Abstract
Background and Aims
The Mediterranean fever (MEFV) gene, which encodes a pyrin protein, is the causative gene of familial Mediterranean fever. Patients with inflammatory bowel disease (IBD) have a significantly higher frequency of MEFV mutations than healthy controls; however, the pathological significance of this difference remains unknown. This study investigated the relationship between MEFV mutations and the clinical characteristics of IBD and refractoriness in patients with a confirmed diagnosis of ulcerative colitis (UC) or Crohn's disease (CD).
Methods
This retrospective cohort included 260 patients with UC and 131 patients with CD who visited Sapporo Medical University Hospital or Kyorin University Hospital from April 2021 to March 2023. Demographic and clinical data were collected, and blood samples were examined for MEFV mutations using next generation sequencing.
Results
Mutations of the MEFV gene were found in 60.8% of UC and 56.5% of CD patients. Two or more overlapping mutations were identified in 26.2% patients with UC and 19.8% patients with CD. In patients with IBD, mutations in exons 2 and 3 were associated with extraintestinal manifestations (EIMs), and the coexistence of exon 2 and 3 mutations further strengthened this association. G250R (P = .0096, odds ratio 3.49 [1.36–8.98]) and G304R (P = .039, odds ratio 2.62 [1.05–6.54]) in exon 2, and P373Q (P = .0016, odds ratio 7.86 [2.19–28.26]) in exons 3, were significantly associated with EIMs; when stratifying patients with IBD, this trend was observed in patients with UC, but not in those with CD.
Conclusion
The MEFV mutation rate was higher in Japanese patients with UC and CD than in healthy controls. MEFV mutations could influence EIMs in patients with IBD.
Keywords: Crohn's disease, extraintestinal complications, inflammatory bowel disease, Mediterranean fever gene, ulcerative colitis
Graphical abstract
Introduction
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is characterized by mucosal immune abnormalities in the digestive tract, caused by a complex interaction among disease-susceptibility genes, environmental factors, and alterations in the intestinal microbiota.1 The pathogenesis of IBD remains unclear; however, several studies have investigated the role of genetic mutations in disease susceptibility. NOD2 was the first reported susceptibility gene for CD2 and since then, >30 IBD-associated gene mutations have been reported,3 but their functions have not been fully elucidated.
The Mediterranean fever (MEFV) gene, which causes familial Mediterranean fever (FMF), is located on the short arm of chromosome 16 and encodes the pyrin protein. Pyrin negatively regulates the activation of interleukin (IL)-1β, an inflammatory cytokine under physiological conditions. Pyrin dysfunction caused by MEFV mutations leads to the excessive activation of IL-1β, resulting in systemic inflammation.4,5
Several cases harboring MEFV mutations and presenting gastrointestinal lesions similar to those observed in patients with IBD have been reported.6, 7, 8, 9, 10, 11, 12 These cases suggest that MEFV-associated enterocolitis may be present in patients previously diagnosed with unclassifiable IBD. Furthermore, MEFV mutations occur not only in MEFV-associated enterocolitis but also in patients diagnosed with UC and CD,13, 14, 15, 16, 17 which indicates that MEFV mutations may be involved in IBD pathogenesis. However, the frequency and location of MEFV mutations vary according to region and race. Most previous reports investigating the association between IBD and MEFV genes have involved populations from Türkiye and Middle Eastern countries.17 To date, no large-scale reports of MEFV gene analysis in Japanese patients with IBD have been reported, and its frequency and relationship with clinical characteristics are unknown.
This study aimed to analyze the frequency of MEFV gene mutations in Japanese patients with UC and CD and to elucidate the relationship between gene mutations and clinical characteristics.
Materials and Methods
Study Design
This was a retrospective cohort study. A total of 400 patients with a confirmed diagnosis of UC or CD who visited the Sapporo Medical University Hospital or Kyorin University Hospital between April 1, 2021, and March 31, 2023, were included. Patients with a confirmed diagnosis of UC or CD based on the diagnostic criteria of the Intractable Diseases, Health, and Labor Sciences Research in Japan18 were registered. Patients who were unable to provide written informed consent were excluded.
Clinical Information
The following clinical information was collected retrospectively from medical records: age, sex, disease, disease type, age at onset, number of years affected, extraintestinal manifestation (EIM), complex perianal fistulas, treatments (thiopurine, calcineurin inhibitors, advanced therapies, apheresis, endoscopic dilatation at least twice a year for patients with CD and surgery), steroid dependency and resistance, number of hospitalizations, serum amyloid A (SAA), and C-reactive protein (CRP) levels.
Treatment-Related Definitions
We defined steroid resistance as no response to prednisolone at 1–1.5 mg/kg/day for 1–2 weeks, steroid dependence as relapse during steroid tapering, and advanced therapies as including biologics and small molecules.
