Mehta Rohini, Jeiran Kianoush, Koenig Aaron B, Otgonsuren Munkzhul, Goodman Zachary, Baranova Ancha, Younossi Zobair
Betty and Guy Beatty Center for Integrated Research, Inova Fairfax Medical Campus, Falls Church, VA, USA.
Center for the Study of Chronic Metabolic and Rare Diseases, George Mason University, Fairfax, VA, 22033, USA.
BMC Med Genet. 2016 Sep 5;17(1):63. doi: 10.1186/s12881-016-0324-0.
Visceral obesity and metabolic syndrome are commonly associated with non-alcoholic fatty liver disease (NAFLD). The progression of steatosis to NASH depends on a number of metabolic and patient-related factors. The mechanisms of genetic predisposition towards the development of NASH and related fibrosis remain unclear. In this study, our aim was to utilize mitotyping and identify mitochondrial haplotypes that may be associated with NAFLD.
We examined mitochondrial haplotypes along with patatin-like phospholipase domain containing 3 (PNPLA3) rs738409 genotype to determine their association with NAFLD phenotypes. Whole blood samples were obtained from 341 patients (BMI > 35) undergoing weight reduction surgery after written consent. Liver biopsies were centrally reviewed by a single pathologist based on predetermined pathologic protocol (41.9 % Non-NASH NAFLD, 30.4 % NASH, 27.5 % controls). A 1,122 bp of the mitochondrial control loop was sequenced for each sample and classified into haplogroups.
The presence of haplogroup L exhibits protection against the development of NASH and pericellular fibrosis. The alleles of PNPLA3 locus showed differential distribution in cohorts with NAFLD, NASH and pericellular fibrosis. Heterozygosity at this locus is independently associated with higher risk of having NASH and pericellular fibrosis.
Mitochondrial genetics play an important role in NASH probably by modulation of oxidative stress and the efficiency of oxidative phosphorylation.
内脏性肥胖和代谢综合征通常与非酒精性脂肪性肝病（NAFLD）相关。脂肪变性进展为非酒精性脂肪性肝炎（NASH）取决于多种代谢和患者相关因素。NASH及其相关纤维化发生的遗传易感性机制仍不清楚。在本研究中，我们的目的是利用线粒体分型并鉴定可能与NAFLD相关的线粒体单倍型。
我们检测了线粒体单倍型以及含patatin样磷脂酶结构域3（PNPLA3）rs738409基因型，以确定它们与NAFLD表型的关联。在获得书面同意后，从341例接受减重手术的患者（BMI＞35）中采集全血样本。由一名病理学家根据预先确定的病理方案对肝活检标本进行集中审查（41.9%为非NASH的NAFLD，30.4%为NASH，27.5%为对照）。对每个样本的线粒体控制区1122bp进行测序并分类为单倍群。
单倍群L的存在对NASH和细胞周纤维化的发生具有保护作用。PNPLA3位点的等位基因在NAFLD、NASH和细胞周纤维化队列中显示出不同的分布。该位点的杂合性与发生NASH和细胞周纤维化的较高风险独立相关。
线粒体遗传学可能通过调节氧化应激和氧化磷酸化效率在NASH中发挥重要作用。
