What question did this study set out to answer?

To identify and characterize genetic variants associated with MASLD using whole-exome sequencing.

June 3, 2026Open Access

Uncovering Genetic Drivers of MASLD in South Asia: A Whole-Exome Sequencing Study in Pakistan

Key Points

To identify and characterize genetic variants associated with MASLD using whole-exome sequencing.
Case-control study involving 200 MASLD patients from Ziauddin Hospital, with 6 selected for WES.
DNA extraction from blood samples followed by variant classification using ClinVar.
Gene-gene interactions analyzed using GeneMANIA, with statistical analysis performed using SPSS.
Fourteen variants classified as pathogenic; SUMO4 rs237025 was most common in MASLD cases (83.3%).
Ten variants classified as likely pathogenic, with PPP1R3A rs1799999 linked to insulin resistance.
Gene interactions indicated strong physical connections among pathogenic variants.

Abstract

OBJECTIVE: To identify and characterise genetic variants associated with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) through whole-exome sequencing (WES), using the ClinVar database as the primary resource for variant evaluation. STUDY DESIGN: A case-control study. Place and Duration of the Study: Department of Gastroenterology and Hepatology, Ziauddin University, Karachi, Pakistan, from January 2022 to July 2024. METHODOLOGY: A total of 200 MASLD patients were recruited from Ziauddin Hospital. Out of 200 cases, six patients were selected along with six age- and gender-matched healthy controls. DNA was extracted from whole blood samples, followed by WES. Variants were classified using the ClinVar database, while gene-gene interactions were analysed using the GeneMANIA platform. Statistical analysis was conducted using SPSS version 28, applying appropriate descriptive statistics based on data distribution. RESULTS: Fourteen variants were classified as pathogenic, 10 as likely pathogenic, 181 as variants of uncertain significance, and 47 as drug response variants. The most frequent pathogenic variant in MASLD cases was SUMO4 rs237025 (83.3%), while PRKCQ rs2236379 was most prevalent in controls (66%). Additionally, variants associated with insulin resistance (PPP1R3A rs1799999) and drug response (KCNJ11 rs5219, PNPLA3 rs738409) were detected in both groups. Gene-gene interaction analysis highlighted strong physical interactions among pathogenic variants, particularly within the complementary pathway. CONCLUSION: This study represents the first WES-based exploration of MASLD in the Pakistani population, contributing novel insights from a region underrepresented in genetic research. Several gene variants were highlighted for their potential relevance to MASLD and associated metabolic traits. While these findings require further validation in larger cohorts, they provide a foundation for uncovering population-specific genetic markers for MASLD. KEY WORDS: MASLD, Whole-exome sequencing, ClinVar.

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