MEFV Gene Analysis
Blood sample (2 mL) of all patients was collected in EDTA-2K collection tubes and frozen at −20 C until the analysis. DNA was extracted using ISOSPIN Blood and Plasma DNA (cat. 312-08131. Nippon Gene, Chiyoda-ku, Tokyo, Japan). The human genome build hg38 was used as the reference genome and the MEFV gene custom amplicon panel (Ion AmpliSeq Made-to-Order Panel. Thermo Fisher Scientific, Waltham, MA) containing the entire exon region of the MEFV gene was created. PCR-amplified amplicons were obtained using the Ion AmpliSeq Library Kit Plus (Cat. 4488990, Thermo Fisher Scientific). The amplicons were sequenced by next-generation sequencing using an Ion GeneStudio S5 system (Thermo Fisher Scientific). After confirming that sufficient quality control was obtained, mapping was performed on 3 types of aligners (hisat2, bwa, and Ion Reporter). Among the amino acid mutations for which the number of cover reads was >100 and the results of the 3 aligners were consistent, mutation frequencies between 20% and 75% were designated as heterozygous mutations, and those with frequencies between 75% and 100% were designated as homozygous mutations. To determine the mutation probability of genes in the Japanese population, ToMMo-38KJPN, a genome database of approximately 38,000 Japanese individuals, was referenced.19
Statistical Analysis
JMP Pro v.17 software (SAS Institute Inc., Cary, NC) was used for the statistical analysis. No imputations were performed for missing data (see Appendix 1, Table A1). Continuous variables were expressed as medians and interquartile range, and binary variables are expressed as percentages. Continuous variables were analyzed using the Wilcoxon rank-sum test. Categorical variables were analyzed using univariate logistic regression and expressed as odds ratios and confidence intervals. A P value < .05 was considered statistically significant.
Results
Patient Characteristics
Total 400 patients were enrolled in the study; however, 9 patients could not be analyzed for the MEFV gene owing to insufficient blood specimens. Therefore, a total of 391 patients were included in the analyses (see Appendix 2, Figure A1) including 260 (66.5%) patients with UC and 131 (33.5%) patients with CD. Median age at disease onset was 28 (range 4–82) years. Overall, 12.3% of patients had EIMs, and 5.4% had complex perianal fistulas; 14.8% of patients were steroid-resistant and 24.8% were steroid-dependent. Thiopurines were used in 49.4% of patients, calcineurin inhibitors in 8.2%, and apheresis in 12.0%. Surgery with bowel resection was performed in 4.6% of patients with UC and in 44.3% of those with CD. At least one advanced therapy (biologics and small molecules) was used in 58.8% of patients (Table 1, see Appendix 1, Table A2). Total 52.3% of patients had a history of hospitalization (Table 1).
Table 1.
Characteristics of the Patients
| UC | CD | Total | |
|---|---|---|---|
| Number of patients | 260 (66.5%) | 131 (33.5%) | 391 |
| Sex (male:female) | 135:125 | 80:51 | 215:176 |
| Age at onset of IBD, median (range) | 32 (4–82) | 23 (10–68) | 28 (4–82) |
| Disease duration (y), median (range) | 9.3 (0.9–44.0) | 12.0 (2.2–51.4) | 9.9 (0.9–51.4) |
| Disease/phenotype | |||
| UC | |||
| Ulcerative proctitis (B1) | 27 of 258 (10.5%) | - | |
| Left-sided colitis (B2) | 69 of 258 (26.7%) | - | |
| Pancolitis (B3) | 162 of 258 (62.8%) | - | |
| CD | |||
| Ileitis (L1) | - | 32 of 130 (24.6%) | |
| Colitis (L2) | - | 20 of 130 (15.4%) | |
| Ileocolitis (L3) | - | 78 of 130 (60.0%) | |
| Extraintestinal manifestations | 31 of 260 (9.6%) | 17 of 131 (13.0%) | 48 of 391 (12.3%) |
| Joint symptoms | 11 of 260 (4.2%) | 7 of 131 (5.3%) | 18 of 391 (4.6%) |
| Skin symptoms | 10 of 260 (3.8%) | 12 of 131 (9.2%) | 22 of 391 (5.6%) |
| Ocular symptoms | 3 of 260 (1.2%) | 0 of 131 (0.0%) | 3 of 391 (0.8%) |
| Hepatobiliary pancreatic diseases (PSC, AIP) | 4 of 260 (1.5%) | 1 of 131 (0.8%) | 5 of 391 (1.3%) |
| Thrombosis | 6 of 260 (2.3%) | 0 of 131 (0.0%) | 6 of 391 (1.5%) |
| Complex perianal fistulas | 4 of 260 (1.5%) | 17 of 131 (13.0%) | 21 of 391 (5.4%) |
| CRP (mg/dL), median (range) | 0.9 (0.1–29.9) | 1.1 (0.1–9.2) | 1.0 (0.1–29.9) |
| SAA (mg/L), median (range) | 55.4 (2.4–2169.2) | 57.7 (1.3–1559.5) | 57.7 (1.3–2169.2) |
| Treatment details | |||
| Steroid dependent | 39 of 260 (15.0%) | 19 of 131 (14.5%) | 58 of 391 (14.8%) |
| Steroid resistant | 86 of 260 (33.1%) | 11 of 131 (8.4%) | 97 of 391 (24.8%) |
| Thiopurine | 113 of 260 (43.4%) | 80 of 131 (61.1%) | 193 of 391 (49.4%) |
| Calcineurin inhibitor | 27 of 260 (10.3%) | 5 of 131 (3.8%) | 32 of 391 (8.2%) |
| Apheresis | 45 of 260 (17.3%) | 2 of 131 (1.5%) | 47 of 391 (12.0%) |
| Endoscopic dilation (at least twice a y) | - | 12 of 131 (9.2%) | |
| Surgery (total colectomy) | 12 of 260 (4.6%) | - | |
| Surgery (related to CD) | - | 58 of 131 (44.3%) | |
| Infliximab | 69 (26.5%) | 76 (58.0%) | 145 (37.1%) |
| Adalimumab | 22 (8.5%) | 31 (23.7%) | 53 (13.6%) |
| Golimumab | 18 (6.9%) | 0 | 18 (4.6%) |
| Vedolizumab | 37 (14.2%) | 8 (6.1%) | 45 (11.5%) |
| Ustekinumab | 32 (12.3%) | 41 (31.3%) | 73 (18.7%) |
| Risankizumab | 0 | 2 (1.5%) | 2 (0.5%) |
| Tofacitinib | 34 (13.1%) | 0 | 34 (8.7%) |
| Filgotinib | 1 (0.4%) | 0 | 1 (0.3%) |
| Upadacitinib | 6 (2.3%) | 1 (0.8%) | 7 (1.8%) |
| Carotegrast | 1 (0.4%) | 0 | 1 (0.3%) |
| Advanced therapies (1 or more) | 119 of 260 (45.8%) | 109 of 131 (83.2%) | 228 of 391 (58.3%) |
| Advanced therapies (2 or more) | 55 of 260 (21.2%) | 38 of 131 (29.0%) | 93 of 391 (23.8%) |
| Hospitalization | 109 of 256 (42.6%) | 92 of 128 (71.9%) | 201 of 384 (52.3%) |
Advanced therapies, biologics, and small molecules.
