Introduction

The divergent impact of tobacco smoking in Crohn’s disease (CD) and ulcerative colitis (UC) has been widely observed, but it’s not completely understood whether the effect of smoking may be modified by genetic makeup. Our present study aims to systematically identify the genetic modifiers of tobacco smoking in relation to CD and UC disease risk based on genome wide screening.

Aims & Methods

We performed a case-only genome wide association meta-analysis to examine the multiplicative interaction effect between tobacco smoking and single nucleotide polymorphisms (SNPs) in two independent IBD cohorts, the 1000IBD cohort (N=990) and the Dutch Parelsnoer-IBD cohort (N=2540). Imputed Global Screening Array genotype datasets combined with classical HLA alleles were used to compare the genotype frequencies between ever versus never smokers, current versus never smokers, and former versus never smokers in patients with IBD. We further separated entire analyses for CD and UC to characterize interactions where opposite direction was observed. Functional mapping and annotation of smoking interaction variants were conducted using FUMA, including positional mapping, eQTL mapping and chromatin interaction mapping.

Results

A total of 572 lead SNPs showed consistent evidence of interaction with tobacco smoking between two independent cohorts (meta-analysis P<5e-5, heterogeneity Q test>0.05). Thirty SNPs exhibited opposite associations with smoking behaviors between CD and UC. (Effect size ratio>5 or <0.1) An HLA Class II haplotype (HLA-DRB1*03:01~HLA-DQA1*05:01~HLA-DQB1*02:01) showed lower frequency in IBD smokers than never smokers. Functional mapped genes were significantly overrepresented in various immune-response regulation pathways as well as collagen metabolic processes and showed enrichment in specific cell types, such as fetal intestine myeloid cells and midbrain neurotypes. These implicated genes also significantly overlapped with the risk genes for mental disorders, including autism spectrum disorders, schizophrenia, and major depressive disorders.

Conclusion

Our findings indicate that the influence of smoking behaviors on IBD risk depends on individual genetic background. Genetic modifiers of tobacco smoking with opposite directions may explain the differential impact of smoking on the susceptibility to CD and UC. Overrepresentation of these mapped genes in multiple mental disorders reflected complex pleiotropy.

Introduction

Colorectal polyposis, characterized by more than 10 adenomas, indicates a higher risk of malignancy and necessitates more frequent screening and genetic assessment. However, there are still a large number of polyposis patients with negative genetic test results. This study aimed to explore the risk genetic variants associated with non-hereditary colorectal polyposis through a genome-wide association study (GWAS).

Aims & Methods

Among patients who underwent colonoscopy at a single referral university hospital from January 2012 to September 2021, a total of 638 patients with 10 or more biopsy-proven cumulative polyps on colonoscopies and without genetic mutations or family history related to colorectal polyposis were included in this study. For the control group, a total of 7087 people who underwent colonoscopy for the purpose of health check-up at the Korea Medical Institute and were normal at least twice in a row were included. To find susceptible loci to non-hereditary colorectal polyposis, GWAS was performed and a genome-wide p-value threshold of 5 × 10^-7 was set to assess statistical significance.
We compared the genetic differences between two groups of patients with non-hereditary colorectal polyposis: those with 10 or more polyp recurrences observed during follow-up colonoscopies and those without such recurrences. We utilized SNPs that were identified as risk variants for non-hereditary colorectal polyposis in this GWAS. For each SNP, we defined the risk allele as the allele associated with increased risk of non-hereditary colorectal polyposis as identified in this GWAS. Genotypes were coded as 0, 1, or 2 based on the number of risk alleles identified at each SNP. We used a polytomous logistic regression model to identify SNPs that significantly increased the risk of polyp recurrence compared to the group without recurrence. Results of all regression analyses were adjusted for age, sex, BMI, smoking history, alcohol consumption history, family history of cancer, history of cancer other than colorectal cancer, comorbidities, and history of medication use.

