| Title: | Genome-wide investigations of the lipid accumulation product index pinpoints polygenic determinants underlying pancreatitis susceptibility |
| Journal: | Mammalian Genome |
| Published: | 15 Apr 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41986517/ |
| DOI: | https://doi.org/10.1007/s00335-026-10215-6 |
Publication 17985
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Abstract
The lipid accumulation product index (LAP) is a robust marker of lipid burden. However, its genetic architecture and causal relevance to pancreatitis remain poorly characterized. We performed a genome-wide association study (GWAS) of LAP in 388,213 European from UK Biobank, followed by colocalization, transcriptome-wide association studies (TWAS), LD score regression and Mendelian randomization for causal relationships. Polygenic risk scores (PRS) were constructed and tested against chronic pancreatitis (CP), hypertriglyceridemic acute pancreatitis (HTG-AP), and acute pancreatitis (AP) using regression models. Gene-environment interactions were evaluated for dietary and lifestyle factors. The GWAS identified 235 independent loci associated with LAP; 18 and 26 genes showed significant colocalization with hepatic and visceral-adipose eQTLs, respectively. TWAS revealed 292 (PrediXcan) and 417 (JTI) genes in visceral fat, and 164 (PrediXcan) and 281 (JTI) in liver, whose expression associated with LAP. Positive genetic correlations were observed between LAP and CP (rg = 0.252) and AP (rg = 0.219). Mendelian randomization supported a causal effect of LAP on CP (β = 6.86 × 10−3, P = 0.030) and AP (β = 1.68 × 10−3, P = 0.045). Each 1-SD increase in LAP-PRS conferred higher risk of HTG-AP (OR = 1.11, 95% CI 1.02-1.20) and CP (OR = 1.07, 95% CI 1.00-1.14), but not AP. Furthermore, a healthier dietary pattern can attenuate the HTG-AP risk genetically driven by LAP PRS. This study delineates the polygenic basis of LAP and establishes its causal role in CP and HTG-AP susceptibility, offering a genetically informed indicator for risk assessment of pancreatitis.</p>
12 Keywords
- Female
- Gene-Environment Interaction
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Lipid Metabolism
- Male
- Mendelian Randomization Analysis
- Multifactorial Inheritance
- Pancreatitis
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
8 Authors
- Chia-Fu Chien
- Zhengwei Qi
- Zhengye Liu
- Hanze Du
- Ziqi Wan
- Haotian Chen
- Xiaoyin Bai
- Jiarui Mi
2 Applications
| Application ID | Title |
|---|---|
| 100787 | New integrated approaches based on phenotype and genetic data to explore the potential pathogenesis and novel biomarkers for the digestive diseases |
| 157997 | Decoding the pathogenesis of digestive disorders and developing predictive tools using phenotypic and genomic data from the UK Biobank |
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