AIP, autoimmune pancreatitis; PSC, primary sclerosing cholangitis.
Frequencies of MEFV Mutations
The frequencies of MEFV mutations are shown in Table 2, Table 3, Table 4. P221R, D424E, and G436R were excluded from the following analysis because their mutation frequency exceeded 50% and their significance as mutations was unknown. Other mutations were positive in 232 of 391 (59.3%) patients, and 204 of 391 (52.2%) patients had mutations according to diagnostic criteria for FMF listed in the Japanese guidelines for autoinflammatory diseases (E84E, E148Q, L110P-E148Q, P369S-R408Q, R202Q, G304R, S503C, M694I, M680I, M694V, V726A). The MEFV mutation frequency was higher than the average Japanese mutation frequency for all alleles. The most common mutation was E148Q in exon 2. Mutations with frequencies not evident in the general population (Q223E, G250R, P373Q, and V487M) were also identified. The frequencies of MEFV mutations G223E, G250R, and P369S were higher in patients with UC than in those with CD.
Table 2.
The Frequency of MEFV Mutations in Patients With IBD
| Variant allele | Hetero | Homo | Total | Allele frequency | All Japanese frequency (ToMMo-38KJPN) | Odds ratio |
|---|---|---|---|---|---|---|
| Exon1 | ||||||
| E84K | 13 | 0 | 13 of 391 | 3.3% | 1.6% | 2.09 [1.20–3.65]a |
| Exon2 | ||||||
| L110P | 32 | 2 | 34 of 391 | 8.7% | 6.9% | 1.28 [0.90–1.83]a |
| P115R | 2 | 0 | 2 of 391 | 0.5% | 0.1% | 4.07 [0.98–16.78]a |
| E148Q | 100 | 23 | 123 of 391 | 31.5% | 22.7% | 1.56 [1.26–1.94]a |
| R202Q | 25 | 1 | 26 of 391 | 6.7% | 3.3% | 2.10 [1.40–3.14]a |
| P221R | 223 | 64 | 287 of 391 | 73.4% | - | - |
| Q223E | 10 | 0 | 10 of 391 | 2.6% | - | - |
| G250R | 23 | 0 | 23 of 391 | 5.9% | - | - |
| G304R | 28 | 0 | 28 of 391 | 7.2% | 2.6% | 2.91 [1.97–4.29]a |
| Exon3 | ||||||
| P369S | 38 | 1 | 39 of 391 | 10.0% | 5.5% | 1.91 [1.37–2.67]a |
| P373Q | 10 | 0 | 10 of 391 | 2.6% | - | |
| R408Q | 32 | 1 | 33 of 391 | 8.4% | 4.7% | 1.85 [1.29–2.65]a |
| R410H | 1 | 0 | 1 of 391 | 0.3% | 0.2% | 1.57 [0.22–11.34]a |
| Exon5 | ||||||
| V487M | 1 | 0 | 1 of 391 | 0.3% | - | - |
| S503C | 13 | 0 | 13 of 391 | 3.3% | 2.5% | 1.34 [0.77–2.33]a |
| Exon8 | ||||||
| D424E | 172 | 39 | 211 of 391 | 54.0% | 31.1% | 2.59 [2.12–3.17]a |
| G436R | 188 | 61 | 249 of 391 | 63.7% | 38.4% | 2.81 [2.29–3.46]a |
| Exon10 | ||||||
| R653H | 1 | 0 | 1 of 391 | 0.3% | 0.01% | 32.48 [3.37–312.90]a |
| M694I | 1 | 0 | 1 of 391 | 0.3% | 0.2% | 1.62 [0.22–11.73]a |
| Compound-mutation ※duplicates above | ||||||
| L110P-E148Q | 34 of 391 | 8.7% | - | - | ||
| P369S-R408Q | 32 of 391 | 8.2% | - | - |
Data are expressed as odds ratios with 95% confidence intervals, calculated using univariate logistic regression analysis.
Table 3.
