Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease

Schiff, Elena R.; Frampton, Matthew; Ben-Yosef, N; Avila, Brandon E.; Semplici, Francesca; Pontikos, Nikolas; Bloom, Stuart; McCartney, Sara; Vega, Roser; Lovat, Laurence; Wood, Eleanor; Hart, AL; Israeli, Eran; Crespi, Daniel; Furman, M; Mann, Steven; Murray, Charles; Segal, Anthony W.; Levine, Adam P.

doi:10.1007/s00439-018-1927-7

Cited by 8 publications

(6 citation statements)

References 58 publications

(63 reference statements)

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“…A follow-up of NOD2 variants revealed three additional amino acid changes that had been excluded in the filtering approaches for segregation in the family: P268S, A612T and A725G (S2 Fig) . The A725G variant was likely benign and there was no strong evidence for a risk effect of this amino acid mutations in common immune or infectious disease. In contrast, NOD2 612T, which was present in the affected father and grandmother but not in the twins, and P268S, which was considered to be too common to have a dominant effect on leprosy risk, had been associated with risk of CD [17,22].…”

Section: Plos Pathogensmentioning

confidence: 88%

Allele-dependent interaction of LRRK2 and NOD2 in leprosy

et al. 2023

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Leprosy, caused by Mycobacterium leprae, rarely affects children younger than 5 years. Here, we studied a multiplex leprosy family that included monozygotic twins aged 22 months suffering from paucibacillary leprosy. Whole genome sequencing identified three amino acid mutations previously associated with Crohn’s disease and Parkinson’s disease as candidate variants for early onset leprosy: LRRK2 N551K, R1398H and NOD2 R702W. In genome-edited macrophages, we demonstrated that cells expressing the LRRK2 mutations displayed reduced apoptosis activity following mycobacterial challenge independently of NOD2. However, employing co-immunoprecipitation and confocal microscopy we showed that LRRK2 and NOD2 proteins interacted in RAW cells and monocyte-derived macrophages, and that this interaction was substantially reduced for the NOD2 R702W mutation. Moreover, we observed a joint effect of LRRK2 and NOD2 variants on Bacillus Calmette-Guérin (BCG)-induced respiratory burst, NF-κB activation and cytokine/chemokine secretion with a strong impact for the genotypes found in the twins consistent with a role of the identified mutations in the development of early onset leprosy.

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Section: Plos Pathogensmentioning

confidence: 88%

Allele-dependent interaction of LRRK2 and NOD2 in leprosy

et al. 2023

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“…It is of interest that NLRP2 was found high on the list of damaging variants in two separate studies of familial CD in AJs [80]. Very little is known about the biology of this NLRP.…”

Section: Inflammasomementioning

confidence: 99%

Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity

Segal

2019

J Intern Med

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The fruitless search for the cause of Crohn's disease has been conducted for more than a century. Various theories, including autoimmunity, mycobacterial infection and aberrant response to food and other ingested materials, have been abandoned for lack of robust proof. This review will provide the evidence, obtained from patients with this condition, that the common predisposition to Crohn's is a failure of the acute inflammatory response to tissue damage. This acute inflammation normally attracts large numbers of neutrophil leucocytes which engulf and clear bacteria and autologous debris from the inflamed site. The underlying predisposition in Crohn's disease is unmasked by damage to the bowel mucosa, predominantly through infection, which allows faecal bowel contents access to the vulnerable tissues within. Consequent upon failure of the clearance of these infectious and antigenic intestinal contents, it becomes contained, leading to a chronic granulomatous inflammation, producing cytokine release, local tissue damage and systemic symptoms. Multiple molecular pathologies extending across the whole spectrum of the acute inflammatory and innate immune response lead to the common predisposition in which defective monocyte and macrophage function plays a central role. Family linkage and exome sequencing together with GWAS have identified some of the molecules involved, including receptors, molecules involved in vesicle trafficking, and effector cells. Current therapy is immunosuppressant, which controls the symptoms but accentuates the underlying problem, which can only logically be tackled by correcting the primary lesion/s by gene therapy or genome editing, or through the development of drugs that stimulate innate immunity.

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“…The aim of this study was to recruit a new cohort of AJ IBD patients and their families, primarily from the UK, for epidemiological and genetic investigations [ 31 ]. Using 864 AJ IBD-affected individuals, up-to-date estimates of the pattern of familial disease and the risk to relatives are provided.…”

Section: Introductionmentioning

confidence: 99%

A New Look at Familial Risk of Inflammatory Bowel Disease in the Ashkenazi Jewish Population

et al. 2018

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Background and AimsThe inflammatory bowel diseases (IBD) are particularly common among the Ashkenazi Jewish (AJ) population. Population-specific estimates of familial risk are important for counseling; however, relatively small cohorts of AJ IBD patients have been analyzed for familial risk to date. This study aimed to recruit a new cohort of AJ IBD patients, mainly from the UK, to determine the familial occurrence of disease.MethodsA total of 864 AJ IBD patients were recruited through advertisements, hospital clinics, and primary care. Participants were interviewed about their Jewish ancestry, disease phenotype, age of diagnosis, and family history of disease. Case notes were reviewed.ResultsThe 864 probands comprised 506 sporadic and 358 familial cases, the latter with a total of 625 affected relatives. Of the UK cases, 40% had a positive family history with 25% having at least one affected first-degree relative. These percentages were lower among those recruited through hospital clinics and primary care (33% for all relatives and 22% among first-degree relatives). Examining all probands, the relative risk of IBD for offspring, siblings, and parents was 10.5, 7.4, and 4, respectively. Age of diagnosis was significantly lower in familial versus sporadic patients with Crohn’s disease.ConclusionsThis study reports familial risk estimates for a significant proportion of the AJ IBD population in the UK. The high rate of a positive family history in this cohort may reflect the greater genetic burden for IBD among AJs. These data are of value in predicting the likelihood of future recurrence of IBD in AJ families.

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Rare coding variant analysis in a large cohort of Ashkenazi Jewish families with inflammatory bowel disease

Cited by 8 publications

References 58 publications

Allele-dependent interaction of LRRK2 and NOD2 in leprosy

Allele-dependent interaction of LRRK2 and NOD2 in leprosy

Studies on patients establish Crohn's disease as a manifestation of impaired innate immunity

A New Look at Familial Risk of Inflammatory Bowel Disease in the Ashkenazi Jewish Population

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