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Jack Satsangi

Publications and source records attributed to Jack Satsangi.

At least 19 recordsLinked to original sources
PubMed2025

Psychological Resilience and Mental Wellbeing Mitigate the Risk of Irritable Bowel Syndrome.

INTRODUCTION: Comorbidities between mental disorders and irritable bowel syndrome (IBS) have been widely reported, yet associations between mental wellbeing and IBS, particularly regarding underlying genetic modification and proteomic signatures, remain underexplored. METHODS: This prospective cohort study analyzed 75,842 IBS-free participants aiming to investigate the prospective association between mental wellbeing and the risk of IBS in UK Biobank. Mental wellbeing was assessed through life satisfaction, positive affect, neuroticism, and depressive/anxiety symptoms. Cox models evaluate the hazard ratio (HR) for mental wellbeing and plasma proteome in relation to incident IBS during follow-up. Proteomic profiling identified mental wellbeing-associated proteins, with pathway enrichment analysis revealing biological mechanisms. Mediation and Mendelian randomization analyses further examine intermediate pathways and causality. RESULTS: With a 12.4-year follow-up period, 1,400 cases of incident IBS were documented. Better mental wellbeing mitigated IBS risk dose-dependently (low risk group: HR, 0.37; 95% confidence interval [CI]: 0.31-0.43). Higher life satisfaction (HR, 0.41; 95% CI: 0.30-0.56) and positive affect (HR, 0.50; 95% CI: 0.41-0.62) were inversely associated with IBS risk, whereas neuroticism (HR, 2.35; 95% CI: 1.92-2.88) and depressive/anxiety symptoms (HR, 3.09; 95% CI: 2.17-4.42) increased the risk. Findings remained consistent in across prevalent IBS and IBS subtypes. Mental wellbeing effects were independent of genetic predisposition. Mediation analyses revealed about 27% of protective effect of mental wellbeing were mediated through reduced depression and anxiety. Mendelian randomization supports causal protective effects of positive mental wellbeing on IBS. Proteomic profiling identified mental wellbeing-associated proteins mainly enriched in cytokine-cytokine receptor interactions. Chromogranin A and gastrin emerged as key protein biomarkers, showing significant associations with both mental wellbeing components and IBS risk. DISCUSSION: Our study demonstrates that enhanced mental wellbeing confers substantial protection against IBS development, highlighting psychological interventions as potential primary prevention strategies.

Humans↗
PubMed2024

Prenatal cannabis exposure is associated with alterations in offspring DNA methylation at genes involved in neurodevelopment, across the life course.

Prenatal cannabis exposure (PCE) is of increasing concern globally, due to the potential impact on offspring neurodevelopment, and its association with childhood and adolescent brain development and cognitive function. However, there is currently a lack of research addressing the molecular impact of PCE, that may help to clarify the association between PCE and neurodevelopment. To address this knowledge gap, here we present epigenome-wide association study data across multiple time points, examining the effect of PCE and co-exposure with tobacco using two longitudinal studies, the Avon Longitudinal Study of Parents and Children (ALSPAC) and the Christchurch Health and Development Study (CHDS) at birth (0 y), 7 y and 15-17 y (ALSPAC), and ~27 y (CHDS). Our findings reveal genome-wide significant DNA methylation differences in offspring at 0 y, 7 y, 15-17 y, and 27 y associated with PCE alone, and co-exposure with tobacco. Importantly, we identified significantly differentially methylated CpG sites within the genes LZTS2, NPSR1, NT5E, CRIP2, DOCK8, COQ5, and LRP5 that are shared between different time points throughout development in offspring. Notably, functional pathway analysis showed enrichment for differential DNA methylation in neurodevelopment, neurotransmission, and neuronal structure pathways, and this was consistent across all timepoints in both cohorts. Given the increasing volume of epidemiological evidence that suggests a link between PCE and adverse neurodevelopmental outcomes in exposed offspring, this work highlights the need for further investigation into PCE, particularly in larger cohorts.

DNA Methylation↗
PubMed2007

Potential role for the common cystic fibrosis DeltaF508 mutation in Crohn's disease.

BACKGROUND: Inflammatory bowel disease (IBD) is an epithelial barrier disease that is thought to result from a dysregulated interaction with bacteria in the intestine of genetically predisposed individuals. The cystic fibrosis transmembrane conductance regulator (CFTR), which is mutated in the autosomal recessive disease cystic fibrosis, modulates gut permeability, mucus production, and epithelial interactions with bacteria. The cystic fibrosis DeltaF508 mutation is commonly found in the general population and has been shown to result in a reduced number of CFTR molecules at the surface of epithelial cells. Given the important biological functions of CFTR in the intestine, we tested whether this mutation is of relevance to IBD. METHODS: Using DNA heteroduplex analysis, we investigated the distribution of DeltaF508 heterozygosity in 2568 subjects from three independent cohorts of Italian, Swedish, and Scottish IBD patients and controls. RESULTS: In all three cohorts an association between DeltaF508 and Crohn's disease (CD) was observed. Specifically, DeltaF508 heterozygosity was markedly underrepresented in CD patients from Italy and Sweden (P = 0.021 and 0.027 versus controls, respectively), while stratification for disease location revealed an absence of DeltaF508 carriers among Scottish CD patients with right-sided colitis (P = 0.023 versus all other locations). CONCLUSIONS: DeltaF508 heterozygosity might exert a protective effect in CD.

