Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy.
Division of Gastroenterology and Hepatology, Department of Medical Sciences, University of Turin, Turin, Italy; Metabolic Liver Disease Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany.
Clin Gastroenterol Hepatol. 2023 Dec;21(13):3314-3321.e3. doi: 10.1016/j.cgh.2023.04.024. Epub 2023 May 4.
Nonalcoholic fatty liver disease (NAFLD) is a complex disease, resulting from the interplay between environmental determinants and genetic variations. Single nucleotide polymorphism rs738409 C>G in the PNPLA3 gene is associated with hepatic fibrosis and with higher risk of developing hepatocellular carcinoma. Here, we analyzed a longitudinal cohort of biopsy-proven NAFLD subjects with the aim to identify individuals in whom genetics may have a stronger impact on disease progression.
We retrospectively analyzed 756 consecutive, prospectively enrolled biopsy-proven NAFLD subjects from Italy, United Kingdom, and Spain who were followed for a median of 84 months (interquartile range, 65-109 months). We stratified the study cohort according to sex, body mass index (BMI) </≥30 kg/m) and age (</≥50 years). Liver-related events (hepatic decompensation, hepatic encephalopathy, esophageal variceal bleeding, and hepatocellular carcinoma) were recorded during the follow-up and the log-rank test was used to compare groups.
Overall, the median age was 48 years and most individuals were men (64.7%). The PNPLA3 rs738409 genotype was CC in 235 (31.1%), CG in 328 (43.4%), and GG in 193 (25.5%) patients. At univariate analysis, the PNPLA3 GG risk genotype was associated with female sex and inversely related to BMI (odds ratio, 1.6; 95% confidence interval, 1.1-2.2; P = .006; and odds ratio, 0.97; 95% confidence interval, 0.94-0.99; P = .043, respectively). Specifically, PNPLA3 GG risk homozygosis was more prevalent in female vs male individuals (31.5% vs 22.3%; P = .006) and in nonobese compared with obese NAFLD subjects (50.0% vs 44.2%; P = .011). Following stratification for age, sex, and BMI, we observed an increased incidence of liver-related events in the subgroup of nonobese women older than 50 years of age carrying the PNPLA3 GG risk genotype (log-rank test, P = .0047).
Nonobese female patients with NAFLD 50 years of age and older, and carrying the PNPLA3 GG risk genotype, are at higher risk of developing liver-related events compared with those with the wild-type allele (CC/CG). This finding may have implications in clinical practice for risk stratification and personalized medicine.
非酒精性脂肪性肝病（NAFLD）是一种复杂的疾病，由环境决定因素和遗传变异的相互作用所致。PNPLA3 基因中的单核苷酸多态性 rs738409 C>G 与肝纤维化和肝细胞癌发生的风险增加相关。在此，我们分析了一个经活检证实的 NAFLD 患者的纵向队列，旨在确定遗传因素对疾病进展影响更大的个体。
我们回顾性分析了来自意大利、英国和西班牙的 756 例连续、前瞻性纳入的经活检证实的 NAFLD 患者，中位随访时间为 84 个月（四分位距，65-109 个月）。我们根据性别、体重指数（BMI）</≥30 kg/m2 和年龄（</≥50 岁）对研究队列进行分层。在随访期间记录与肝脏相关的事件（肝失代偿、肝性脑病、食管静脉曲张出血和肝细胞癌），并使用对数秩检验比较组间差异。
总体而言，中位年龄为 48 岁，大多数患者为男性（64.7%）。PNPLA3 rs738409 基因型为 CC 的患者有 235 例（31.1%），CG 的有 328 例（43.4%），GG 的有 193 例（25.5%）。单因素分析显示，PNPLA3 GG 风险基因型与女性性别相关，与 BMI 呈负相关（比值比，1.6；95%置信区间，1.1-2.2；P=0.006；比值比，0.97；95%置信区间，0.94-0.99；P=0.043）。具体而言，PNPLA3 GG 风险纯合子在女性中比男性更常见（31.5% vs 22.3%；P=0.006），在非肥胖 NAFLD 患者中比肥胖患者更常见（50.0% vs 44.2%；P=0.011）。在按年龄、性别和 BMI 分层后，我们观察到在携带 PNPLA3 GG 风险基因型的非肥胖、年龄大于 50 岁的女性亚组中，与肝脏相关的事件发生率增加（对数秩检验，P=0.0047）。
50 岁及以上、非肥胖的携带 PNPLA3 GG 风险基因型的 NAFLD 女性患者发生与肝脏相关的事件的风险高于携带野生型等位基因（CC/CG）的患者。这一发现可能对临床实践中的风险分层和个体化医学具有重要意义。
