗和脂质积累增加。
结论:总的来说,这些数据支持常见SUN1变异体rs6461378在NAFLD和代谢性疾病中的潜在因果作用.
■非酒精性脂肪性肝病(NAFLD),估计全球患病率近30%,是发病率和死亡率日益增长的原因,没有批准的药物治疗。我们的数据为扩大NAFLD遗传学和病理生理学的当前概念提供了理论基础,包括核包膜。特别是Sad1和包含1的UNC84域(SUN1),作为这种常见肝病的新贡献者。此外,如果未来的研究证实了常见的SUN1H118Y变异体的因果关系,它有可能成为NAFLD和代谢性疾病广泛相关的治疗靶点.
Non-alcoholic fatty liver disease (NAFLD), and its progressive form steatohepatitis (NASH), represent a genetically and phenotypically diverse entity for which there is no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy with early-onset NAFLD/NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NAFLD.
Using hepatic steatosis as the outcome of interest, we performed an association meta-analysis of nuclear envelope-related coding variants in three large discovery cohorts (N >120,000 participants), followed by phenotype association studies in large validation cohorts (N >600,000) and functional testing of the top steatosis-associated variant in cell culture.
A common protein-coding variant, rs6461378 (SUN1 H118Y), was the top steatosis-associated variant in our association meta-analysis (p <0.001). In ancestrally distinct validation cohorts, rs6461378 associated with histologic NAFLD and with NAFLD-related metabolic traits including increased serum fatty acids, type 2 diabetes, hypertension, cardiovascular disease, and decreased HDL. SUN1 H118Y was subject to increased proteasomal degradation relative to wild-type SUN1 in cells, and SUN1 H118Y-expressing cells exhibited insulin resistance and increased lipid accumulation.
Collectively, these data support a potential causal role for the common SUN1 variant rs6461378 in NAFLD and metabolic disease.
Non-alcoholic fatty liver disease (NAFLD), with an estimated global prevalence of nearly 30%, is a growing cause of morbidity and mortality for which there is no approved pharmacologic therapy. Our data provide a rationale for broadening current concepts of NAFLD genetics and pathophysiology to include the nuclear envelope, and particularly Sad1 and UNC84 domain containing 1 (SUN1), as novel contributors to this common liver disease. Furthermore, if future studies confirm causality of the common SUN1 H118Y variant, it has the potential to become a broadly relevant therapeutic target in NAFLD and metabolic disease.