Background: Existing literature provides compelling evidence that mutations in the glucagon-like peptide 1 receptor gene (GLP1R) are instrumental in the onset of obesity and type 2 diabetes (T2D). A cardinal dysfunction shared by both obesity and T2D is insulin resistance. Notably, this insulin resistance also underpins metabolic dysfunction associated liver disease (MASLD). Using a genome-first approach and drawing on data from two extensive biobank datasets, this study delves into the relationship between GLP1R gene variants and MASLD diagnosis. Our primary focus is to discern the association of these gene variants with steatotic liver disease. The significance of this research lies in its potential clinical implications: establishing a connection between GLP1R gene variants and MASLD onset and progression could reshape treatment strategies. This is especially pertinent given the recent emergence of GLP1 agonists as a promising therapeutic option for MASLD.
Methods: Data was extracted on SNP variants in GLP1R and liver disease diagnoses. We analyzed the association of GLP1R gene variants with a variety of metabolic, hepatic, and clinical phenotypes in the UKBiobank and Penn Medicine Biobank. PC1-10, Age, sex, and BMI were considered as covariates to account for potential confounders.
Results: We identified a specific rare and highly deleterious missense GLP1R gene variant (rs10305510). GLP1R rs10305510 has a minor allele frequency of 0.5% in the general population, but this prevalence increases to 2% in the African American population. Analysis of the UKB revealed that this variant was significantly associated with decreased plasma levels of triglycerides, vitamin D, and urea. Additionally, it had significant associations with elevated levels of lipoprotein A and HbA1c. Analysis from the PMBB further showed that GLP1R rs10305510 was associated with an increased risk of hepatocellular carcinoma diagnosis (OR=2.3; 95% CI 1.1, 5.1; p=0.03).
Conclusions: The identified rare and highly deleterious missense variant in the GLP1R gene which is predominant in the African American population, and it is associated with alterations in metabolic parameters integral to the MASLD cardiovascular criteria and an increased risk of hepatocellular carcinoma. Future studies should explore how this GLP1R variant impacts the efficacy of GLP1 agonist treatments. Delving deeper into the intricate relationships between this variant, obesity, MASLD, and T2D risk, especially within larger MASLD cohorts, is essential for advancing our understanding and potential clinical applications.

Garret FitzGerald

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