10 new genetic risk regions linked to liver condition in pregnancy: Study
ICP also tied to higher chance of liver, pancreas, gallbladder disease
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Researchers have identified 27 genetic variants linked to intrahepatic cholestasis of pregnancy (ICP), including those located in 10 newly discovered DNA regions, uncovering key genes involved in the metabolism of bile acids and fatty molecules, according to a study.
In addition, ICP was not only linked to a well-established higher risk of pregnancy-related complications, but also to a higher chance of liver, pancreas, or gallbladder disease and certain autoimmune conditions, suggesting shared biological pathways beyond pregnancy.
“Taken together, our findings lay a strong foundation for future research into the [underlying mechanisms] of ICP and its related comorbidities [coexisting health conditions],” researchers wrote.
The findings were described in the study, “Genome-wide meta-analysis identifies genetic drivers of bile acid metabolism in intrahepatic cholestasis of pregnancy,” which was published in Nature Communications.
ICP usually develops in third trimester of pregnancy
Cholestasis is a condition marked by the slowing or stalling of the digestive fluid bile as it flows from the liver to the small intestine. ICP is a form of cholestasis that usually develops in the third trimester of pregnancy. It typically presents with itching and high blood levels of bile acids (bile’s main component), and it’s associated with adverse maternal and fetal outcomes.
In this study, a team of researchers set out to understand the biological mechanisms associated with ICP by conducting a meta-analysis of genome-wide association studies (GWAS). This type of study collects genetic and clinical information from thousands of people to establish genetic changes linked to the risk of a certain clinical feature, such as a disease.
Across these Europe-based GWAS studies, the researchers analyzed data from 4,738 women with prior ICP and 436,834 women without a history of ICP.
The team identified 27 independent genetic variants significantly associated with ICP that were located across 26 distinct DNA regions, called loci. Notably, 10 of those regions have not been previously linked to ICP.
Additional genetic analyses identified 24 genes across 11 loci in liver tissue, 20 genes in seven loci in whole blood, and 21 genes in nine loci in the pancreas that were most likely to play a causal role in ICP.
Further analyses confirmed an overrepresentation of ICP-related genes activated in the liver and pancreas, “a finding not reported in earlier studies,” the researchers wrote.
Variants may influence multiple metabolic, liver-related processes
The researchers also found that six of the 26 identified loci — three novel and three previously associated with ICP — harbor genes implicated in bile acid metabolism. The newly identified regions included the genes INHBA, MLXIPL, and ABCC2.
INHBA encodes a subunit of the activin A protein — a member of the TGF-beta superfamily — that is involved in liver function and bile acid metabolism, while MLXIPL regulates carbohydrate metabolism in the liver and bile acid production. The ABCC2 gene encodes a critical cellular transporter responsible for pumping bilirubin into bile so this waste molecule can eventually be excreted in feces.
The research team then explored how ICP-related genetic variants affect the body by analyzing their potential association with 35 blood biomarkers in the UK Biobank, an extensive repository assessing genetic and health data. They found 149 significant associations, indicating that the identified genetic variants influence multiple metabolic and liver-related processes.
They then analyzed whether the ICP-related variants were also associated with other diseases. They found that 10 of the variants were also linked to the formation of gallstones, nine to surgery to remove the gallbladder (the small organ where bile is stored), and others to body weight, height, and diabetes. Gallstones are hardened deposits of bile inside the gallbladder.
These findings highlight the crucial roles of bile acid, cholesterol, and [fat] metabolism in the [disease mechanisms] of ICP and suggest potential genetic links to pancreatitis.
Eight variants were specific to ICP, and only one of these showed a clear connection with liver and bile acid-related functions.
Researchers found that women with a history of ICP were at significantly higher risk of developing the pregnancy complications gestational diabetes and preeclampsia (sudden high blood pressure and organ dysfunction), gallbladder and bile duct diseases, as well as certain hormonal, autoimmune, and inflammatory conditions. Bile ducts are the tubes that transport bile.
The team then developed a genetic polygenic risk score (PRS), a single score combining the effect of multiple genetic variants, for ICP, which strongly predicted the condition. In addition, this PRS was also associated with gallstones and pancreas inflammation (pancreatitis), suggesting shared genetic risk factors.
“These findings highlight the crucial roles of bile acid, cholesterol, and [fat] metabolism in the [disease mechanisms] of ICP and suggest potential genetic links to pancreatitis,” the researchers wrote. “To our knowledge, this genetic overlap has not been reported in previous genetic studies of ICP. Nonetheless, the specific genetic link remains inconclusive and requires further validation.”