The Frequency of MEFV Mutations in Patients With UC
| Variant allele | Hetero | Homo | Total | Allele frequency | All Japanese frequency (ToMMo-38KJPN) | Odds ratio |
|---|---|---|---|---|---|---|
| Exon1 | ||||||
| E84K | 8 | 0 | 8 of 260 | 3.1% | 1.6% | 1.93 [0.95–3.92]a |
| Exon2 | ||||||
| L110P | 22 | 2 | 24 of 260 | 9.2% | 6.9% | 1.37 [0.90–2.09]a |
| P115R | 1 | 0 | 1 of 260 | 0.4% | 0.1% | 3.05 [0.42–22.20]a |
| E148Q | 68 | 17 | 85 of 260 | 32.7% | 22.7% | 1.66 [1.28–2.15]a |
| R202Q | 14 | 1 | 15 of 260 | 5.8% | 3.3% | 1.80 [1.07–3.05]a |
| P221R | 137 | 46 | 183 of 260 | 70.4% | - | - |
| Q223E | 8 | 0 | 8 of 260 | 3.1% | - | - |
| G250R | 17 | 0 | 17 of 260 | 6.5% | - | - |
| G304R | 19 | 0 | 19 of 260 | 7.3% | 2.6% | 2.97 [1.86–4.76]a |
| Exon3 | ||||||
| P369S | 30 | 1 | 31 of 260 | 11.9% | 5.5% | 2.34 [1.60–3.41]a |
| P373Q | 6 | 0 | 6 of 260 | 2.3% | - | - |
| R408Q | 25 | 1 | 26 of 260 | 10.0% | 4.7% | 2.23 [1.49–3.36]a |
| R410H | 1 | 0 | 1 of 260 | 0.4% | 0.2% | 2.36 [0.33–17.10]a |
| Exon5 | ||||||
| V487M | 1 | 0 | 1 of 260 | 0.4% | - | - |
| S503C | 8 | 0 | 8 of 260 | 3.1% | 2.5% | 1.23 [0.61–2.50]a |
| Exon8 | ||||||
| D424E | 102 | 31 | 133 of 260 | 51.2% | 31.1% | 2.32 [1.82–2.96]a |
| G436R | 113 | 47 | 160 of 260 | 61.5% | 38.4% | 2.57 [2.00–3.30]a |
| Exon10 | ||||||
| R653H | 1 | 0 | 1 of 260 | 0.4% | 0.01% | 48.90 [5.07–471.68]a |
| M694I | 1 | 0 | 1 of 260 | 0.4% | 0.2% | 2.44 [0.43–17.68]a |
| Compound-mutation ※duplicates above | ||||||
| L110P-E148Q | 24 of 260 | 9.2% | - | - | ||
| P369S-R408Q | 25 of 260 | 9.6% | - | - |
Data are expressed as odds ratios with 95% confidence intervals, calculated using univariate logistic regression analysis.
Table 4.
The Frequency of MEFV Mutations in Patients With CD
| Variant allele | Hetero | Homo | Total | Allele frequency | All Japanese frequency (ToMMo-38KJPN) | Odds ratio |
|---|---|---|---|---|---|---|
| Exon1 | ||||||
| E84K | 5 | 0 | 5 of 131 | 3.8% | 1.6% | 2.41 [0.98–5.91]a |
| Exon2 | ||||||
| L110P | 10 | 0 | 10 of 131 | 7.6% | 6.9% | 1.11 [0.58–2.12]a |
| P115R | 1 | 0 | 1 of 131 | 0.8% | 0.1% | 6.08 [0.83–44.39]a |
| E148Q | 32 | 6 | 38 of 131 | 29.0% | 22.7% | 1.39 [0.95–2.03]a |
| R202Q | 11 | 0 | 11 of 131 | 8.4% | 3.3% | 2.70 [1.45–5.02]a |
| P221R | 86 | 18 | 104 of 131 | 79.4% | - | - |
| Q223E | 2 | 0 | 2 of 131 | 1.5% | - | - |
| G250R | 6 | 0 | 6 of 131 | 4.6% | - | - |
| G304R | 9 | 0 | 9 of 131 | 6.9% | 2.6% | 2.78 [1.41–5.49]a |
| Exon3 | ||||||
| P369S | 8 | 0 | 8 of 131 | 6.1% | 5.5% | 1.12 [0.55–2.30]a |
| P373Q | 4 | 0 | 4 of 131 | 3.1% | - | |
| R408Q | 7 | 0 | 7 of 131 | 5.3% | 4.7% | 1.13 [0.53–2.43]a |
| R410H | 0 | 0 | 0 of 131 | 0% | 0.2% | - |
| Exon5 | ||||||
| V487M | 0 | 0 | 0 of 131 | 0% | - | - |
| S503C | 5 | 0 | 5 of 131 | 3.8% | 2.5% | 1.54 [0.63–3.78]a |
| Exon8 | ||||||
| D424E | 70 | 8 | 78 of 131 | 59.5% | 31.1% | 3.26 [2.30–4.62]a |
| G436R | 75 | 14 | 89 of 131 | 67.9% | 38.4% | 3.40 [2.35–4.91]a |
| Exon10 | ||||||
| R653H | 0 | 0 | 0 of 131 | 0% | 0.01% | - |
| M694I | 0 | 0 | 0 of 131 | 0% | 0.2% | - |
| Compound-mutation ※duplicates above | ||||||
| L110P-E148Q | 10 of 131 | 7.6% | - | - | ||
| P369S-R408Q | 7 of 131 | 5.3% | - | - |
Data are expressed as odds ratios with 95% confidence intervals, calculated using univariate logistic regression analysis.
