Intrahepatic Cholestasis of Pregnancy (ICP)

Summary

Intrahepatic Cholestasis of Pregnancy (ICP) is a cholestatic disorder that typically manifests in the second or third trimester of pregnancy. It is clinically characterized by pruritus (itching) and elevated concentrations of serum aminotransferases and bile acids, posing risks such as preterm delivery and fetal distress. Genome-wide association study (GWAS) meta-analyses have revealed shared genetic and metabolic underpinnings between ICP and circulating lipids, lipoproteins, and glucose.

Genetic Determinants and Metabolic Overlap

A meta-analysis using the Nightingale Health NMR Platform identified and replicated several genetic loci associated with both circulating metabolites and ICP. Replicated loci include GCKR, ABCG8, ABCB11, ABCB1–ABCB4, CYP7A1, SERPINA1, GAPDHS–TMEM147, SULT2A1, and HNF4A, alongside novel loci such as UGT8, NUP153, and HKDC1. Pathway enrichment analyses indicate that these loci are primarily involved in bile acid, glucose, and lipid metabolism.

Apolipoprotein and Lipid Trait Associations

At specific loci like CYP7A1, ABCB1, and SERPINA1, ICP-predisposing alleles are associated with elevated concentrations of intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) subclasses. Conversely, the direction of association is reversed at the GCKR, ABCB11, and HNF4A loci. These differences highlight the complex metabolic landscape of ICP and have implications for evaluating therapeutic targets, as drugs affecting lipid profiles in pregnant patients must be carefully managed.

Citations

• Karjalainen, M. K., Karthikeyan, S., Oliver-Williams, C., et al. (2024). Genome-wide characterization of circulating metabolic biomarkers. Nature, 628, 130–138. Source paper: s41586-024-07148-y.pdf