Institute of Cellular Medicine, Newcastle University Medical School, Newcastle upon Tyne, UK.
J Hepatol. 2012 Feb;56(2):448-54. doi: 10.1016/j.jhep.2011.05.029. Epub 2011 Jul 12.
BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a complex disease trait where genetic variations and environment interact to determine disease progression. The association of PNPLA3 with advanced disease has been consistently demonstrated but many other modifier genes remain unidentified. In NAFLD, increased fatty acid oxidation produces high levels of reactive oxygen species. Manganese-dependent superoxide dismutase (MnSOD), encoded by the SOD2 gene, plays an important role in protecting cells from oxidative stress. A common non-synonymous polymorphism in SOD2 (C47T; rs4880) is associated with decreased MnSOD mitochondrial targeting and activity making it a good candidate modifier of NAFLD severity.
The relevance of the SOD2 C47T polymorphism to fibrotic NAFLD was assessed by two complementary approaches: we sought preferential transmission of alleles from parents to affected children in 71 family trios and adopted a case-control approach to compare genotype frequencies in a cohort of 502 European NAFLD patients.
In the family study, 55 families were informative. The T allele was transmitted on 47/76 (62%) possible occasions whereas the C allele was transmitted on only 29/76 (38%) occasions, p=0.038. In the case control study, the presence of advanced fibrosis (stage>1) increased with the number of T alleles, p=0.008 for trend. Multivariate analysis showed susceptibility to advanced fibrotic disease was determined by SOD2 genotype (OR 1.56 (95% CI 1.09-2.25), p=0.014), PNPLA3 genotype (p=0.041), type 2 diabetes mellitus (p=0.009) and histological severity of NASH (p=2.0×10(-16)).
Carriage of the SOD2 C47T polymorphism is associated with more advanced fibrosis in NASH.
非酒精性脂肪性肝病（NAFLD）是一种复杂的疾病特征，其中遗传变异和环境相互作用决定疾病的进展。PNPLA3 与进展期疾病的关联已得到一致证实，但许多其他修饰基因仍未被识别。在 NAFLD 中，脂肪酸氧化增加会产生高水平的活性氧。锰依赖性超氧化物歧化酶（MnSOD），由 SOD2 基因编码，在保护细胞免受氧化应激方面发挥重要作用。SOD2 中的一个常见非同义多态性（C47T；rs4880）与 MnSOD 线粒体靶向和活性降低有关，使其成为 NAFLD 严重程度的良好修饰候选基因。
通过两种互补方法评估 SOD2 C47T 多态性与纤维化性 NAFLD 的相关性：我们在 71 个家族三胞胎中寻求父母向患病子女的等位基因优先传递，并在 502 例欧洲 NAFLD 患者的队列中采用病例对照方法比较基因型频率。
在家族研究中，55 个家庭是信息丰富的。T 等位基因在 76 个可能的情况下有 47/76（62%）的传递，而 C 等位基因只有 29/76（38%）的传递，p=0.038。在病例对照研究中，随着 T 等位基因数量的增加，晚期纤维化（分期>1）的存在增加，p=0.008 呈趋势。多变量分析显示，易患晚期纤维化疾病的决定因素是 SOD2 基因型（OR 1.56（95% CI 1.09-2.25），p=0.014）、PNPLA3 基因型（p=0.041）、2 型糖尿病（p=0.009）和 NASH 的组织学严重程度（p=2.0×10(-16)）。
携带 SOD2 C47T 多态性与 NASH 中的更晚期纤维化有关。
