DOP36 Family-specific host genetic and gut microbial signatures have a beneficial role in early identification of familial inflammatory bowel diseases

Abstract Background Familial IBD may have its own signatures with respect to host genetic variants and/or gut microbiome. However, available data focussing on this topic is still limited, particularly for Asian patients with familial IBD. We aimed to investigate the possible host genetic and gut microbial signatures in familial IBD through a combined analysis of genomic and metagenomic profiles. Methods All patients were affiliated with a prospectively recruited cohort of patients with IBD (NCT03589183) and met the diagnostic criteria of Crohn’s disease (CD) or ulcerative colitis (UC). We constructed a unique family cohort comprising ≥2 affected individuals with familial IBD and ≥1 their unaffected, healthy first-degree relative (FDR) in each family. Whole-exome sequencing for rare variants followed by a genome-wide single-nucleotide polymorphism analysis for common variants was performed. A polygenic risk score (PRS) was calculated separately in Crohn’s disease (CD), ulcerative colitis (UC) or IBD. Gut microbial community was analysed by 16s rRNA sequencing of stool samples. Results Eight Korean families comprising 16 with familial IBD (12 concordant IBD, 4 discordant IBD) and 9 FDRs were included for analysis. Whole-exome sequencing identified four family-specific candidate genes (LAMA5, MYO15B, TTN, and WDR66) with rare missense variants that were transmitted preferentially to the affected FDRs in at least ≥3 families (Figure 1). An in silico analysis identified the deleterious effect of the identified variants on the gene products including LAMA5 (SIFT = 0, PolyPhen-2 = 0.72). The patients with CD, but not those with UC, had a significantly higher mean PRS than controls (PRS = 2.137 vs. 0.742, p-value = 0.030). Metagenomic sequencing revealed significant differences in α- and β-diversity of gut microbiota among the patients with CD, those with UC, and unaffected FDRs (all p < 0.05), showing lower microbial richness in the patients with familial IBD (p = 0.02). In various taxonomic levels, compared with unaffected FDRs, the patients with familial IBD showed the significantly differential abundance of several gut bacteria (all corrected p < 0.05; Figure 2). Conclusion Family-specific host genetic and gut microbial signatures have a beneficial role in early-identification of familial IBD (NCT03515070).

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Whole exome sequencing of patients who resolved Crohn’s disease and complex regional pain syndrome following treatment for paratuberculosis

Gut Pathogens ◽

10.1186/s13099-019-0311-z ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

J. Todd Kuenstner ◽

Maher Kali ◽

Christine Welch

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Exome Sequencing ◽

Complex Regional Pain Syndrome ◽

Whole Exome Sequencing ◽

Pain Syndrome ◽

Whole Exome

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Mutation spectrum ofNOD2reveals recessive inheritance as a main driver of Early Onset Crohn’s Disease

10.1101/098574 ◽

2017 ◽

Cited By ~ 1

Author(s):