The number of mutations per disease is shown in Table 5. Mutation rates were higher in patients with UC than in those with CD (UC, 60.8%; CD, 56.5%). The number of patients with a single mutation was similar for UC (34.6%) and CD (36.6%); however, the number of patients with 2 or more overlapping mutations was higher in patients with UC (26.2%) as compared to those with CD (19.8%).
Table 5.
Number of MEFV Mutations in UC and CD
| Total | Positive | Number of mutations |
|||||
|---|---|---|---|---|---|---|---|
| Mono | 2 | 3 | 4 | 5 | |||
| IBD | 391 | 232 (59.3%) | 138 (35.3%) | 69 (17.6%) | 20 (5.1%) | 3 (0.8%) | 2 (0.5%) |
| UC | 260 | 158 (60.8%) | 90 (34.6%) | 47 (18.1%) | 17 (6.5%) | 3 (1.5%) | 1 (0.4%) |
| CD | 131 | 74 (56.5%) | 48 (36.6%) | 22 (16.8%) | 3 (2.3%) | 0 (0%) | 1 (0.8%) |
P221R, D424E, and G436R were excluded from this analysis because their mutation frequency exceeded 50% and their significance as mutations was unknown.
Comparison of MEFV Mutations and Clinical Features
Next, we examined the relationship between each exon mutation and clinical features (Appendix 2, Figures A2–A6, Tables 6 and 7, see Appendix 1, Tables A3–A5). In patients with IBD (Appendix 2, Figure A2, Table 6, and see Appendix 1, Table A3), exon 1 mutations were significantly associated with ocular symptoms. Exon 2 mutations were significantly associated with EIMs and the use of calcineurin inhibitors. Exon 3 mutations were significantly associated with the age at onset, thrombosis, and with SAA and CRP levels (Appendix 2, Figure A5). Furthermore, the coexistence of exon 2 and 3 mutations was significantly associated with hepatobiliary pancreatic diseases and with steroid resistance, whereas no association was observed with either mutation alone.
Table 6.
Association Between MEFV Exon Mutations and Clinical Features
| IBD |
P Value | UC |
P Value | CD |
P Value | |
|---|---|---|---|---|---|---|
| Odds ratio | Odds ratio | Odds ratio | ||||
| Exon 1 | ||||||
| Ocular symptoms | 15.67 (1.33–184.90) | .029a | 17.85 (1.44–220.88) | .025a | - | n.s.a |
| Exon 2 | ||||||
| Extraintestinal manifestations | 2.01 (1.07–3.77) | .029a | 1.93 (0.89–4.22) | n.s.a | 2.19 (0.76–6.31) | n.s.a |
| Calcineurin inhibitor | 2.81 (1.27–6.24) | .011a | 3.14 (1.28–7.71) | .013a | 1.65 (0.27–10.21) | n.s.a |
| Exon 3 | ||||||
| Sex (female) | 1.59 (0.87–2.90) | n.s.a | 2.05 (1.01–4.18) | .047a | 0.56 (0.14–2.23) | n.s.a |
| Thrombosis | 7.37 (1.44–37.60) | .016a | 6.26 (1.21–32.4) | .028a | - | n.s.a |
| Exon 5 | ||||||
| Surgery (stenosis, fistula, abscess) | 2.67 (0.87–8.22) | n.s.a | 6.89 (1.27–37.47) | .026a | 1.94 (0.31–11.99) | n.s.a |
| Exon 2 + 2 | ||||||
| Steroid resistant | 2.18 (1.08–4.39) | .030a | 1.99 (0.86–4.61) | n.s.a | 2.72 (0.76–9.78) | n.s.a |
| Exon 2 + 3 | ||||||
| Extraintestinal manifestations | 2.92 (1.22–6.99) | .016a | 3.88 (1.45–10.38) | .0069a | 1.13 (0.13–9.96) | n.s.a |
| Joint symptoms | 2.56 (0.70–9.40) | n.s.a | 4.29 (1.06–17.47) | .042a | - | n.s.a |
| Hepatobiliary pancreatic diseases (PSC, AIP) | 8.52 (1.37–53.14) | .022a | 11.19 (1.50–83.53) | .019a | - | n.s.a |
| Thrombosis | 6.38 (1.12–36.34) | .037a | 5.55 (0.96–32.09) | n.s.a | - | n.s.a |
| Steroid dependent | 2.52 (1.18–5.40) | .017a | 2.40 (1.01–5.70) | .047a | 1.90 (0.21–17.38) | n.s.a |
| Calcineurin inhibitor | 4.09 (1.60–10.46) | .0033a | 3.63 (1.29–10.20) | .014a | 5.00 (0.48–51.89) | n.s.a |
| Exon 2 + 5 | ||||||
| Skin symptoms | 4.35 (0.46–40.61) | n.s.a | 13.78 (1.14–166.32) | .039a | - | n.s.a |
| Complex perianal fistulas | 4.58 (0.49–42.85) | n.s.a | 42.33 (2.97–603.19) | .0057a | - | n.s.a |
P221R, D424E, and G436R were excluded from this analysis because their mutation frequency exceeded 50% and their significance as mutations was unknown.
AIP, autoimmune pancreatitis; n.s., not significant; PSC, primary sclerosing cholangitis.
Data are expressed as odds ratios with 95% confidence intervals. P values were calculated using univariate logistic regression analysis.
Table 7.
