Combo of variants in ABCB4 gene could lead to ICP, study finds
Women with specific missense mutation and at least one other mutation affected
A specific variant in the ABCB4 gene does not cause intrahepatic cholestasis of pregnancy (ICP) on its own, but it may increase the disease’s risk and severity when combined with other ABCB4 variants, according to a small study in China.
While this mutation “was found in both ICP patients and healthy pregnant women,” those who developed ICP also carried other ABCB4 variants that were “not found in healthy pregnant women,” the researchers wrote.
The study, “Association between ABCB4 variants and intrahepatic cholestasis of pregnancy,” was published in Scientific Reports.
ICP twice as common in some parts of China than in Europe or N America
ICP is a form of cholestasis — a condition marked by a slowed flow of the digestive fluid bile from the liver to the intestines — that develops during pregnancy. It causes bile acids, the main components of bile, to build in the liver and leak into the bloodstream, leading to such cholestasis symptoms as itchy skin. With pregnancy, the buildup can carry risks that include premature birth.
While the exact cause of ICP is unclear, it may involve a combination of genetics, hormones, and the environment.
The frequency of ICP varies by race and geographical location, with the highest rates reported in South America. In some regions of China, ICP can be about twice as common as in Europe, North America, and Australia, where “about 1-2% of pregnant women suffer from ICP,” the researchers wrote.
However, “most studies on ICP are focused on European and American populations, with little research on the Chinese population,” the researchers wrote.
Certain genetic changes in the ABCB4 gene have been linked to ICP, which codes for MDR3, an enzyme that helps neutralize bile components to prevent damage to cells of the tubes that transport bile. Enzymes are types of proteins that accelerate chemical reactions.
Researchers with Wannan Medical College in Anhui looked at ABCB4 variants in 120 pregnant women being treated at a hospital in that eastern China province.
These women were divided into two groups: 30 who had ICP, and 90 who did not. On average, the two groups were the same age (26.9 vs. 27.2 years) and had been pregnant for the same period of time (35.5 vs. 36.6 months).
Four specific mutations in ABCB4 gene linked with ICP
Using DNA collected from blood samples, the researchers analyzed the 27 exons of the ABCB4 gene to look for alterations. Exons are the sections of DNA that contain the instructions for producing the resulting protein.
Four mutations were identified: c.175C>T, c.504C>T, c.711A>T, and c.1954A>G. The first three are called synonymous variants, meaning they do not change the MDR3 protein’s sequence of amino acids (its building blocks), and therefore don’t affect its structure (shape).
But c.1954A>G is a missense mutation, meaning it changes the genetic code in a way that produces an amino acid that’s different from the usual amino acid at that position. Computer models predicted that this mutation changed MDR3’s structure, but it was unlikely to cause disease on its own.
However, this genetic variant was more common among the group of pregnant women with ICP than the healthy group (26.7% vs. 6.7%). Moreover, while no other ABCB4 variants were detected in the six healthy women who carried the c.1954A>G mutation, all eight women with ICP who carried c.1954A>G also had at least one of the three ABCB4 synonymous variants.
Specifically, six of these eight women had c.1954A>G combined with one synonymous variant, and the remaining two women had two other ABCB4 synonymous variants.
Further analyses showed that women with c.1954A>G plus two other ABCB4 variants had significantly higher blood levels of liver damage markers, including bile acids and liver enzymes, compared with those who had c.1954A>G plus one other variant.
This suggested “an aggravation of ICP” with an increasing number of synonymous variants in addition to c.1954A>G, the researchers wrote.
Study findings suggest that the c.1954 A > G missense variant “itself may not cause clinical symptoms,” the team concluded. Rather, it may need to be combined with “other variants (c.175 C > T, c.504 C > T, c.711 A > T) to cause clinical symptoms of ICP.”
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