Science Editor

Researchers have identified mutations in a set of proteins that predispose their carriers to preeclampsia, a complication that shows up in between 5 percent and 10 percent of pregnancies. Their work appeared in the March 22, 2011, online issue of PLoS Medicine.

There is currently no treatment for preeclampsia, which ends only when pregnancy does. In extreme cases, it can be fatal for mother and baby, and the premature delivery that can become necessary when preeclampsia goes out of control has health risks of its own.

The genes that the team identified are all part of the complement regulatory system, which keeps the complement system from attacking the body's own tissues.

The complement system, corresponding author Jane Salmon told BioWorld Today, is "a very primitive host defense system." But like most rapid response task forces, the complement system is not exactly a guided missile. From the point of view of the complement system, Salmon said, "anything that is coated with immunoglobulin has a flag 'get rid of me.' . . . They are not such smart cells."

Nor do they know when to call it a day. Cells have to express complement regulatory protein to protect themselves from falling victim to the complement system's zeal. Otherwise during, for example, a pneumonia infection, "you would do in your lung once you got done with the bug," Salmon said. To keep an overzealous complement system from destroying the body, cells express complement regulatory proteins.

Salmon and her colleagues became interested in the complement regulatory system for several reasons. First, animal studies done a few years back showed that "to have a normal pregnancy, you need to regulate complement activation."

The authors also noticed a possible link between preeclampsia and another disorder, atypical hemolytic uremia. "Typical" hemolytic uremia, Salmon explained, is out-of-control clotting, most often in response to E. coli infection. Hemolytic uremia can lead to kidney failure.

Atypical hemolytic uremia has the same symptoms, but minus the E. coli. It "seems to be genetic." The disorder can show up during pregnancy – and when it does, clinically "it looks a lot like preeclampsia," Salmon said.

Together, those findings were enough to prompt Salmon and her team to look for genetic alterations in three genes of the complement cascade: membrane cofactor protein, complement factor I and complement factor H.

They looked at 250 women with lupus or antiphospholipid antibody syndrome, both of which are autoimmune disorders that are associated with a greater likelihood of having a complicated pregnancy. Forty of those women had either developed preeclampsia during an earlier pregnancy, or developed it during the course of the study. Of the 40, nearly 20 percent had mutations in at least one of the three genes.

Salmon and her team next went on to see whether the same variations might be found in patients with preeclampsia, but no autoimmune disease. They were: Five out of 59 women with preeclampsia, but no autoimmune disease, had mutations in one of the three proteins.

The exact genes that Salmon and her team looked at do not, in fact, explain most cases of preeclampsia. But Salmon is convinced that a more thorough search will uncover a bigger role for the complement system in preeclampsia: "We only looked at three genes," she said, whereas the complement cascade consists of about 30 altogether. Also, so far, "we're missing the whole paternal component." The team looked only at maternal genes, but the placenta is fetal tissue, meaning it has dad's genes as well.

Salmon is optimistic that as they look at other parts of the complement system, the team will find additional places where the complement system malfunctions.

Salmon, and several of her co-authors, have professional relationships with Taligen Therapeutics Inc., acquired recently by Alexion Pharmaceuticals Inc. (See BioWorld Today, Feb. 1, 2011.)

Alexion is the maker of eculizumab (Soliris), which is approved for the treatment of paroxysmal nocturnal hemoglobinuria, and is in clinical trials for the treatment of atypical hemolytic uremic syndrome. If the similarities between atypical hemolytic uremia and preeclampsia hold up on the molecular level, eculizumab could be a potential treatment for preeclampsia.

Whether eculizumab itself proves useful, Salmon contended the findings have potential for prediction of who is at risk for preeclampsia, as well as for treating and preventing it. "I think this is just the beginning of the story."