Association Between MEFV-Mutated Alleles and Clinical Features
| IBD |
P Value | UC |
P Value | CD |
P Value | |
|---|---|---|---|---|---|---|
| Odds ratio | Odds ratio | Odds ratio | ||||
| E84K | ||||||
| Ocular symptoms | 15.67 (1.33–184.90) | .029a | 17.85 (1.44–220.88) | .025a | - | n.s.a |
| P115R | ||||||
| Thrombosis | 76.8 (4.19–1408.13) | .0034a | - | n.s.a | - | n.s.a |
| G250R | ||||||
| Extraintestinal manifestations | 3.49 (1.36–8.98) | .0096a | 3.48 (1.13–10.66) | .029a | 3.67 (0.62–21.77) | n.s.a |
| Skin symptoms | 4.09 (1.26–13.29) | .019a | 3.92 (0.76–20.09) | n.s.a | 5.75 (0.94–35.35) | n.s.a |
| Hepatobiliary pancreatic diseases (PSC, AIP) | 11.59 (1.84–73.14) | .0092a | 16.07 (2.11–122.11) | .0073a | - | n.s.a |
| Calcineurin inhibitor | 6.00 (2.26–15.94) | .0003a | 5.77 (1.94–17.16) | .0016a | 6.05 (0.57–64.51) | n.s.a |
| Advanced therapies (≥2) | 2.17 (0.91–5.20) | n.s.a | 2.84 (1.02–7.86) | .044a | 1.23 (0.22–7.05) | n.s.a |
| G304R | ||||||
| Extraintestinal manifestations | 2.62 (1.05–6.54) | .039a | 2.95 (0.98–8.87) | n.s.a | 2.04 (0.39–10.74) | n.s.a |
| Skin symptoms | 3.19 (1.00–10.19) | .050a | 3.43 (0.67–17.42) | n.s.a | 3.20 (0.58–17.51) | n.s.a |
| Steroid resistant | 2.04 (0.82–5.04) | n.s.a | 2.91 (1.03–8.19) | .043a | 0.72 (0.085–6.13) | n.s.a |
| Surgery (stenosis, fistula, abscess) | 1.59 (0.65–3.89) | n.s.a | 4.83 (1.19–19.63) | .028a | 1.01 (0.26–3.93) | n.s.a |
| P373Q | ||||||
| Extraintestinal manifestations | 7.86 (2.19–28.26) | .0016a | 16.81 (2.94–96.15) | .0015a | 2.31 (0.23–23.60) | n.s.a |
| Hepatobiliary pancreatic diseases (PSC, AIP) | 31.5 (4.61–215.15) | .0004a | 63.00 (7.02–565.62) | .0002a | - | n.s.a |
| Calcineurin inhibitor | 13.11 (3.57–48.10) | .0001a | 20.09 (3.49–115.67) | .0008a | 10.25 (0.86–121.49) | n.s.a |
| S503C | ||||||
| Complex perianal fistulas | 1.49 (0.18–12.05) | n.s.a | 11.86 (1.09–128.70) | .042a | - | n.s.a |
| Surgery (stenosis, fistula, abscess) | 3.01 (0.95–9.49) | n.s.a | 8.07 (1.44–45.08) | .017a | 1.94 (0.31–11.99) | n.s.a |
P221R, D424E, and G436R were excluded from this analysis because their mutation frequency exceeded 50% and their significance as mutations was unknown. Advanced therapies, biologics and small molecules.
AIP, autoimmune pancreatitis; CD, Crohn's disease; n.s., not significant; PSC, primary sclerosing cholangitis.
Data are expressed as odds ratios with 95% confidence intervals. P values were calculated using univariate logistic regression analysis.
Next, we examined the relationship between each MEFV-mutated allele and clinical features. In patients with IBD (see Appendix 2, Figure A2, Table 7, and Appendix 1, Table A3), E84K was significantly associated with ocular symptoms. P115R was significantly associated with thrombosis. G250R was significantly associated with EIMs, skin symptoms, hepatobiliary pancreatic diseases, and the use of calcineurin inhibitors. G304R was significantly associated with EIMs and skin symptoms. P373Q was significantly associated with age at onset, EIMs, hepatobiliary pancreatic diseases, and the use of calcineurin inhibitors, and with SAA and CRP levels. Three or more gene mutations of MEFV-mutated alleles were significantly associated with high SAA levels (P = .0443) and steroid dependence (P = .0258, odds ratio 2.56 [1.12–5.84]).
Stratification of patients according to UC and CD showed that exon 1 mutations were significantly associated with ocular symptoms in patients with UC (see Appendix 2, Figure A3, Tables 6 and 7, see Appendix 1, Table A4). In patients with UC, exon 2 mutations were significantly associated with the use of calcineurin inhibitors. Exon 3 mutations were significantly associated with female sex, age at disease onset, thrombosis, SAA and CRP levels. Exon 5 mutations were significantly associated with surgery (stenosis, fistula, abscess). Furthermore, in patients with UC, the coexistence of exon 2 and 3 mutations was significantly associated with EIMs, joint symptoms, hepatobiliary pancreatic diseases, and steroid dependence, whereas no association was observed with either mutation alone. Exon 2 and 5 mutations were significantly associated with skin symptoms. In patients with UC, the E84K was significantly associated with ocular symptoms. The G250R mutation was significantly associated with EIMs, hepatobiliary pancreatic diseases, use of calcineurin inhibitors, use of 2 or more advanced therapies, number of hospitalizations, and CRP levels. The G304R mutation was significantly associated with steroid resistance and history of surgery. The P373Q mutation was significantly associated with age at onset, EIMs, hepatobiliary pancreatic diseases, and the use of calcineurin inhibitors, and with SAA and CRP levels (see Appendix 2, Figure A7). The S503C mutation was significantly associated with complex perianal fistulas and surgical history. Three or more MEFV-mutated alleles were not associated with any clinical symptoms.
