By Jim Jarvis, MD
Dept of Pediatrics and Genetics, Genomics, & Bioinformatics Program,
University at Buffalo Jacobs School of Medicine & Biomedical Sciences

Have you ever wondered, even if just a little bit, why it is that for every complex genetic trait, whether it’s coronary artery disease, type 2 diabetes, or preterm labor, prevalence rates are always higher in economically challenged, socially marginalized, and historically traumatized populations?  I have been pondering this question for more than 15 years.  As a Native American person, I can tell you that our communities are pretty tired of being told, “It’s because you have bad genes,” and we’re not buying that answer anyway.

Last month, I was part of a small group invited by our Association of American Indian Physicians to assist in developing culturally appropriate ways to inform tribal governments and physicians caring for American/Indian Alaskan Native (AI/AN) people of the results and implications of the Adverse Childhood Experiences  (ACE) study.  During our discussions, I was asked whether there was any known link between ACEs and rheumatic diseases, a reasonable question since both rheumatoid arthritis and systemic lupus show prevalence rates that are 5-10x higher in our AI/AN communities than in the broader population.  Well, it turns out that there is a link.

The study, Cumulative childhood stress and autoimmune diseases in adults (Psychosom Med 2009; 71: 243-250.  doi:  10.1097/PSY.0b013e3181907888) is actually 8 years old, and I’m surprised I hadn’t noticed it sooner.  In this paper, the authors queried ACE data from  >15,000 adults in the San Diego Kaiser Health Foundation cohort who were part of Dr. Vince Fellitti’s original study (which, in case you’ve been residing on Mars for the past decade, links adult health outcomes to specific traumatic childhood experiences).  Their outcome variable was hospitalization for any of 21 different autoimmune/rheumatic diseases, which, of course, would under-detect an effect of ACEs on an illness like rheumatoid arthritis, which is seldom a primary cause for hospitalization. Compared to people with ACE scores of 0, people with ACE scores of > 2 showed a 100% increased risk for hospitalizations related to rheumatic diseases. Given that ACE scores of > 5 are twice as common in our AI/AN communities than in the broader population, no one should be surprised that we also have high rates of rheumatic disease.

The important question is whether the association is actually causal.  As we learn more about the effects of trauma and toxic stress on the epigenomes of cells of the central nervous system and the immune system, a causal connection becomes quite plausible.  Furthermore, we know from animal data that epigenetic changes associated with trauma responses can be transmitted across the generations (see the fascinating paper in Nature Neurosciences 2014; doi:10.1038/nn.3594).  To AI/AN people, the idea that the multiple generations in which we have faced cultural loss, poverty, racism, violence, and social marginalization has led to the observed high rates of rheumatic diseases rings true. It certainly provides a much better explanation than “you have bad genes.”

The good news, both for AI/AN people and for rheumatologists, is that the epigenome is wonderfully plastic.  Indeed, we have shown in my laboratory that one of the primary things that successful therapy for JIA does is reorganize the epigenomes of multiple different cells types.  Furthermore, multiple studies have demonstrated effective interventions that can attenuate the effects of chronic, intergenerational trauma (see Science 2014; DOI: 10.1126/1248429).

So what’s the take-home in all this?  For me, these studies are a reminder that, even though we are pediatric subspecialists, we are still pediatricians.  We are predisposed by both inclination and training to understand the social determinants of health.  Could there be a link between ACEs and JIA?  Could the traumas of our patients’ parents, grandparents, or great grandparents be manifesting themselves in the children we care for?  In our Mohawk culture, we speak of the seven generations to come who will be affected by what we do and say, or by what others do and say to us. It is my fondest hope that somewhere in CARRA, right now, there’s a young fellow or junior faculty member willing to ask the kinds of questions that emerge from the ACE study and its applicability to our own subspecialty. The answers may affect the next seven generations.