Letter to the editor on “Genome-wide interaction study with BMI identifies CYP7A1 and GIPR as genetic modulators of MASLD”

Dear Editor,

The recent study conducted by Jamialahmadi et al. [1], titled “Genome-wide interaction study with BMI identifies CYP7A1 and GIPR as genetic modulators of MASLD” marks a significant advancement in our understanding of the genetic architecture underlying metabolic dysfunction-associated steatotic liver disease (MASLD) [1]. Utilizing a genome-wide SNP×BMI interaction approach to analyze alanine aminotransferase (ALT) levels within the UK Biobank cohort, the authors identified 13 loci, including two novel genes CYP7A1 and GIPR which modulate liver fat content in a manner dependent on body mass index (BMI). This research not only elucidates new biological pathways involved in the pathogenesis of MASLD but also offers critical insights for precision medicine strategies addressing this globally prevalent condition.

MASLD affects approximately 32% of the global population; however, genome-wide association studies (GWAS) have accounted for only a fraction of its heritability [2]. Traditional GWAS that focus solely on main genetic effects often neglect gene-environment interactions, a key limitation that this study addresses. The authors employed BMI, which is a major risk factor for MASLD, as an environmental modifier to uncover genetic loci whose effects are amplified or moderated by adiposity. This strategy successfully identified eight established MASLD-associated loci (e.g., PNPLA3, TM6SF2) along with five novel interactions, with GIPR and UBXN2B/CYP7A1 further validated for direct associations with hepatic proton density fat fraction (PDFF). This innovative approach effectively bridges the “missing heritability” gap by demonstrating how adiposity dynamically influences genetic susceptibility.

The intronic variant GIPR rs34783010-T has emerged as a significant modulator. Paradoxically, the minor T allele is associated with lower BMI but higher levels of HbA1c, increased diabetes risk, and elevated liver fat content, resembling a lipodystrophy-like phenotype. This observation aligns with reduced plasma gastric inhibitory polypeptide (GIP) levels in carriers, suggesting either impaired GIP receptor (GIPR) function or clearance. These findings provide genetic validation for GIPR agonism as a therapeutic strategy, exemplified by the dual GLP-1 receptor/GIPR agonist tirzepatide, which has recently demonstrated efficacy in re-solving metabolic-associated steatotic liver disease and reducing fibrosis [3]. The study posits that GIPR genotype may serve as a predictor for response to incretin-based therapies, thereby enabling personalized treatment approaches for MASLD and type 2 diabetes.

The UBXN2B/CYP7A1 locus revealed compelling mechanistic insights. Fine-mapping and epigenomic analyses prioritized rs10504255, which is a variant located within a hepatocyte-specific enhancer that regulates CYP7A1 expression. The PDFF-increasing allele disrupts the binding of activators such as HNF1A and PPARG while enhancing the binding of repressors like REST and FOXA1; this alteration potentially reduces CYP7A1 transcription. CYP7A1 encodes the rate-limiting enzyme responsible for converting cholesterol into bile acids. CRISPR activation of this enhancer resulted in upregulation of CYP7A1 in hepatocytes, confirming its regulatory role. Notably, knockouts of the zebrafish cyp7a1 orthologue exhibited reduced liver fat under metabolic challenge conditions, which supports its causal role in hepatic lipid accumulation. Furthermore, human data linked the risk allele to dyslipidemia, gallstones, and cardiovascular disease, which mirrors phenotypes observed in individuals homozygous for loss-of-function mutations in CYP7A1. This suggests that modulating bile acid synthesis, particularly within an obesity context, could ameliorate MASLD; however, careful monitoring for hypercholesterolemia would be essential.

This study emphasizes that the efficacy of weight loss in MASLD may be influenced by genetic background. For example, carriers of the PNPLA3 G-allele exhibit a more significant reduction in liver fat following bariatric surgery [4]. Similarly, genotypes of GIPR and CYP7A1 could stratify patients for targeted therapies: GIPR agonists (such as tirzepatide) may provide benefits to individuals carrying the diabetogenic GIPR rs34783010-T allele. The contrasting associations of CYP7A1 with ALT in lean versus obese individuals, as highlighted by Jamialahmadi et al., pave the way for precision hepatology through the integration of geneenvironment interactions, functional genomics, and crossspecies validation. Their identification of GIPR and CYP7A1 as BMI-dependent modulators of MASLD offers a framework for developing genotype-guided therapeutic approaches. Future research should investigate longitudinal interactions among these loci, dietary factors, and emerging pharmacotherapies to optimize personalized management strategies for MASLD while underscoring the necessity for adiposity-stratified interventions.

Abbreviations

ALT

analyze alanine aminotransferase

BMI

body mass index

GIP

gastric inhibitory polypeptide

GIPR

gastric inhibitory polypeptide receptor

GWAS

genome-wide association studies

MASLD

metabolic dysfunction-associated steatotic liver disease

PDFF

proton density fat fraction