In patients with CD (see Appendix 2, Figure A4, Tables 6 and 7, Appendix 1, Table A5), the coexistence of exon 2 and exon 3 mutations was significantly associated with the number of hospitalizations, whereas no association was observed with either exon mutation alone. In patients with CD, no association was found between other MEFV-mutated exons or alleles and clinical features.
Finally, we investigated the association between exon 8, which is also common in healthy Japanese individuals, and the clinical features of IBD individually because the frequency of D424E and G436R mutations was more than 20% higher than the average Japanese mutation frequency (based on the Japanese Whole Genome Reference Panel ToMMo-38KJPN).19 In this study, 60.6% (151/249) of patients with exon 8 mutations also had other MEFV mutations. To exclude the influence of other gene mutations, we compared the clinical characteristics between 2 groups: those with no MEFV mutations (n = 61) and those with only exon 8 mutations (n = 98). In patients with UC, CRP levels were significantly lower in those with the D424E mutation in exon 8 (median 0.38 mg/dL, interquartile range 0.18–1.61 mg/dL) and no other exon mutations than those in patients without the MEFV mutation (median 1.71 mg/dL, interquartile range 0.36–3.75 mg/dL) (P = .040, Wilcoxon rank-sum test).
Discussion
This retrospective cohort study examined the relationship between mutations in the MEFV gene and the clinical features of IBD, including refractoriness, in patients with a confirmed diagnosis of UC or CD. The present study included, 391 patients with IBD, and showed that even after excluding mutations with a mutation frequency of >50%, 232 patients (59.3%) had MEFV mutations. The MEFV mutation frequency in this study was higher than the average frequency in the Japanese population for all alleles.19
In patients with IBD, mutations in exons 1, 2, and 3 were associated with EIMs, and elevated SAA and CRP levels. The coexistence of exon 2 and 3 mutations further strengthened this association and was associated with steroid dependent. Finally, we examined the relationship between mutations in each MEFV-mutated allele and the clinical features. In patients with IBD, E84K, P115R, G250R, G304R, and P373Q mutations were associated with EIMs, and elevated SAA and CRP levels. Regarding the association between MEFV mutations and the clinical characteristics of patients with IBD, a similar trend was observed in patients with UC.
The MEFV gene, which causes FMF, encodes a pyrin protein. Pyrin negatively regulates the activation of IL-1β, an inflammatory cytokine, under physiological conditions, and dysfunction of pyrin caused by MEFV mutations leads to excessive activation of IL-1β, resulting in systemic inflammation.4,5 MEFV mutations may act as susceptibility factors for many inflammatory diseases such as polyarteritis nodosa, juvenile idiopathic arthritis, and systemic lupus erythematosus.20, 21, 22, 23, 24 In patients with IBD, MEFV mutations are associated with intestinal stenosis, anal lesions, and EIMs.13,25, 26, 27, 28 These mutations have also been associated with high CRP and SAA levels.29,30 However, most of these reports were derived from patients in Mediterranean coastal regions, such as Türkiye, and most of the identified gene mutations were in exons 2 or 10. In a systematic review, Papadopoulos et al.17 reported that MEFV mutations were present in 23.8% of patients with IBD, which was significantly higher than the frequency in healthy individuals. In our study, by analyzing mutations in the entire exon region, we were able to confirm mutations not only in exons 2 and 10 but also in exons 1, 3, and 10, which contributed to the observed higher MEFV gene mutation frequency of 58.8%. IL-1β activity is elevated in active lesions of IBD, and IL-1β activity may be involved in the severity and refractory status of IBD.31,32 Thus, it is possible that increased activation of IL-1β due to MEFV mutations may influence the clinical characteristics of IBD.
Our study revealed an association between MEFV mutations and EIMs in patients with IBD. The mechanisms underlying EIMs are unclear, and different characteristics are observed depending on the organ involved, such as complication rates, sex-based differences, and the relationship with IBD disease activity.27,33, 34, 35, 36, 37 In patients harboring MEFV mutations associated with high levels of CRP and SAA, severe intestinal inflammation may be involved in EIMs. In addition, uveitis and pyoderma gangrenosum improve following treatment with IL-1β inhibitors,38,39 which indicates that IL-1β is directly involved in the development of EIMs. Changes in the gut microbiota may be involved in EIMs.40,41 Dörner et al. demonstrated that the translocation of bacterial outer membrane vesicles to the liver triggered enhanced NLRP3 inflammasome activation, which in turn promoted liver inflammation and fibrosis in both mouse models and patients with primary sclerosing cholangitis IBD.40 Further investigations are required to confirm the association between the gut microbiota of patients with IBD carrying MEFV mutations and EIMs.
