Whole-Exome Sequencing identified Olfactory Receptor genes as a key contributor to extreme obesity with progression to nonalcoholic steatohepatitis in Mexican patients

Abstract

ABSTRACT: Introduction and objectives: Obesity is a global health problem that triggers fat liver accumulation. The prevalence of obesity and the risk of non-alcoholic steatohepatitis (NASH) among young obese Mexican is high. Furthermore, genetic predisposition is a key factor in weight gain and disrupts metabolism. Herein, we used Whole-Exome Sequencing to identify potential causal variants and the biological processes that lead to obesity with progression to NASH among Mexican patients. Materials and Methods: Whole-Exome Sequencing was performed in nine obese patients with NASH diagnosis with a BMI ≥30 kg/m2 and one control (BMI=24.2 kg/m2) by using the Ion S5TM platform. Genetic variants were determined by Ion Reporter software. Enriched GO biological set genes were identified by the WebGestalt tool. Genetic variants within ≥2 obese NASH patients and having scores of SIFT 0.0-0.05 and Polyphen 0.85-1.0 were categorized as pathogenic. Results: A total of 1359 variants with a probable pathogenic effect were determined in obese patients with NASH diagnosis. After several filtering steps, the most frequent pathogenic variants found were rs25640-HSD17B4, rs8105737-OR1I1, rs998544-OR5R1, and rs4916685, rs10037067, and rs2366926 in ADGRV1. Notably, the primary biological processes affected by these pathogenic variants were the sensory perception and detection of chemical stimulus pathways in which the olfactory receptor gene family was the most enriched. Conclusions: Variants in the olfactory receptor genes were highly enriched in Mexican obese patients that progress to NASH and could be potential targets of association studies.

Keywords

• Extreme obesity
• NASH
• Whole-exome sequencing
• olfactory receptors
• HSD17B4