Child's Genes Affect Mom's Risk for Rheumatoid Arthritis

Laird Harrison

October 24, 2014

SAN DIEGO — Children's genes might increase their mothers' risk for rheumatoid arthritis, a new study shows.

The finding could change the way physicians look at family history when advising women who are planning to conceive. "You could ask the husband about his genetic background," said Giovanna Cruz, MS, a graduate student at the University of California, Berkeley.

"Normally, the spouse would not be considered family," she told Medscape Medical News. However, fetal microchimerism, in which a small number of fetal cells circulate in the mother's body, can persist for several decades in some women.

Cruz presented the study here at the American Society of Human Genetics 2014 Annual Meeting.

Previous research has linked rheumatoid arthritis to a variety of genetic and environmental factors, including lifestyle and previous infections.

Some versions of the immune system gene HLA-DRB1, known collectively as the shared epitope alleles, are associated with the condition. Human leukocyte antigen (HLA) genes are involved in the process the immune system uses to distinguish one's own cells from foreign cells.

Women are 3 times more likely to develop rheumatoid arthritis than men, and they do so most often when they are in their 40s and 50s. This suggests that factors related to pregnancy could play a causative role, said Cruz.

More Women With Arthritis

Cruz and her colleagues analyzed the genes of mothers and their children with and without the shared epitope or other forms of HLA genes associated with risk for rheumatoid arthritis.

So far, the researchers have recruited 300 mothers with rheumatoid arthritis, 550 of their children, and 200 of the children's fathers. The control group consists of 300 mothers without rheumatoid arthritis, 530 of their children, and 260 of their children's fathers.

Having a shared epitope-positive child significantly increased the risk for rheumatoid arthritis in a shared epitope-negative mother (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.43 - 4.58), but not in a shared epitope-positive mother (OR 1.48; 95% CI, 0.83-2.62).

The researchers found that ancestry, parity, and history of transfusion did not affect the results.

This suggests that beyond a woman's own genetic risk for rheumatoid arthritis, there is a risk conferred by delivering a child with certain high-risk alleles.

Even pregnancies that don't come to term could influence a mother's risk for rheumatoid arthritis, said coauthor Lisa Barcellos, PhD, MPH, associate professor of epidemiology at the University of California, Berkeley.

One theory to explain this phenomenon is that a woman's immune system detects proteins produced by the fetus and mistakenly tags lingering fetal cells as a threat, causing an immune reaction and symptoms of rheumatoid arthritis, Cruz said.

The finding might affect the timing of treatment, said coauthor Lindsey Criswell, MD, chief of rheumatology at the University of California, San Francisco. "There is a tendency to intervene earlier and earlier in rheumatology," she told Medscape Medical News.

The researchers plan to conduct a multigenerational genetic analysis that includes mothers of people with the disease, and to explore the role of HLA-encoded proteins and microchimerism. They would also like to expand their patient population to other ethnic groups; all the women in this study were white.

This finding could help us understand rheumatoid arthritis in shared epitope-negative women, said Lina Diaz-Gallo, PhD, from the Karolinska Institute in Stockholm, who was not involved in the study.

Patients who are negative for the shared epitope generally develop a less severe form of rheumatoid arthritis, and less research has been done in these women, said told Medscape Medical News.

The study raises the question of whether treatment should begin before patients develop symptoms, she added.

"It's really nice, and I think it's novel," Dr Diaz-Gallo said. "But it needs to be replicated."

Ms Cruz and Dr Diaz-Gallo have disclosed no relevant financial relationships.

American Society of Human Genetics (ASHG) 2014 Annual Meeting: Abstract 394. Presented October 19, 2014.

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