Understanding the genetics of lupus
Lupus is referred to in lots of ways. It’s “a woman’s disease.” It’s “a family disease.” These references—although somewhat true—point to one important factor about lupus. The disease seems to have a hereditary component.
With more questions than answers, medical experts are betting on genetics to help with diagnosis and treatment.
“I believe that genetics will be the most useful in helping us understand how many different subsets there are of lupus, and what it is about some patients that causes them to have terrible renal disease while others only have mild symptoms,” says Lindsey Criswell, MD, MPH, chief of the Division of Rheumatology at the University of California, San Francisco.
Over the last five years, genetics research about lupus has led to more discoveries of how genes can affect lupus development. Turns out, those generalizations about lupus being “a family disease” are not just anecdotal: Genetics research is proving this observation to be empirically true. If genetics research advancements continue on the same trajectory, medical experts might one day be able to look at a person’s genetic profile, predict the risk for developing lupus, and maybe even stop the disease before it begins.
Lupus can run in the family
Shannon Siegel vividly remembers how her husband, John, struggled with lupus—the abdominal pain, blood in his urine, and of course, the butterfly rash on his face. John had fought these symptoms since he was 11 years old.
He and Shannon started dating when they were 17. Shannon remembers that after they went off to college, John spent more time in the hospital and seemed to be more susceptible to infections.
The couple married in 1990, and as the years went by, John’s list of symptoms got longer and the effects became more severe. Random fevers and flulike symptoms would last for days at a time. His abdominal pain went from every so often to every day. “Maybe for a day, he’d be more comfortable, then the next week it was fevers and rashes,” recalls Shannon, a stay-at-home mom from Huntsville, Alabama.
The numerous doctors who saw John over the years either didn’t guess lupus, or they dismissed it as a possibility. “The doctors told us it’s not a Caucasian man’s disease,” Shannon says. “It was always set aside as ‘that can’t be you.’”
It’s true that women are 9 to 10 times more likely than men to develop lupus, and people of color are 3 to 4 times more likely to develop the disease than Caucasians. Yet John’s father and grandfather had both suffered from unexplained kidney complications—which happen to be one of the worst manifestations of lupus.
In addition, family members of a person with lupus, particularly children and siblings, are more likely to develop lupus than someone who doesn’t have an affected family member. That’s because we pass along our genes to our children, and have genes similar to those of our siblings. If those genes contain a variation, that variation is passed along, too.
Different genes can result in different experiences with lupus
In 2010, genetics researchers had identified about 30 genetic variations that were linked to lupus. That number has since grown to nearly 100, Criswell says.
Think of genetic variations as misprints in a recipe. DNA code is essentially the recipe, or the instructions, for making a living creature. If the recipe is supposed to say 2.5 cups, but instead it says 5.2, the cake is going to come out differently. The same goes for DNA misprints linked to lupus. The code is supposed to instruct the immune system to function a certain way, but a misprint leads to something different.
Human DNA comprises 23 pairs of chromosomes. One specific example of a genetic variant linked to lupus is a gene located on chromosome pair number 6, called TNFAIP3, says Courtney Montgomery, PhD, associate member of Oklahoma Medical Research Foundation in Oklahoma City.
Montgomery and Criswell were authors of a study, published back in February 2011 in the journal Nature Genetics, that showed how the TNFAIP3 gene codes for a protein that can cause inflammation if there are certain types of variations.
Montgomery said there are a handful of other gene variations that are similar to TNFAIP3. And like any other gene, they can be passed from one generation to the next.
Genes influence who gets lupus and how severe it is
Lupus is extremely heterogeneous—different from person to person. “Some people have mild symptoms, while others can end up in the emergency room every time they have a flare,” Montgomery says. The value of knowing what gene variation they have is that researchers can then study how the disease plays out as a result.
John was finally diagnosed with lupus in 2002, when Shannon was pregnant with their second daughter. He died in October 2011. Shannon still sounds surprised that doctors ignored the possibility of lupus for so long simply because he was Caucasian and male.
Researchers are investigating why lupus is more common among women and why men in some families might be more susceptible than others. They are also looking at why certain ethnic groups are more or less susceptible to severe lupus symptoms than others.
In the last five years, clinical trials have made a deliberate effort to include non-European people with lupus to see how genetic ancestry can influence lupus development or symptoms. For example, the TNFAIP3 variation is strongest in Koreans and Europeans with lupus, Montgomery says.
Recent research is also looking at whether common genetic variations explain why Asians and African Americans tend to develop more severe lupus symptoms than Europeans. “There’s no question that individuals with different continental ancestries are predisposed to different forms, or severity, of the disease,” Criswell says.
For better or worse, another development over the last five years is showing that genetics is not the only factor. Having certain gene variations can make a person susceptible to developing lupus, but it doesn’t mean they necessarily will, Criswell says.
Certain environmental conditions have to trigger those gene variations into action. These environmental factors can include drugs or medications, infections, and stress.
Hope for the next generation
Even though doctors took decades to find the right diagnosis for John, Shannon immediately knew what was happening when their oldest daughter, Katie An, started to see blood in her urine and experience abdominal pain. The symptoms started when she was 13, not much older than her father was when his symptoms began.
When the symptoms progressed to rashes and fevers, Shannon took Katie An to the same doctor who treated her father. “He didn’t want to immediately label it as, ‘John had lupus, so this must be lupus,’ ” Shannon says. “But there were so many things that physically matched her father, including the lab results, that the doctor said this must be a genetic thing.”
As she coped with her daughter’s diagnosis, Shannon says she struggled to keep her composure. “On the inside, I was thinking that I lost John, I can’t lose Katie An too.”
Her source of hope comes from how much has changed in understanding and treating lupus. “The medical research is moving so fast,” Shannon says.
Criswell says the future of this fast-moving research is this: to be able to look at the genetic variations that cause someone to be susceptible to lupus and predict whether they’ll actually develop the disease, how severe it will be, and, most important, which treatments have worked best for people with those specific genetic variations.
That way, parents like Shannon can rest assured that even when lupus is passed down to the next generation, it won’t have the same impact.
“As we fully define more genetic variations,” Criswell says, “we hope we can prevent the disease from developing in the first place.”