Environment More Than Genes Impacts Age of IBD Diagnosis

Early-life and environmental exposures are more strongly linked to age at diagnosis of inflammatory bowel disease (IBD) than genetic factors, a large study of IBD patients reported.

Published in Clinical Gastroenterology and Hepatology, the study found that environment influences the onset of both ulcerative colitis (UC) and Crohn’s disease (CD), and exposures typical in Western society lower the age of diagnosis. These factors include birth in a developed nation, delivery by C-section, and more bathrooms in the home, according to Oriana M. Damas, MD, MSCTI, an associate professor of clinical medicine at the University of Miami Miller School of Medicine, Miami, Florida, and colleagues.

Environmental factors explained 21% of the variance in age of CD diagnosis and 39% in that of UC, with age at diagnosis, the study’s primary outcome. In models incorporating a genetic and an environmental risk score, environment was the only significant factor associated with younger age of diagnosis in all groups.

Several epidemiologic studies have examined environmental culprits in IBD, and others have examined genetic risk factors, Damas said in an interview. “But we had not seen any studies that examined the influence of both these on age of IBD development.” Her group’s working hypothesis that environment would have a greater impact than genetics was borne out.

“Additionally, very few studies have examined the contribution of genetics or environmental factors in Hispanic individuals, and our study examined the contribution of these factors in this understudied population,” she added.

According to Damas, the findings’ most immediate clinical relevance is for counseling people with a family history of IBD. “I think it’s important for concerned patients to know that IBD is not solely genetic and that several environmental factors can shape disease risk to a greater extent than genetic predisposition,” she said.

Westernization is increasingly considered a contributor to the global increase in IBD, which has been diagnosed in an estimated 2.39 million Americans. In genetically predisposed individuals, environmental culprits in developed countries are thought to negatively shape the intestinal microbiome’s composition into a less tolerant and more proinflammatory state, the authors noted. 

According to the “hygiene hypothesis,” the over-sanitization of the developed-world life is partly to blame. “A cleaner environment at home, part of the hygiene hypothesis, has been postulated as a theory to help explain the rise of autoimmune diseases in the 21st century and may play an important part in explaining our study findings,” the authors wrote.

Population-based studies have also pointed to antibiotics, nonsteroidal anti-inflammatory drugs, smoking, cesarean delivery lack of breastfeeding, and nonexposure to farm animals as other risk factors for IBD. 

Study Details

To compare the impact of environmental vs genetic risk factors, the questionnaire-based study looked at 2952 IBD patients from a tertiary-care referral center — 58.9% with CD, 45.83% of Hispanic background, and 53.18% of non-Hispanic White (NHW) ethnicity. There were too few available Black and Asian patients be included in the cohort. Data were collected from 2017 to 2022.

The mean age of patients was 39.71 years, and 34.14% were defined as born outside of the US mainland. Foreign-born patients were further characterized as from developed nations vs developing nations, and 81.3% in this subgroup came from the latter. A detailed questionnaire probed 13 potential environmental factors from type of birth to domestic living conditions, medications, and smoking across several different age groups. Blood was drawn to genotype participants and to create a genetic risk score.

Early plastic water bottle use — which has been linked to inflammatory microplastics in the intestines — and homes with more than one bathroom (and presumably less exposure to infections) were also associated with younger age at diagnosis. Susceptibility to environmental exposures was similar in Hispanic and NHW patients. 

“It was interesting to find an association between reported plastic water bottle use and younger age of IBD diagnosis,” said Damas. “Because this is a self-reported intake, we need more studies to confirm this. However, this finding falls in line with other recent studies showing a potential association between microplastics and disease states, including IBD. The next step is to measure for traces of environmental contaminants in human samples of patients with IBD.”

Unlike previous studies, this analysis did not find parasitic infections, pets, and antibiotics to be associated with age of IBD diagnosis. 

“This is an interesting and important study,” commented Ashwin Ananthakrishnan, MBBS, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston, who was not involved in the study. “There are few environmental risk factor studies looking at non-White populations and to that end, this is a very large and well-done analysis looking at environmental factors among Hispanic patients with IBD.” He added that while most studies have just compared factors between cases and controls, “this is an interesting examination of the impact of such factors on age of onset.”

Ananthakrishnan stressed, however, that further work is needed to expand on these findings.” The addition of a control group would help determine how these factors actually modify disease risk. It is also intriguing that environmental factors more strongly predict age of onset than genetic risk. That only highlights the fact that IBD is in large part an environmentally influenced disease, suggesting there is exciting opportunity for environmental modification to address disease onset.”

Offering another outsider’s perspective, Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City and not a participant in the study, agreed that the findings highlight the contribution of early life and childhood environmental factors to IBD risk relative to genetic variants. “The relative importance of the environment compared to genetic risk toward IBD, timing of exposure, and impact on age at IBD diagnosis is a novel and important finding. These data will help contextualize how we communicate disease risk and potential prevention approaches.” 

She added that future research should measure various exposures, such as pollutants in preclinical biological samples. “Mechanistic data on their downstream effects are needed to understand IBD pathogenesis and develop prevention efforts.” 

According to the authors, theirs is the first study of its kind to examine the contribution of cumulative environmental factors, age-dependent exposures, and genetic predisposition to age of IBD diagnosis in a diverse IBD cohort.

The authors listed no specific funding for this study and had no conflicts of interest to declare. Ananthakrishnan and Agrawal had no relevant competing interests.