Genetics Seem to be Involved in One IC Subtype, Widespread Pain

While some IC patients are sure IC has a genetic component, others feel the opposite as being the only person in their family with bladder issues. Determining whether IC is genetic is certainly a challenge. One thing the vast majority of the IC community can agree on, though, is that there are a fair number of related conditions often found in IC patients. Whether all of those conditions have a genetic connection is a whole other debate.

In July of this year, however, researchers from Utah and New York presented research on this very topic.(1) They examined the genetic connection for IC and five related conditions. After years of related research, Drs. Kristina Allen-Brady, Abby J. Fyer and Myrna Weissman weren’t all that surprised at what they found.

Where the Research Began

Years ago, Fyer and Weissman were involved with a study about panic disorders. Researchers in the study interviewed patients and wrote detailed case histories. Along with panic disorder, Weissman and Fyer, who are professors in the in the Dept. of Psychiatry at Columbia University Medical Center, noticed many of the patients also talked about having bladder problems.

Weissman, a professor of epidemiology and psychiatry at Vagelos College of Physicians and Surgeons and the Mailman School of Public health at Columbia University as well as chief of the Division of Translational Epidemiology at New York State Psychiatric Institute, took the data to a urologist for his input. Dr. Steven Kaplan concluded the patients likely had IC. From there, Fyer, Weissman and Kaplan began another study examining the relationship between psychological diagnoses and IC.

“We looked at their family members and at them in terms of their psychiatric diagnosis,” Fyer said. “And there was an excess of panic disorder in the people with IC.”

A few years later, Weissman and Fyer connected with Allen-Brady, a research assistant professor at the University of Utah School of Medicine in the Division of Genetic Epidemiology. Allen-Brady submitted a paper about genetic research on IC patients and their family members. Weissman reviewed the paper for publication. Once the paper was accepted, Weissman and Fyer reached out to Allen-Brady to share their similar findings. Fyer and Weissman had found some suggtive genetic linkage on chromosome 13. Allen-Brady had one family with similar results on chromosome 13 as well as a family history of panic disorder and fibromyalgia.

“And we thought, ‘We’re on to something,'” Allen-Brady said. “‘There is something here; there is something to be found. There is an overlap of these disorders. It could be a syndrome. These disorders seem to overlap.'”

The more literature the trio looked at, the more connections they saw along with the need for more studies. So began a collaboration of researchers seeking to find answers to why these conditions overlap in certain patients and their families.

The Study Framework

For their most recent study, Allen-Brady, Fyer and Weissman identified subjects through the Utah Population Database. While the database has information going back to the 1800s — meaning 15 or 16 generations deep in some families — the medical diagnosis records only go back to 1995. The researchers used the data to identify subjects for the study by looking at families with unexplained pain disorders and some psychiatric conditions.

“We’re mostly looking at horizontal relatives like cousins,” Allen-Brady said. “We don’t have electronic medical record data on great-grandparents.”

Specifically, the study looked for patients with IC, fibromyalgia, irritable bowl syndrome, myaglic encephalomyelitis/chronic fatigue, major depressive disorder and panic disorder. Then they figured out the risk for first-, second- and third-degree relatives by looking at probands. Probands are people who are impacted by a genetic condition or worried they are at risk.(2)

“And that’s what this paper is all about to delve deeper into the data,” Allen-Brady said. “To look at probands who don’t have the disorder and look in their family members to see if they have one of these pain disorders… and also panic and depression.”

The Study Method

Using the family study method, the researchers looked at patients, starting with IC patients. Fyer said if both a patient and at least one relative had IC, the study considered IC as genetically transmitted. In fact, the team found a higher rate of IC in only second-degree relatives, suggesting a more limited genetic contribution when looking at only IC.

“We wanted to see if familial transmission of IC was related to familial transmission of fibromyalgia, IBS, chronic fatigue, panic and depression,” Fyer said. “If you can identify that, then it might suggest different ways of treating.”

