Publications by authors named "Ariella Amar"

5 Publications

  • Page 1 of 1

Streptococcus Salivarius: A Potential Salivary Biomarker for Orofacial Granulomatosis and Crohn's Disease?

Inflamm Bowel Dis 2019 07;25(8):1367-1374

Department of Medical and Molecular Genetics, Faculty of Life Science and Medicine, King's College London, London, United Kingdom.

Background: Orofacial granulomatosis (OFG) is a rare disease characterised by chronic, noncaseating, granulomatous inflammation primarily affecting the oral cavity. Histologically, it is similar to Crohn's disease (CD), and a proportion of patients have both OFG and CD. The cause of OFG remains elusive, but it has been suggested that microbial interactions may be involved. The aim of this study was to compare the salivary microbial composition of subjects with OFG and/or CD and healthy controls.

Methods: Two hundred sixty-one subjects were recruited, of whom 78 had OFG only, 40 had both OFG and CD, 97 had CD only with no oral symptoms, and 46 were healthy controls. Bacterial community profiles were obtained by sequencing the V1-V3 region of the 16S rRNA gene.

Results: There were no differences in richness or diversity of the salivary bacterial communities between patient groups and controls. The relative abundance of the Streptococcus salivarius group was raised in patients with OFG or CD only compared with controls, whereas that of the Streptococcus mitis group was lower in CD compared with both OFG and controls. One S. salivarius oligotype made the major contribution to the increased proportions seen in patients with OFG and CD.

Conclusions: The salivary microbiome of individuals with OFG and CD was similar to that found in health, although the proportions of S. salivarius, a common oral Streptococcus, were raised. One specific strain-level oligotype was found to be primarily responsible for the increased levels seen.
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http://dx.doi.org/10.1093/ibd/izz022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635823PMC
July 2019

Association of genetic variants in CHEK2 with oesophageal squamous cell carcinoma in the South African Black population.

Carcinogenesis 2019 06;40(4):513-520

Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.

Oesophageal squamous cell carcinoma (OSCC) has a high incidence in southern Africa and a poor prognosis. Limited information is available on the contribution of genetic variants in susceptibility to OSCC in this region. However, recent genome-wide association studies have identified multiple susceptibility loci in Asian and European populations. In this study, we investigated genetic variants from seven OSCC risk loci identified in non-African populations for association with OSCC in the South African Black population. We performed association studies in a total of 1471 cases and 1791 controls from two study sample groups, which included 591 cases and 852 controls from the Western Cape and 880 cases and 939 controls from the Johannesburg region in the Gauteng province. Thereafter, we performed a meta-analysis for 11 variants which had been genotyped in both studies. A single nucleotide polymorphism in the CHEK2 gene, rs1033667, was significantly associated with OSCC [P = 0.002; odds ratio (OR) = 1.176; 95% confidence interval (CI): 1.06-1.30]. However, single nucleotide polymorphisms in the CASP8/ALS2CR12, TMEM173, PLCE1, ALDH2, ATP1B2/TP53 and RUNX1 loci were not associated with the disease (P > 0.05). The lack of association of six of these loci with OSCC in South African populations may reflect different genetic risk factors in non-African and African populations or differences in the genetic architecture of African genomes. The association at CHEK2, a gene with key roles in cell cycle regulation and DNA repair, in an African population provides further support for the contribution of common genetic variants at this locus to the risk of oesophageal cancer.
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http://dx.doi.org/10.1093/carcin/bgz026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556703PMC
June 2019

Exome Sequencing and Genotyping Identify a Rare Variant in NLRP7 Gene Associated With Ulcerative Colitis.

J Crohns Colitis 2018 Feb;12(3):321-326

Department of Medical and Molecular Genetics, King's College London, London, UK.

Background And Aims: Although genome-wide association studies [GWAS] in inflammatory bowel disease [IBD] have identified a large number of common disease susceptibility alleles for both Crohn's disease [CD] and ulcerative colitis [UC], a substantial fraction of IBD heritability remains unexplained, suggesting that rare coding genetic variants may also have a role in pathogenesis. We used high-throughput sequencing in families with multiple cases of IBD, followed by genotyping of cases and controls, to investigate whether rare protein-altering genetic variants are associated with susceptibility to IBD.

Methods: Whole-exome sequencing was carried out in 10 families in whom three or more individuals were affected with IBD. A stepwise filtering approach was applied to exome variants, to identify potential causal variants. Follow-up genotyping was performed in 6025 IBD cases [2948 CD; 3077 UC] and 7238 controls.

Results: Our exome variant analysis revealed coding variants in the NLRP7 gene that were present in affected individuals in two distinct families. Genotyping of the two variants, p.S361L and p.R801H, in IBD cases and controls showed that the p.S361L variant was significantly associated with an increased risk of ulcerative colitis [odds ratio 4.79, p = 0.0039] and IBD [odds ratio 3.17, p = 0.037]. A combined analysis of both variants showed suggestive association with an increased risk of IBD [odds ratio 2.77, p = 0.018].

Conclusions: The results suggest that NLRP7 signalling and inflammasome formation may be a significant component in the pathogenesis of IBD.
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http://dx.doi.org/10.1093/ecco-jcc/jjx157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290881PMC
February 2018

Mutations in DONSON disrupt replication fork stability and cause microcephalic dwarfism.

Nat Genet 2017 Apr 13;49(4):537-549. Epub 2017 Feb 13.

Department of Pediatrics, Security Forces Hospital, Riyadh, Saudi Arabia.

To ensure efficient genome duplication, cells have evolved numerous factors that promote unperturbed DNA replication and protect, repair and restart damaged forks. Here we identify downstream neighbor of SON (DONSON) as a novel fork protection factor and report biallelic DONSON mutations in 29 individuals with microcephalic dwarfism. We demonstrate that DONSON is a replisome component that stabilizes forks during genome replication. Loss of DONSON leads to severe replication-associated DNA damage arising from nucleolytic cleavage of stalled replication forks. Furthermore, ATM- and Rad3-related (ATR)-dependent signaling in response to replication stress is impaired in DONSON-deficient cells, resulting in decreased checkpoint activity and the potentiation of chromosomal instability. Hypomorphic mutations in DONSON substantially reduce DONSON protein levels and impair fork stability in cells from patients, consistent with defective DNA replication underlying the disease phenotype. In summary, we have identified mutations in DONSON as a common cause of microcephalic dwarfism and established DONSON as a critical replication fork protein required for mammalian DNA replication and genome stability.
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http://dx.doi.org/10.1038/ng.3790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5450907PMC
April 2017

Pooled sequencing of 531 genes in inflammatory bowel disease identifies an associated rare variant in BTNL2 and implicates other immune related genes.

PLoS Genet 2015 Feb 11;11(2):e1004955. Epub 2015 Feb 11.

Department of Medical and Molecular Genetics, Kings College London, Guy's Hospital, London, United Kingdom; Division of Medical Biochemistry, University of Cape Town, Cape Town, South Africa.

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn's disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10-10, OR = 2.3[95% CI = 1.75-3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1-5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.
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http://dx.doi.org/10.1371/journal.pgen.1004955DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335459PMC
February 2015