Genes are somewhat to blame for rheumatoid arthritis (RA), but not as much as previously believed, according to a new study published online recently in Arthritis & Rheumatism.
Although the exact cause of rheumatoid arthritis is not known, previous research has suggested that about 60 percent of a person’s chance of getting RA depends on genetics, and about 40 percent is due to nongenetic or environmental factors. The new research flips those numbers around.
This can be comforting to patients who are afraid they might pass RA to their children or are worried that they will get it if a close relative has it. It also means that there are fewer genes to be discovered that may carry RA risk.
“From a research perspective this is important, since it would imply that we may have already identified a slightly larger proportion of the genetic risk factors than we thought, which would in turn imply that nongenetic factors may play a larger role in the development of RA,” explains lead study author Thomas Frisell, PhD, a research coordinator of the clinical epidemiology unit in the department of medicine at Karolinska Institute in Stockholm.
The researchers set out to determine a more accurate estimate of the heritability of RA – the contribution of genes to the development of the disease. They also wanted to learn more about what increases or decreases a family member’s risk, such as gender, the relationship (for instance, sibling or parent), the age at which someone develops RA and whether that person has the RA blood markers known as rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPAs).
According to the researchers, few population-based studies have addressed these questions. Most studies have been based on particular groups of patients, not large populations, and have lacked control groups, which help ensure more accurate results.
The researchers analyzed data from more than 90,000 RA patients identified through three large Swedish population registries. For each study subject with RA, five people – known as controls – were randomly selected from the Swedish Total Population Register, matched to the study subject's gender, age, county of residence and marital status.
The results showed that first-degree relatives (parents, siblings, offspring) of study subjects had three times the average risk of developing the disease, and second-degree relatives (grandparents, grandchildren, aunts, uncles, nephews, nieces, half-siblings) had two times the average risk. The average risk of getting RA for someone in the general population is about 1 in 200, so for someone with a first degree relative, that means the risk goes up to 1 in 67, and for someone with a second-degree relative, the risk goes up to 1 in 100.
These findings suggest an overall heritability of 40 percent – significantly lower than previous estimates of about 60 percent. And that means nongenetic or environmental causes are 60 percent responsible for the disease.
Eric L. Matteson, MD, chair of the division of rheumatology at Mayo Clinic in Rochester, Minn., called the study “quite a good contribution.” He was not surprised by the findings. “We look at families and populations of RA and it’s been our view, too, that genes explain only a part of what’s going on,” says Dr. Matteson.
“What the study says is that genes explain some of the risk but they don’t explain all of the risk,” says Dr. Matteson. “What’s missing are environmental influences like smoking.” Other factors may also be at play. “We think obesity plays a role for sure, so weight management among people who don’t already have RA is important. And there’s high interest in the role of gut bacteria and how that might influence risk,” says Dr. Matteson.
The study found RA to be equally heritable in both men and women. Why, then, do more women develop the disease? “That’s a very good question,” says Frisell. “We can speculate that women as a group are exposed to more of several risk factors that could be hormonal or even lifestyle-related.”
The results, however, showed two major differences in heritability. First, a relative’s odds of developing RA were significantly higher if the study subject was “seropositive” as opposed to “seronegative,” meaning they tested positive for one of the two RA blood markers – rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA).
“This provides further evidence that [seropositive and seronegative RA] are two somewhat different diseases, but with some overlap in what causes them,” says Frisell. “This may also explain why we so far have not been able to identify many risk genes for seronegative RA; perhaps there are not all that many to be found.”
Second, family members were also more likely to develop RA if the study subject developed the diseaser early in life. In other words, says Dr. Matteson, “Heritability plays more of a role in people who get it when younger. They probably have higher expression of the genes that confer RA risk.”
The bottom-line message to people with RA? “It may be comforting for individuals with RA who have, or are planning to have, children to see that even though these diseases are heritable, the relative risk is only three [times higher] in first-degree relatives,” says Frisell. “Since the disease is relatively rare in the first place, a threefold increase in risk is still a very low risk. And the risk is even lower if you have a seronegative disease.”
Dr. Matteson agrees. “It’s quite a nice study, and it does say if you have a family member who has RA, it’s not inevitable that they’re going to get it; in fact, it’s still more likely than not that they’re not going to.”