Samarasinghe Saumya Madushani, Hewage Asanka Sudeshini, Siriwardana Rohan Chaminda, Tennekoon Kamani Hemamala, Niriella Madunil Anuk, De Silva Sumadee, Abeysuriya Visula
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, No 90, Cumarathunga Munidasa Mawatha, Colombo 03, Sri Lanka.
Colombo North Center for Liver Diseases, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
BMC Gastroenterol. 2025 Mar 10;25(1):151. doi: 10.1186/s12876-025-03738-w.
Single nucleotide polymorphisms (SNPs) in patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2) and membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes were reported to be strongly associated with non-alcoholic fatty liver disease (NAFLD) pathogenicity among different populations. We investigated whether these SNPs are associated with prognostic factors and genetic biomarkers of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) in the Sri Lankan context.
We conducted an exploratory study to evaluate the prevalence of five SNPs (PNPLA3 rs738409, PNPLA3 rs2281135, PNPLA3 rs2294918, TM6SF2 rs58542926 and MBOAT7 rs641738) as genetic risk factors for NASH-HCC pathogenicity. We genotyped 48 NASH-HCC patient samples collected at a clinical setting using a minisequencing method. Impact of each SNP with tumor prognostic factors such as nodularity, tumor size and AFP (alpha-feto protein) level was analyzed using chi square test. We also analyzed the expression of micro RNA-122 (miR-122) in serum and leukocyte telomere length via quantitative real-time PCR. Associations between each SNP with micro RNA-122 (miR-122) expression level and leukocyte telomere length of NASH-HCC patients were analyzed using one-way analysis of variance (ANOVA) test and independent t test. Relationships among tested SNPs and some well-established HCC risk factors such as age, BMI, gender, diabetes status and the cirrhotic stage were also analyzed using chi square test, independent t-test and One-way ANOVA test.
Our analyses demonstrated significant associations between PNPLA3 rs2281135 variant and tumor nodularity. Also, PNPLA3 rs2281135 and PNPLA3 rs2294918 variants were significantly associated with miR-122 expression levels of NASH-HCC patients. Further, age and body mass index (BMI) were significantly associated with PNPLA3 rs2281135 variant in our study cohort.
We found that in the Sri Lankan NASH-related HCC cohort, some PNPLA3 variants (rs2281135 and rs2294918) correlate with tumor nodularity, higher miR-122 expression, and distinct demographic features such as age and BMI. Our work highlights the role of specific SNPs in tumor aggressiveness, contributing to the precision screening for HCC in NASH patients.
据报道，在不同人群中，含帕他汀样磷脂酶结构域蛋白3（PNPLA3）、跨膜6超家族成员2（TM6SF2）和含膜结合O-酰基转移酶结构域7（MBOAT7）基因中的单核苷酸多态性（SNP）与非酒精性脂肪性肝病（NAFLD）的发病机制密切相关。我们调查了在斯里兰卡背景下，这些SNP是否与非酒精性脂肪性肝炎（NASH）相关肝细胞癌（HCC）的预后因素和遗传生物标志物有关。
我们进行了一项探索性研究，以评估五个SNP（PNPLA3 rs738409、PNPLA3 rs2281135、PNPLA3 rs2294918、TM6SF2 rs58542926和MBOAT7 rs641738）作为NASH-HCC发病机制遗传危险因素的患病率。我们使用微测序方法对在临床环境中收集的48份NASH-HCC患者样本进行基因分型。使用卡方检验分析每个SNP对肿瘤预后因素如结节性、肿瘤大小和甲胎蛋白（AFP）水平的影响。我们还通过定量实时PCR分析血清中微小RNA-122（miR-122）的表达和白细胞端粒长度。使用单因素方差分析（ANOVA）检验和独立t检验分析每个SNP与NASH-HCC患者的微小RNA-122（miR-122）表达水平和白细胞端粒长度之间的关联。还使用卡方检验、独立t检验和单因素方差分析检验分析了所检测的SNP与一些已确定的HCC危险因素如年龄、BMI、性别、糖尿病状态和肝硬化阶段之间的关系。
我们的分析表明PNPLA3 rs2281135变异与肿瘤结节性之间存在显著关联。此外，PNPLA3 rs2281135和PNPLA3 rs2294918变异与NASH-HCC患者的miR-122表达水平显著相关。此外，在我们的研究队列中，年龄和体重指数（BMI）与PNPLA3 rs2281135变异显著相关。
我们发现，在斯里兰卡与NASH相关的HCC队列中，一些PNPLA3变异（rs2281135和rs2294918）与肿瘤结节性、较高的miR-122表达以及年龄和BMI等不同的人口统计学特征相关。我们的工作突出了特定SNP在肿瘤侵袭性中的作用，有助于对NASH患者进行HCC的精准筛查。
