Govardhan Bale, Anand V Kulkarni, Nagaraja Rao Padaki, Balachandran Menon P, Mithun Sharma, Sasikala Mitnala, Sowmya T R, Anuradha Sekaran, Smita C Pawar, Nageshwar Reddy D, Ravikanth Vishnubhotla
Asian Healthcare Foundation, Plot No 2/3/4/5, Survey No 136/1, Mindspace Road, Gachibowli, Hyderabad, Telangana 500032, India.
AIG Hospitals, Plot No 2/3/4/5, Survey No 136/1, Mindspace Road, Gachibowli, Hyderabad, Telangana 500032, India.
J Clin Exp Hepatol. 2024 Jul-Aug;14(4):101371. doi: 10.1016/j.jceh.2024.101371. Epub 2024 Feb 19.
A splice variant in gene is demonstrated to protect against nonalcoholic fatty liver disease (NAFLD), and mitigate the effect of Patatin-like phospholipase domain-containing 3 (-I148M). It is being explored as a putative drug target and in polygenic risk scores. Based on whole exome sequencing (WES) in our cohort of biopsy proven NAFLD and limited data on the variant in our ethnicity, we sought to explore its role.
This is a cross-sectional study that recruited 1,020 individuals with ultrasound/biopsy-confirmed NAFLD and matched controls. Liver enzymes and lipid profiles were estimated (Beckman coulter LX750/DXH800); WES was performed in NAFLD patients and controls (Illumina; HiSeqX); -A-INS/I148M- variants were genotyped (sequencing/qR T-PCR); HSD17B13 protein expression was estimated (immunohistochemistry); the Student's t-test/Mann-Whitney U/Chi-square test and odds ratio (95% confidence interval) were used.
There was no significant difference (Odds ratio = 0.76; 95% CI -0.57 to 1.03; = 0.76) in the frequency of the rs72613567-A-INS between controls and patients (17.8% vs. 14.4%). No difference in the ALT (Alanine transaminase; 72.24 ± 65.13 vs. 73.70 ± 60.06; = 0.51) and AST levels (Aspartate aminotransferase; 60.72 ± 55.59 vs. 61.63 ± 60.33; = 0.91) between wild and variant carriers were noted. Significantly elevated liver enzymes were seen in -148-variant/wild compared with -148-variant/variant (90.44 ± 59.0 vs. 112.32 ± 61.78; = 0.02). No difference in steatosis ( = 0.51) between -wild and variant carriers was noted. No other variants in the intron-exon boundaries were identified. Although, protein expression differences were noted between wild and variant carriers, no difference in the extent of steatosis was seen.
Our study reports lack of association of the splice variant with reduced risk of NAFLD, and mitigating the effect of variant. Ethnicity-based validation must be carried out before including it in assessing protection against NAFLD.
基因中的一种剪接变体被证明可预防非酒精性脂肪性肝病（NAFLD），并减轻含Patatin样磷脂酶结构域3（-I148M）的影响。它正作为一种假定的药物靶点和用于多基因风险评分而被探索。基于我们经活检证实的NAFLD队列中的全外显子组测序（WES）以及我们种族中该变体的有限数据，我们试图探索其作用。
这是一项横断面研究，招募了1020名经超声/活检确诊的NAFLD患者及匹配的对照。评估了肝酶和血脂谱（贝克曼库尔特LX750/DXH800）；对NAFLD患者和对照进行了WES（Illumina；HiSeqX）；对-A-INS/I148M-变体进行了基因分型（测序/qRT-PCR）；评估了HSD17B13蛋白表达（免疫组织化学）；使用了学生t检验/曼-惠特尼U检验/卡方检验和比值比（95%置信区间）。
对照与患者之间rs72613567-A-INS频率无显著差异（比值比 = 0.76；95%CI -0.57至1.03； = 0.76）（17.8%对14.4%）。野生型和变体携带者之间的ALT（丙氨酸转氨酶；72.24 ± 65.13对73.70 ± 60.06； = 0.51）和AST水平（天冬氨酸转氨酶；60.72 ± 55.59对61.63 ± 60.33； = 0.91）无差异。与-148-变体/变体相比，-148-变体/野生型中肝酶显著升高（90.44 ± 59.0对112.32 ± 61.78； = 0.02）。-野生型和变体携带者之间的脂肪变性无差异（ = 0.51）。未在基因内-外显子边界鉴定出其他变体。虽然野生型和变体携带者之间存在蛋白表达差异，但脂肪变性程度无差异。
我们的研究报告该剪接变体与降低NAFLD风险及减轻变体影响缺乏关联。在将其纳入评估对NAFLD的保护作用之前，必须进行基于种族的验证。