The major SNPs in exon 10, including R653H and M694I, lead to dysfunction of the B30.2 domain of PYRIN, which directly inhibits caspase-1 activity.42 It is unclear how other gene mutations contribute to the pathogenesis of FMF or other inflammatory diseases. Among MEFV mutations, several reports have indicated an association between MEFV exon 2 mutations and the pathogenesis of IBD. Administration of colchicine or anti-IL-1β monoclonal antibody (canakinumab) has improved IBD-like endoscopic findings in patients with MEFV exon 2 mutations.6, 7, 8, 9, 10, 11,43 Yamada et al. reported that patients with CD and E148Q had significantly higher IL-1β and IL-18 levels and caspase-1 activity in peripheral blood mononuclear cells compared with patients with CD without E148Q.44 Nakase et al. reported that THP-1 cells transfected with exon 2 mutation plasmids produced significantly higher levels of IL-1β, tumor necrosis factor-α, IL-6, and IL-8 than controls.43 Thus, in vitro results also suggest that the presence of exon 2 mutations leads to an immune state prone to inflammation. Therefore, our data suggest that exon 2 mutations, which are more frequent in Japanese patients, contribute to IBD pathophysiology. However, as MEFV mutation sites and environmental factors differ with respect to ethnicity and geographical location, further studies on the involvement of MEFV mutations in IBD pathology are required.
This study found that the association between MEFV mutations and clinical characteristics of patients with IBD tended to be stronger in patients with UC. However, previous studies have shown an association between MEFV mutations and EIMs, intestinal stenosis, and high levels of CRP and SAA, not only in patients with UC but also in patients with CD.26,44 Given the association between the gut microbiota and clinical symptoms in patients with FMF, we considered that in addition to MEFV mutations, the gut microbiota of individual patients may have influenced the clinical features of IBD.
Some limitations of this study should be acknowledged. First, the study was limited to only 2 hospital centers, which may have biased the treatment of patients with IBD. Second, the clinical information was collected retrospectively, and there were variations in the disease duration. Lastly, the number of cases was insufficient for the study of EIMs. Therefore, to control these limitations, a multicenter study with a longer observation period is warranted.
Conclusion
This study found that the MEFV mutation rate was higher in Japanese patients with UC and CD than in healthy controls. Our study suggests that MEFV mutations could influence EIMs in patients with IBD.
Acknowledgments
The authors would like to thank Editage (www.editage.jp) for English language editing. This English language editing was supported by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research [grant number 23K15017 to K.W.].
Authors’ Contributions
Tomoya Nakamura: Data acquisition, study design, data assessment and verification, statistical analysis. Kohei Wagatsuma: Data acquisition, study design, data assessment and verification, statistical analysis. Yuki Hayashi: Data acquisition, study design, data assessment and verification, statistical analysis. Hiromu Morikubo: Data acquisition. Daisuke Saito: Data acquisition. Masashi Idogawa: Data acquisition, study design, data assessment and verification, statistical analysis. Masanori Nojima: Statistical analysis. Jun Miyoshi: Data acquisition. Minoru Matsuura: Study design, data acquisition, data assessment and verification. Tadakazu Hisamatsu: Study design, data acquisition, data assessment and verification. Hiroshi Nakase: Study design, data acquisition, data assessment and verification, statistical analysis. All authors had access to the relevant data, participated in data interpretation, critically reviewed the manuscript, and provided final approval of the submitted final draft.
Footnotes
Conflicts of Interest: These authors disclose the following: Hiromu Morikubo reports receiving grant support from Takeda Pharmaceutical Co. Ltd. and the Japan Foundation for Applied Enzymology. Jun Miyoshi reports receiving grant support from AbbVie GK; and consulting and lecture fees from EA Pharma Co., Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Jansen Asia Pacific Pte. Ltd., Pfizer Inc., Mitsubishi Tanabe Pharma Corporation, JIMRO Co., Miyarisan Co., Ltd., and Takeda Pharmaceutical Co., Ltd. Minoru Matsuura reports receiving lecture fees from AbbVie GK, Takeda Pharmaceutical Co. Ltd., Janssen Pharmaceuticals K.K., Pfizer Inc., Mochida Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Ltd., Celltrion Healthcare Japan K.K., Kissei Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Viatris Inc., EA Pharma Co., Ltd., JIMRO Co., and ZERIA Pharmaceutical Co. Ltd. Tadakazu Hisamatsu reports receiving grant support from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, and Kissei Pharmaceutical Co. Ltd.; consulting fees from Mitsubishi Tanabe Pharma Corporation, EA Pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and Abivax; and lecture fees from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA Pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., and Kissei Pharmaceutical Co. Ltd. The remaining authors disclose no conflicts.
Funding: This work was supported by the Health and Labour Sciences Research Grants for Research on Intractable Diseases from the Ministry of Health, Labour, Welfare of Japan [Investigation and Research for Intractable Inflammatory Bowel Disease; grant number 23809845 to T.H.]; and the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research [grant number 23K15017 to K.W.].
Ethical Statement: Written Informed consent was obtained from all patients. The study protocol was approved by the Ethical Review Committee of Sapporo Medical University (Reference number 322-216). The study complied with the Declaration of Helsinki, the Ethical Guidelines for Medical Research Involving Human Subjects, and the Ethical Guidelines for Human Genome and Genetic Analysis Research.
Data Transparency Statement: Raw data were generated by the Department of Gastroenterology and Hepatology at the Sapporo Medical University School of Medicine. The datasets from this study are available from the corresponding author upon reasonable request.
Reporting Guidelines: This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: guidelines for reporting observational studies, and the STROBE checklist for cohort studies was completed.
Material associated with this article can be found, in the online version, at https://doi.org/10.1016/j.gastha.2025.100836.
Supplementary Material
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