S1839 Frameshift Mutations in the TLR4 Gene with Potential Protective Effect on Progression to Fibrosis in MASLD Patients: A Pilot Study

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Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is defined by the presence of hepatic fat detectable via imaging or histology, excluding secondary causes of hepatic fat accumulation. It is the most common cause of chronic liver disease. Fibrosis occurs in about 20% of these patients . Toll-like receptors (TLRs) are a group of receptors that detect pathogen-associated molecular patterns. TLR4 activation by Gram-negative bacterial lipopolysaccharides (LPS) triggers inflammatory cytokines production and fibrogenesis. The aim of this study is to perform whole-genome sequencing of TLR4 gene and compare the identified mutations found in MASLD patients and controls. Methods: Our study recruited 30 Lebanese patients diagnosed with MASLD and 19 healthy subjects. Clinical and demographical data were collected for both groups. Ultrasound liver imaging and FibroScan were performed on all subjects to confirm the presence or absence of MASLD and to determine the stage of steatosis and fibrosis . MASLD patients were categorized into early fibrosis (F0-F1) and moderate to severe fibrosis (F2-F3-F4). Our study recruited 30 patients diagnosed with MASLD and 19 healthy subjects. Genotypic analysis of the TLR4 gene from peripheral blood samples of both groups was performed. Results: The majority of MASLD patients were males (67%), while the control group was evenly split (48% male). The median age was 49 years ±11 for MASLD patients and 59 years ±9 for healthy controls. Among MASLD patients, 44% were overweight and 41% were obese. Moreover, of the MASLD patients, 23% had type II diabetes mellitus, 33% had dyslipidemia and 57% had hypertension. 47% of MASLD patients had at least one elevated liver function test (LFT). Early fibrosis (F0-F1) was found in 77% (23/30 patients) of MASLD patients. Frameshift mutations in MASLD patients were exclusively observed in exons 1 (4 patients) and exon 3 (25 patients), with none in exon 2. The majority of MASLD patients with frameshift mutations between amino acid positions 246-248 of exon 3 had no fibrosis despite having S2-S3 steatosis (15/16 patients). Interestingly, 74% (14/19) of healthy controls shared identical frameshift mutations in amino acid positions 242-249 with the previously mentioned subgroup (15/16 patients). Conclusion: Our pilot study suggests that certain frameshift mutations in the TLR4 gene might have a protective effect against fibrosis progression in MASLD patients. Further studies are needed to confirm our findings.

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