Results

A total of 71 risk variants were discovered, which were new single-nucleotide polymorphisms (SNPs) not found in previous GWAS associated with colorectal cancer and polyp (Figure 1). 5 genes (UPF3A, BICRA, CBWD6, PDE4DIP, ABCC4) nearest or overlapped with 7 SNPs (rs566295755, rs2770288, rs1012003, rs201270202, rs71264659, rs1699813, rs149368557) previously reported directly or indirectly related to the development of colorectal cancer were proven to be risk variants significantly associated with non-hereditary colorectal polyposis. In addition, two new genes (CNTN4, CNTNAP3B) that have not previously been reported to be associated with colorectal cancer or polyp were newly identified.
The SNP rs149368557 was identified as being significantly associated with an increased risk of polyp recurrence in non-polyposis hereditary colorectal cancer (p-value: 0.049, odds ratio: 2.991, 95% confidence interval: 1.006–8.899).

Conclusion

In this study, we found 71 novel risk variants associated with non-hereditary colorectal polyposis. The SNP rs149368557 was identified as being significantly associated with an increased risk of polyp recurrence in non-hereditary colorectal polyposis. The risk variants and genes discovered in this study might be utilized as novel targets to prevent colorectal cancer in the future.

Introduction

Inflammatory bowel disease (IBD), consisting of Crohn’s disease (CD) and Ulcerative colitis (UC), is a group of chronic, relapsing disorders in the gastrointestinal tract. The disease mechanisms are largely unknown. We hypothesized that the interaction of genetic variants and tobacco smoking can influence the disease risk of IBD and impact the disease progression in CD and UC differently.

Aims & Methods

3530 IBD patients were included in the present study via Parelsnoer IBD Biobank (PSI), a Dutch prospective, nationwide biobank of IBD patients. Phenotypic data on smoking status at the time of diagnosis was obtained through the PSI questionnaire. Genome-wide genotyping was conducted on all PSI participants using the Global Screening Array and divided into two independent datasets, the discovery (N=990) and replication cohort (N=2540). Case-only study design was applied to estimate the interaction effects for IBD, CD, and UC separately with subsequent meta-analysis between discovery and replication cohorts.

Results

572 lead single nucleotide polymorphisms (SNPs) were demonstrated with interaction effect of smoking (meta-analysis P < 5e-5, heterogeneity Cochrane Q test P > 0.05). 30 interacting SNPs showed distinct opposite effects between CD and UC (the ratio of interaction effect sizes between CD and UC > 5 or < 0.1). Our analysis also confirmed 9 previously reported interacting SNPs in the regions of NOTCH4, TSBP1-AS1, HLA-DRA, HLA-DRA-HLA-DRB5, HLA-DRB9, DNMT3A, MUC22, and CCR3.

Conclusion

Our present study identified a large number of new interaction loci for IBD on a genome wide scale and shed new light on the disease mechanisms.

Disclosure

No conflict of interest

Introduction

Primary cancer of the appendix is rare and accounts for 0.4% of all gastrointestinal (GI) malignancies with an incidence of approximately 1.2 cases per 100,000 people per year in the United States. Patients with inflammatory bowel disease (IBD), including ulcerative colitis (UC), Crohn’s disease (CD), and indeterminate colitis (IC), face increased risk for the development of colorectal dysplasia and carcinoma. Although appendiceal inflammation occurs histologically in 40-80% of colectomy specimens from patients with IBD, appendiceal neoplasms have been reported only infrequently. A direct association between IBD and appendiceal neoplasia, including whether IBD predisposes to the development of appendiceal neoplasia, is unclear.

Aims & Methods

We aimed to describe the clinical characteristics, outcomes, and incidence of appendiceal neoplasms in patients with IBD. Using bioinformatics and natural language processing tools to mine the electronic medical record at our large referral center, all patients > 18-years-old with IBD who had an appendiceal neoplasm were identified from January 1992 to April 2023. Relevant demographic and clinical data were abstracted.