Julie E. Horowitz ◽

Neil Warner ◽

Jeffrey Staples ◽

Eileen Crowley ◽

Ryan Murchie ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Early Onset ◽

Low Frequency ◽

Compound Heterozygous ◽

Recessive Inheritance ◽

Whole Exome ◽

Pediatric Onset

AbstractInflammatory bowel disease (IBD), clinically defined as Crohn’s disease (CD), ulcerative colitis (UC), or IBD-unclassified, results in chronic inflammation of the gastrointestinal tract in genetically susceptible hosts. Pediatric onset IBD represents ≥25% of all IBD diagnoses and often presents with intestinal stricturing, perianal disease, and failed response to conventional treatments.NOD2was the first and is the most replicated locus associated with adult IBD, to date. To determine the role ofNOD2and other genes in pediatric IBD, we performed whole-exome sequencing on a cohort of 1,183 patients with pediatric onset IBD (ages 0-18.5 years). We identified 92 probands who were homozygous or compound heterozygous for rare and low frequencyNOD2variants accounting for approximately 8% of our cohort, suggesting a Mendelian recessive inheritance pattern of disease. Additionally, we investigated the contribution of recessive inheritance ofNOD2alleles in adult IBD patients from the Regeneron Genetics Center (RGC)-Geisinger Health System DiscovEHR study, which links whole exome sequences to longitudinal electronic health records (EHRs) from 51,289 participants. We found that ~7% of cases in this adult IBD cohort, including ~10% of CD cases, can be attributed to recessive inheritance ofNOD2variants, confirming the observations from our pediatric IBD cohort. Exploration of EHR data showed that 14% of these adult IBD patients obtained their initial IBD diagnosis before 18 years of age, consistent with early onset disease. Collectively, our findings show that recessive inheritance of rare and low frequency deleteriousNOD2variants account for 7-10% of CD cases and implicateNOD2as a Mendelian disease gene for early onset Crohn’s Disease.Author SummaryPediatric onset inflammatory bowel disease (IBD) represents ≥25% of IBD diagnoses; yet the genetic architecture of early onset IBD remains largely uncharacterized. To investigate this, we performed whole-exome sequencing and rare variant analysis on a cohort of 1,183 pediatric onset IBD patients. We found that 8% of patients in our cohort were homozygous or compound heterozygous for rare or low frequency deleterious variants in the nucleotide binding and oligomerization domain containing 2(NOD2)gene. Further investigation of whole-exome sequencing of a large clinical cohort of adult IBD patients uncovered recessive inheritance of rare and low frequencyNOD2variants in 7% of cases and that the relative risk forNOD2variant homozygosity has likely been underestimated. While it has been reported that having >1NOD2risk alleles is associated with increased susceptibility to Crohn’s Disease (CD), our data formally demonstrate what has long been suspected: recessive inheritance ofNOD2alleles is a mechanistic driver of early onset IBD, specifically CD, likely due to loss of NOD2 protein function. Our data suggest that a subset of IBD-CD patients with early disease onset is characterized by recessive inheritance ofNOD2alleles, which has important implications for the screening, diagnosis, and treatment of IBD.

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Is Whole Exome Sequencing Clinically Practical in the Management of Pediatric Crohn's Disease?

Gut and Liver ◽

10.5009/gnl15176 ◽

2015 ◽

Vol 9 (6) ◽

pp. 767 ◽

Cited By ~ 6

Author(s):

Seak Hee Oh ◽

Jiwon Baek ◽

Kyung Mo Kim ◽

Eun-Ju Lee ◽

Yusun Jung ◽

...

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome

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99 Whole Exome Sequencing of 42 Crohn's Disease Patients and Identification of Rare Variants Associated With Crohn's Disease

Gastroenterology ◽

10.1016/s0016-5085(12)60094-8 ◽

2012 ◽

Vol 142 (5) ◽

pp. S-24

Author(s):

David Ellinghaus ◽

Susanna Nikolaus ◽

Philip C. Rosenstiel ◽

Stefan Schreiber ◽

Andre Franke

Keyword(s):

Crohn’S Disease ◽

Crohn's Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Rare Variants ◽

Whole Exome

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Mo1126 FAMILY-SPECIFIC HOST GENETIC AND GUT MICROBIAL SIGNATURES HAVE A BENEFICIAL ROLE IN EARLY IDENTIFICATION OF FAMILIAL INFLAMMATORY BOWEL DISEASES

Gastroenterology ◽

10.1016/s0016-5085(20)32667-6 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-797

Author(s):

Chang Kyun Lee ◽

Yoo Min Park ◽

Eunji Ha ◽

Ki-Nam Gu ◽

Kwangwoo Kim ◽

...

