Evaluation and analysis of novel germline variants in ethanol metabolism pathway genes predisposition to liver disease

• Published in: Gene 2023-07, Vol.873, p.147451-147451, Article 147451
• Main Authors: Das, Partha Pratim, Jyoti Kalita, Manash, Jyoti Talukdar, Anjan, Mohd Khan, Faraz, Dutta, Kalpajit, Kalita, Simanta, Goswami, Nabajyoti, Hazarika, Gautam, Samudrala, Gourinath, ghaznavi Idris, Mohammed, Dutta, Sangit, Medhi, Subhash
• Format: Article
• Language: English
• Subjects: ALD; ALDH1L2; Genotyping; Liver disease; NAFLD; Targeted-resequencing
• ISSN: 0378-1119; 1879-0038
• DOI: 10.1016/j.gene.2023.147451

[Display omitted] •The germline variants analysis from alcohol metabolism pathway genes obtained a significant variant in the ALDH1L2 gene (rs199841702) found to associate with alcoholic liver disease.•Most of the available online in-silico Pathogenicity prediction tools predicted ALDH1L2 (c.337C > G, p.Pro113Ala) gene variant as ‘deleterious’ and ‘pathogenic’.•The presence of the GC genotype in ALDH1L2 (rs19984170)polymorphism may indicate an increased risk of developing ALD. The pathogenetic events of liver disease are seemingly determined by factors linked to ethanol metabolism. The variations in genes encoding enzymes of the ethanol metabolic pathway can influence exposure to alcohol and thus may act as risk factors for the development of liver disease. The present study aimed to understand the genetic aspect of germline variations in ethanol metabolic pathway genes in two major categories of liver disease i.e. ALD and NAFLD. Targeted Re-sequencing was performed in the two disease categories along with healthy control followed by an assessment and evaluation of the variants in a case vs control manner. The pathogenicity prediction was evaluated using SIFT, PolyPhen, PROVEN, LRT, CADD, FATHMM, EIGEN, REVEL and VarSome, while MD simulation of a novel significant variant was performed using the GROMACS 5.1.4 package. The annotation of targeted re-sequencing results revealed 2172 variants in different locations of the genes. Upon recurrent assessment predominantly focusing on exonic missense variants from these genes of the alcohol metabolism pathway, the ALDH1L2 [c.337C > G, p.Pro113Ala, (rs199841702)] variant was found highly significant with comprehensive results. The amino acid substitution tool that predicted protein stability due to a point mutation showed a decrease in stability. The genotyping distribution of the identified novel variant in the population revealed that heterozygosity is significantly distributed in ALD patients. However, the predominant association between the inherited variant and the cause of developing disease needs further robust study.