Results

In total, 44 patients were included (61.4% female) with a median age of 53 years at appendix neoplasm diagnosis. A majority had UC (68.2%). Of these, four (13.3%) had backwash ileitis, 27 (90%) had extensive colitis, 12 (40%) had a history of colorectal neoplasia, and 6 (20%) had primary sclerosing cholangitis (PSC). Median duration of IBD prior to appendix neoplasm diagnosis was 17 years. The most common type of appendix neoplasm was adenocarcinoma (36.4%), followed by appendiceal mucinous neoplasm (34.1%), and carcinoid or neuroendocrine tumor (22.7%). The most common presenting symptom associated with diagnosis of appendix neoplasm was abdominal pain/distension (36.4%). Appendix neoplasm diagnosis was made by cross-sectional imaging in a majority of patients (47.7%). The most common type of IBD-directed therapy at the time of appendix neoplasm diagnosis was 5-aminosalicylate (5-ASA) agents (25%). All patients had appendix neoplasm surgically resected. Median appendix neoplasm size was 2.7 cm. The most common histologic tumor grade was grade 1 (31.8%). Two (4.5%) patients had lymph node involvement and 7 (15.9%) patients had metastatic disease at the time of appendix neoplasm diagnosis. Twelve (27.2%) patients received adjuvant chemotherapy. Three patients with UC (6.8%) had recurrence of appendix neoplasm after surgical resection due to peritoneal seeding with a median time to recurrence from initial diagnosis of 78 months.

Conclusion

Appendix neoplasms are more commonly seen in patients with longstanding extensive UC in those presenting with abdominal pain/distension. The most common types of appendix neoplasia included adenocarcinoma and appendiceal mucinous neoplasms. A minority of patients had metastatic disease at the time of appendiceal neoplasia diagnosis. Although the incidence and recurrence of appendix neoplasia in patients with IBD is relatively low, likely related to the small area of mucosa at-risk relative to the colorectum, the recognition of appendix neoplasms as a potential complication of longstanding disease remains unclear. Further studies to compare appendiceal neoplasia in patients with and without IBD are needed to determine if IBD predisposes to the development of this neoplastic complication.

References

1. Ruoff C, Hanna L, Zhi W, Shahzad G, Gotlieb V, Saif MW. Cancers of the appendix: review of the literatures. ISRN Oncol. 2011;2011:728579. doi:10.5402/2011/728579
2. Nehme F, Schneider A, Hamid F. Appendiceal Adenocarcinoma Associated With Ulcerative Colitis. ACG Case Rep J. 2019;6(11):e00255. Published 2019 Nov 25. doi:10.14309/crj.0000000000000255
3. Van de Moortele M, De Hertogh G, Sagaert X, Van Cutsem E. Appendiceal cancer : a review of the literature. Acta Gastroenterol Belg. 2020;83(3):441-448.
4. Orta L, Trindade AJ, Luo J, Harpaz N. Appendiceal mucinous cystadenoma is a neoplastic complication of IBD: case-control study of primary appendiceal neoplasms. Inflamm Bowel Dis. 2009;15(3):415-421. doi:10.1002/ibd.20764

Disclosure

Siri A. Urquhart, M.D.: Discloses no conflicts.
John B. Kisiel, M.D.: Research funding and intellectual property licensed to Exact Sciences.
Nayantara Coelho-Prabhu, M.B.B.S.: Research funding from Fujifilm, Cook Endoscopy, and Alexion Pharma.

Introduction

The Mediterranean diet identified as a priority because it contributes to the normalization of key metabolic parameters in patients with non-alcoholic fatty liver disease (NAFLD). However, it is necessary to take into account the possibilities of following such a diet and the nutrigenetic characteristics of patients in different regions of the world. Purpose: to study the effect of nutrigenetic parameters in patients with NAFLD on the effectiveness of non-drug treatment.

Aims & Methods

Purpose: to study the effect of nutrigenetic parameters in patients with NAFLD on the effectiveness of non-drug treatment. 105 patients (55 men and 50 women) with NAFLD were examined. In patients, the features of eating disorders (ED) were studied (DEBQ questionnaire), nutrigenetic parameters - 5 polymorphisms: Pro12Ala of the PPARG2 gene (rs1801282), 101027 of the ADRB2 gene (rs1042714) and Arg16Gly of the ADRB2 gene (1010282); (rs4994) and Thr54Ala of the FABP2 gene (rs1799883) associated with the risk of metabolic disorders.