Keyword(s):

Inflammatory Bowel Diseases ◽

Early Identification ◽

Beneficial Role ◽

Specific Host ◽

Bowel Diseases ◽

Host Genetic ◽

Inflammatory Bowel

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Whole-Exome Sequencing of Patients With Recurrent HSV-2 Lymphocytic Mollaret Meningitis

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa589 ◽

2020 ◽

Author(s):

Alon Schneider Hait ◽

Michelle M Thomsen ◽

Simon M Larsen ◽

Marie Helleberg ◽

Maibritt Mardahl ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Whole Exome ◽

Ubiquitin Proteasome ◽

The Central Nervous System ◽

Host Genetic ◽

Lymphocytic Meningitis ◽

Simplex Virus ◽

Herpes Simplex Virus 2 ◽

Interferon Responses

Abstract Recurrent lymphocytic meningitis, also referred to as Mollaret meningitis, is a rare neurological disease characterized mainly by reactivation of herpes simplex virus 2 (HSV-2) from sensory ganglia. However, the underlying host immune determinants and viral factors rendering some individuals unable to maintain HSV-2 latency are largely unknown. We collected a cohort of 15 patients diagnosed with Mollaret meningitis. By whole-exome sequencing we identified rare host genetic variants predicted to be deleterious in molecules involved in (1) ubiquitin-proteasome pathways, (2) the autophagy machinery, and (3) cell proliferation/apoptosis. Moreover, infection of patient cells with HSV-2 or stimulation by virus-derived double-stranded DNA ligands revealed reduced antiviral interferon responses in most patients. These findings may contribute to a better understanding of disease pathogenesis and protective immunity to HSV in the central nervous system, and may ultimately be of importance for identification of targets for development of improved prophylaxis and treatment of this disease.

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Whole Exome Sequencing of Ulcerative Colitis–associated Colorectal Cancer Based on Novel Somatic Mutations Identified in Chinese Patients

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz020 ◽

2019 ◽

Vol 25 (8) ◽

pp. 1293-1301 ◽

Cited By ~ 3

Author(s):

Pengguang Yan ◽

Yanan Wang ◽

Xiangchen Meng ◽

Hong Yang ◽

Zhanju Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Ulcerative Colitis ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Somatic Mutations ◽

Meta Analysis ◽

Chinese Patients ◽

Genomic Alteration ◽

Whole Exome ◽

Sporadic Crcs

AbstractBackgroundCarcinogenesis is a severe consequence of chronic ulcerative colitis. We investigated the somatic mutations and pathway alterations in ulcerative colitis–associated colorectal cancer (CRC) in Chinese patients compared with sporadic CRCs to reveal potential therapeutic targets in ulcerative colitis–associated CRC.MethodsWhole exome sequencing was performed on archival tumor tissues and paired adjacent nondysplastic mucosa from 10 ulcerative colitis–associated CRC patients at a high risk of carcinogenesis. Genomic alteration profiles from 223 primary CRCs from The Cancer Genome Atlas served as sporadic CRC controls. A meta-analysis was performed to investigate differences in major genetic mutations between ulcerative colitis–associated and Crohn’s disease–associated CRCs.ResultsWe identified 44 nonsilent recurrent somatic mutations via whole exome sequencing, including 25 deleterious mutations involved in apoptosis and the PI3K-Akt pathway (COL6A3, FN1), autophagy (ULK1), cell adhesion (PODXL, PTPRT, ZFHX4), and epigenetic regulation (ARID1A, NCOR2, KMT2D, NCOA6, MECP2, SUPT6H). In total, 11 of the 25 mutated genes significantly differed between ulcerative colitis–associated CRC and sporadic CRC (APC, APOB, MECP2, NCOR2, NTRK2, PODXL, RABGAP1, SIK3, SUPT6H, ULK1, USP48). Somatic TP53 mutations occurred in 33% of ulcerative colitis–associated CRCs. Subsequent meta-analysis revealed distinct mutation profiles for Crohn’s disease– and ulcerative colitis–associated CRCs. Mutations involving the NF-kB pathway and epigenetic regulation were more common in ulcerative colitis–associated CRCs than in sporadic CRCs.ConclusionDistinct genomic alteration profiles of deleterious somatic mutations were found in ulcerative colitis–associated and sporadic CRCs. Mutations of epigenetic regulators, such as KMT2D and NCOA6, were common, suggesting an epigenetic pathomechanism for colitis-associated carcinoma in Chinese patients.

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