Presentation Information
[SY7-6]Analysis of Inflammasome-Related Gene Variants in Colchicine-Responsive, MEFV Mutation-Negative Patients with Inflammatory Bowel Disease Unclassified
*Kohei Wagatsuma1, Masashi Idogawa1,2, Motohiro Esaki3, Taku Kobayashi4, Fumihito Hirai5, Katsuhiro Arai6, Reiko Kunisaki7, Shinichiro Shinzaki8, Tadakazu Hisamatsu9, Hiroshi Nakase1 (1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Sapporo Medical University School of Medicine, Japan, 2. Division of Medical Genome Sciences, Department of Genomic and Preventive Medicine, Sapporo Medical University School of Medicine, 3. Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, Saga University, 4. Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, 5. Department of Gastroenterology, Faculty of Medicine, Fukuoka University, 6. Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, 7. Inflammatory Bowel Disease Center, Yokohama City University Medical Center, 8. Department of Gastroenterology, Hyogo Medical University School of Medicine, 9. Department of Gastroenterology and Hepatology, Kyorin University School of Medicine)
Background: We previously reported that 60.1% of patients with inflammatory bowel disease unclassified (IBDU) carried Mediterranean fever (MEFV) gene mutations, and that colchicine was effective in 84.6% of these patients. We also demonstrated that their intestinal microbiota composition differed from that of healthy controls (HCs) and patients with inflammatory bowel disease. However, some MEFV mutation-negative patients also responded to colchicine, suggesting the existence of a subgroup of enterocolitis associated with variants in inflammasome-related genes other than MEFV.
Methods: Whole-genome sequencing was performed in 31 colchicine-responsive, MEFV mutation-negative patients with IBDU [variant(-) group] to identify variants in inflammasome-related genes. Clinical characteristics and intestinal microbiota profiles were compared with those of 190 MEFV mutation-positive patients with IBDU [variant(+) group].
Results: Variants were identified in CARD8 (80.6%), ATG16L1 (61.3%), NLRP6 (54.8%), NLRP1 (38.7%), NLRP3 (25.8%), IRGM (19.4%), ATG16L2 (16.1%), NEK7 (12.9%), NLRC4 (9.7%), NAIP (9.7%), AIM2 (6.5%), and NOD2 (3.2%). Multiple variants were detected in 93.5% of the patients. Rare variants with a frequency of <1% or unknown frequency in the Japanese population were identified in NLRP3, NLRC4, NOD2, and AIM2. Compared with the variant(+) group, the variant(-) group had higher frequencies of asthma (25.8% vs. 7.4%), drug allergy (29.0% vs. 4.7%), and oral aphthae (25.8% vs. 8.4%), but a lower frequency of hematochezia (35.5% vs. 56.3%). CRP (7.4 vs. 0.8 mg/dL) and serum amyloid A levels (161.7 vs. 16.5 μg/mL) were markedly elevated in the variant(-) group. In the intestinal microbiota analysis, Enterococcus, which was increased in the variant(+) group compared with HCs, was not increased in the variant(-) group, whereas Subdoligranulum, which was decreased in the variant(+) group, was further decreased in the variant(-) group.
Conclusions: These findings suggest the presence of a subgroup of IBDU associated with inflammasome-related gene variants.
Methods: Whole-genome sequencing was performed in 31 colchicine-responsive, MEFV mutation-negative patients with IBDU [variant(-) group] to identify variants in inflammasome-related genes. Clinical characteristics and intestinal microbiota profiles were compared with those of 190 MEFV mutation-positive patients with IBDU [variant(+) group].
Results: Variants were identified in CARD8 (80.6%), ATG16L1 (61.3%), NLRP6 (54.8%), NLRP1 (38.7%), NLRP3 (25.8%), IRGM (19.4%), ATG16L2 (16.1%), NEK7 (12.9%), NLRC4 (9.7%), NAIP (9.7%), AIM2 (6.5%), and NOD2 (3.2%). Multiple variants were detected in 93.5% of the patients. Rare variants with a frequency of <1% or unknown frequency in the Japanese population were identified in NLRP3, NLRC4, NOD2, and AIM2. Compared with the variant(+) group, the variant(-) group had higher frequencies of asthma (25.8% vs. 7.4%), drug allergy (29.0% vs. 4.7%), and oral aphthae (25.8% vs. 8.4%), but a lower frequency of hematochezia (35.5% vs. 56.3%). CRP (7.4 vs. 0.8 mg/dL) and serum amyloid A levels (161.7 vs. 16.5 μg/mL) were markedly elevated in the variant(-) group. In the intestinal microbiota analysis, Enterococcus, which was increased in the variant(+) group compared with HCs, was not increased in the variant(-) group, whereas Subdoligranulum, which was decreased in the variant(+) group, was further decreased in the variant(-) group.
Conclusions: These findings suggest the presence of a subgroup of IBDU associated with inflammasome-related gene variants.