Results

Two polymorphisms associated with disorders of the ED gene (Pro12Ala PPARG2 and Trp64Arg ADRB3) were identified. Sex differences in the frequency of genotypes of the Pro12Ala polymorphism of the PPARG2 gene were not found (pχ2 = 0.90). 83.6% of men and 82.0% of women were carriers of the PPARG2 gene polymorphism (OR=1.10, CI=0.24-4.99) of the Pro12Pro genotype (AB=1.10, men and 16.7% of women of the genotype Pro12Ala (OR = 0.91, OR) = 0.20 - 4.13). The distribution of genotypes and allelic variants of the ADRB3 gene polymorphism had significant differences (px2 = 0.05). The Trp64Trp genotype of the ADRB3 gene polymorphism were found in 80.0% of men and 55.0% of women, the Trp64Arg genotype in 20.0% of men and 32.5% of women, the Arg64Arg genotype was found only in women. An analysis of the distribution of 64Trp and 64Arg alleles by sex using a multiplicative model showed that the significance of the association of the minor female 64Arg allele was confirmed by an odds ratio of 3.13 (CI = 1.01–9.70) versus 0.32 (CI = 0.01–9 .70). 10 - 0.99) for the minor allele. A significant association (px2 = 0.02) of the protective minor allele 12Ala with emotionally restrictive types of ED (OR = 0.11, CI = 0.10 - 0.97) was established, while the external type of oblique ED was associated with the carriage of the main allele polymorphism 12Pro of the Pro12Ala PPARG2 gene (OR = 8.71, CI = 1.03-7.66). Analysis of the distribution of 64Trp and 64Arg alleles depending on the type of EP disorder showed a significant association (px2 = 0.006) of the metabolically unfavorable minor 64Arg allele with the external type of ED disorders (OR = 5.53, CI = 1.48-20.68), while emotional and restrictive types were associated with the carrier of the main 64Trp allele (OR = 0.18, CI = 0.05-0.68). In patients with NAFLD, the external type of ED disorder prevails (p<0.05).

Conclusion

To increase the effectiveness of non-drug treatment, one should take into account nutrigenetic features - the presence of ProARA2 polymorphisms of the PPARG2 gene and Trp64Arg of the ADRB3 gene, which are associated with the peculiarities of nutrient metabolism and malnutrition in patients with NAFLD.

Disclosure

Nothing to disclose

Clinical Case Summary

Biliary pathology is a frequent motive for consultation in hospitals, and abdominal ultrasound is the first line-imaging test for its study. The genetic syndrome LPAC (Low Phospholipid-Associated Cholelithiasis) leads to the development of intrahepatic lithiasis. In this syndrome, there is a decrease in biliary phospholipids secretion caused by a mutation in the ABCB4 gene, responsible for a dysfunction of the MDR3 transporter. Despite being considered a rare entity, it accounts for 1-5% admissions for biliary pathology, affecting young women more frequently.
Two of three clinical criteria must be met for its diagnosis: symptoms onset before the age of 40, recurrence after cholecystectomy and compatible ultrasound appearance (presence of intrahepatic hyperechogenic spots, &quot;comet tail&quot; images or intrahepatic lithiasis with acoustic shadowing). Identification of the ABCB4 gene mutation is not a diagnostic criterion since it only appears in 50% of patients. Medical treatment with ursodeoxycholic acid is effective and cholecystectomy can be avoided.
We present a 23-year-old male who consulted for epigastric pain associated with vomiting. Laboratory tests showed elevation of amylase greater than three times above the upper limit of normal, which allowed the diagnosis of acute pancreatitis. Liver profile, calcium and triglycerides were within normal limits. The patient had no previous alcoholic intake. Abdominal ultrasound ruled out cholelithiasis but identified multiple intrahepatic hyperechogenic spots and &quot;comet tail&quot; signs. The patient was diagnosed with LPAC syndrome and treatment with ursodeoxycholic acid was initiated. During follow-up he did not present new episodes of biliary symptomatology.
The detection of the typical ultrasound signs of LPAC syndrome is the main tool for its suspicion. This disease is not as uncommon as it may seem, so it is essential to think about it in order to make a correct diagnosis and treatment of these patients.

References

Ultrasound image of intrahepatic lithiasis