Lupus not identical in twins

Pattern of chemical tags on DNA linked to the autoimmune disease

Lupus can tell identical twins apart by the distinguishing marks the pairs carry on their DNA.

Fewer DNA methylation marks may leave one twin vulnerable to the inflammatory autoimmune disease, even while the other sibling remains healthy, a new study appearing online December 22 in Genome Research shows.

The finding suggests that environmental factors determine whether genetically susceptible twins will contract lupus, or systemic lupus erythematosus, which is characterized by the immune system attacking the body’s own cells.

Researchers have previously identified at least 17 different genes involved in lupus. If genes alone were responsible for determining whether a person gets lupus, then every time one identical twin got the disease, the other should too.

But that doesn’t happen. Between 40 percent and 75 percent of the time, when one twin develops lupus the other stays healthy, indicating that some environmental factor must trigger the disease, says Bruce Richardson, a rheumatologist at the University of Michigan Medical School in Ann Arbor.

Scientists have looked beyond differences in the genes of healthy people and people who get autoimmune disorders and found that people with lupus and rheumatoid arthritis have lower levels of DNA methylation than healthy people. DNA methylation is a type of chemical mark that generally helps reduce how active genes are without changing the genes themselves.

Lower levels of methylation could lead to over-activity of genes, including ones that control immune responses. Environmental triggers can influence DNA methylation levels.

But previous studies haven’t ruled out a genetic contribution for lupus, Richardson says, because the healthy controls and lupus patients in those studies didn’t have exactly the same genetic makeup.

Now, a study of identical twins in which one of the pair has lupus shows that the sick twin has lower levels of DNA methylation on at least 49 different genes than their healthy sibling does, report scientists led by Esteban Ballestar of the Bellvitge Biomedical Research Institute in Barcelona. These methylation differences between the twins don’t appear to be random: The team found that other people with lupus shared the same methylation pattern as the sick twin, and that healthy people did not share that pattern.

The team examined methylation of 807 genes. That is only a fraction of the number of genes in the human genome, and Ballestar plans to expand the search. He expects to find many other genes also have lower levels of methylation in people with lupus.

It is not clear whether twins start out with different levels of methylation, or if something in the environment, such as a viral infection, triggers the changes later, Ballestar says. The discovery also does not prove that methylation patterns alone cause lupus. An underlying genetic susceptibility is probably also necessary to develop the disease, he says.

Because changes in methylation don’t alter genes, the finding may also suggest future treatment possibilities.

“Although it’s really speculative in the context of autoimmune disorders, one thing about methylation changes is that they are potentially reversible,” Ballestar says.

Currently there are no drugs to boost methylation in people.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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