Blood-Derived DNA Methylation Signatures of Crohn Disease and Severity of Intestinal Inflammation

Background & Aims Crohn diseaseis a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricture (B2), within 5 years. We analyzed DNA methylationpatterns in blood samples of pediatric patients with Crohn diseaseat diagnosis and later time points to identify changes that associate with and might contribute to diseasedevelopment and progression. Methods We obtained blood samples from 164 pediatric patients (1–17 years old) with Crohn disease(B1 or B2) who participated in a North American studyand were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylationpatterns were analyzed in samples collected at time of diagnosis and 1–3 years later at approximately 850,000 sites. We used genetic associationand the concept of Mendelian randomizationto identify changes in DNA methylationpatterns that might contribute to the development of or result from Crohn disease. Results We identified 1189 5′-cytosine–phosphate–guanosine-3′ ( CpG) sitesthat were differentially methylated between patients with Crohn disease(at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn diseasevs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn diseasemore closely resembled patterns observed in controls, irrespective of diseaseprogression to B2. We identified methylation changes at 3 CpG sitesthat might contribute to the development of Crohn disease. Most CpG methylation changes associated with Crohn diseasedisappeared with treatment of inflammation and might be a result of Crohn disease. Conclusions Methylation patterns observed in blood samples from patients with Crohn diseaseaccompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn disease–associated patterns of DNA methylationobserved in blood samples are a result of the inflammatory features of the diseaseand are less likely to contribute to diseasedevelopment or progression.