Fyer, Weissman and Allen-Brady began the first step toward finding the common causal factor that contributes to this group of disorders. The family study method entails starting with a patient who didn’t have a condition, such as fibromyalgia, and then looking at the data to determine whether the patient’s relatives were more at risk for fibromyalgia than the population at large. As they looked at whether families had an increased risk for these conditions based on a relative with a related condition, Fyer said the conditions overlapped quite often.

“We found in almost all cases — much to our surprise — it looked like in first-, second- and third-degree relatives that things were as a group interrelated,” she said.

Allen-Brady pointed out this doesn’t apply to all IC patients, but rather to a certain subtype of patients. In fact, in 2022, the AUA’s updated guidelines for IC includes three unique groups of IC patients, including one labeled Chronic Overlapping Pain Conditions.(3)

“Based on these results and based on other evidence in the literature, I think we agree that there is a subset of cases that seem to be syndromic,” Allen-Brady said.

The Conclusions

By the end of the study, the three researchers concluded the evidence supports the theory that IC and the other related conditions they examined could have a genetic link.

“Our conclusion is what we hoped would happen,” Fyer said. “But in science what you hope will happen never happens! We were really surprised.”

Just as they had theorized for years, data supports their hypothesis of a syndromic type of IC which is more likely to have comorbid conditions and/or have close relatives with those same conditions.

“We don’t know the extent of disorders that are a part of the syndrome,” Allen-Brady said. “We only looked at these six, but there could definitely be other disorders that are part of the syndrome.”

Future Research

Both Allen-Brady and Fyer quickly agreed they are sticking around with IC research.

“We would love to do an actual genetic study where we take people who have these disorders, who have a strong family history of these disorders and do some sequencing and look at genetic risks to see if we can identify causal variants,” Allen-Brady said.

Finding funding for such studies is difficult, however. They are hopeful for some grants to come through.

“The big challenge for us is that these supporters span multiple different institutions at NIH,” Allen-Brady said. “It’s very challenging to get funded. We don’t fit into a single category. This is where we struggle. It’s hard for us to move forward without finding funding resources.”

Ultimately, their goal is to find better treatment for patients. Identifying the genes behind this syndrome could help improve treatment for patients. Allen-Brady said treating the syndrome at its root cause could potentially treat multiple conditions at once.

“Potentially, if you could find a treatment that works for the syndrome, then you could treat perhaps all of those disorders,” she said.

Impact for Patients

Though the research about genetics’ role in the syndromic subtype of IC is not complete, such research can help right now for patients. Allen-Brady said she’d encourage clinicians to talk with IC patients, especially those newly diagnosed, about other symptoms they have as well as related diagnoses in their families. This can help patients and their family members get diagnosed sooner.

“If you catch people early on [with diagnosis], then you may be able to improve their outcomes,” Fyer said. “And I think that’s a really important thing.”

“If they had known earlier what it was and received treatment and support, they probably wouldn’t have [struggled as much],” she said. “I think it’s very important to try and get these patients diagnosed early.”

Editors Note From Jill Osborne

The widespread pain phenotype, for which I am one, shares one common factor: central sensitization. Patients with widespread pain often have very sensitive skin, a wicked sense of smell, anxiety, catastrophizing and, sadly, a variety of pain conditions. The key question is why.

As a redhead, I carry the double recessive MC1R gene. My mother (a blonde) and my father (black hair) each carried this gene which, when combined, result in redheaded children. This is quite common in our scandinavian ancestry and I have a redheaded brother and numerous redheaded cousins.

Living as a redhead is interesting. Redheads have quantitatively more nerves than most people. We have more sensitive skin. As a child, for example, I couldn’t use bubble bath without itching. Redheads are the bane of many anesthesiologists who have found that we are harder to anesthetize. Even simple dental work often requires more anesthetic.

Does being a redhead play a role in my pelvic pain? I think it could. I’ve worked with many redheads over the years who have also struggled with various pain conditions and believe that this is an example of genetics playing a role in pelvic pain. However, we also now know that childhood trauma, major injuries and abuse can also trigger central sensitization and nerve sensitivity. So, when I look at the research above, I have to wonder if they probed for trauma in the patients they studied. Were those families influenced, for example, by a history of alcoholism and/or abuse which could have also caused trauma, widespread pain and injury to the central nervous system. It’s an important question to consider.