Adolescent↗
PubMed2007

Genetics of the innate immune response in inflammatory bowel disease.

The discovery of nucleotide-binding oligomerization domain 2/caspase recruitment domain-containing protein 15 (NOD2/CARD15) as the first susceptibility gene in Crohn's disease (CD) has shifted the focus of research into the pathogenesis of inflammatory bowel disease (IBD) firmly to the innate immune response and the integrity of the epithelial barrier. The subsequent implication in IBD of variant alleles of OCTN, DLG5, MDR1, and TLRs has provided further support for a new, more complex model of innate immunity function in the gastrointestinal tract. In this review, we examine the recent advances in our understanding of the influence of genetics of the innate immune response on IBD. We will focus on germline variation of genes encoding pathogen-recognition receptors, proteins involved in epithelial homeostasis and secreted antimicrobial proteins.

Genetic Predisposition to Disease↗
PubMed2006

New genes in inflammatory bowel disease: lessons for complex diseases?

The chronic inflammatory bowel diseases Crohn's disease and ulcerative colitis are common causes of gastrointestinal disease in northern Europe, affecting as many as one in 250 people. Although mortality is low, morbidity associated with these diseases is substantial. We review the recent advances in the genetics of inflammatory bowel disease, with particular emphasis on the data that have been generated since the discovery of the CARD15 (NOD2) gene in 2001.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

Novel susceptibility genes in inflammatory bowel disease.

The inflammatory bowel disease, Crohn's disease and ulcerative colitis, are polygenic disorders with important environmental interactions. To date, the most widely adopted approach to identifying susceptibility genes in complex diseases has involved genome wide linkage studies followed by studies of positional candidate genes in loci of interest. This review encompasses data from studies into novel candidate genes implicated in the pathogenesis of inflammatory bowel disease. Novel techniques to identify candidate genes-genome wide association studies, yeast-two hybrid screening, microarray gene expression studies and proteomic profiling, are also reviewed and their potential role in unravelling the pathogenesis of inflammatory bowel disease are discussed.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Contribution of CARD15 variants in determining susceptibility to Crohn's disease in Sweden.

OBJECTIVE: Crohn's disease (CD) is a chronic inflammatory bowel disorder caused by environmental and genetic factors. Mutations in the CARD15 gene have been associated with CD. No previous case-control CARD15 study has been performed in the Swedish population. MATERIAL AND METHODS: The study comprised of 321 individuals: 178 with CD and 143 healthy controls (HCs), all from Stockholm County. All were genotyped for the three main CD-associated CARD15 variants (R702W, G908R and 1007fs) and phenotypic associations were investigated. RESULTS: The allele frequencies of the R702W variant (4.5% CD versus 0.7% HC, p=0.008, OR = 6.8) and the G908R variant (2.0% CD versus 0% HC, p=0.045) were more common in CD patients than in controls. No significant difference in1007fs variant allele frequency was found between CD patients and controls (2.0% CD versus 1.7% HC, p = 0.8, OR = 1.1). Carriage of CARD15 variants was more common in the CD patients than in controls (15.2% CD versus 4.2% HC, p = 0.001, OR = 4.1, population attributable risk (PAR) = 11.4%). Genotype-phenotype analysis demonstrated that CARD15 variants were associated with ileal disease (p=0.0006, OR = 9.3, CI = 2.2-34) and protective for colonic CD (p = 0.01, OR = 0.18). An association between CARD15 variants and ileal CD (p=0.004, OR = 6.6) was confirmed by multivariate analyses. CONCLUSIONS: The CARD15 variants R702W and G908R, but not 1007fs, are associated with susceptibility to CD in Stockholm County. Genotype-phenotype analysis shows an association with ileal CD. The contribution of these CARD15 mutations in Swedish CD patients overall is low in relation to studies elsewhere in Central Europe and North America, but is consistent with emerging data from elsewhere in Scandinavia and in Northern Europe.

Alleles↗
PubMed2005

Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis.

BACKGROUND AND AIMS: The MDR1 gene encodes P-glycoprotein 170, an efflux transporter that is highly expressed in intestinal epithelial cells. The MDR1 exonic single nucleotide polymorphisms (SNPs) C3435T and G2677T have been shown to correlate with activity/expression of P-glycoprotein 170. METHODS: This was a case-control analysis of MDR1 C3435T and G2677T SNPs in a large well-characterized Scottish white cohort (335 with ulcerative colitis [UC], 268 with Crohn's disease [CD], and 370 healthy controls). We conducted 2-locus haplotype and detailed univariate and multivariate genotypic-phenotypic analyses. RESULTS: The MDR1 3435 TT genotype (34.6% vs 26.5%; P = .04; odds ratio [OR], 1.60; 95% confidence interval [95% CI], 1.04-2.44) and T-allelic frequencies (58.2% vs 52.8%; P = .02; OR, 1.28; 95% CI, 1.03-1.58) were significantly higher in patients with UC compared with controls. No association was seen with CD. The association was strongest with extensive UC (TT genotype: 42.4% vs 26.5%; P = .003; OR, 2.64; 95% CI, 1.34-4.99; and T allele: 63.9% vs 52.8%; P = .009; OR, 1.70; 95% CI, 1.24-2.29), and this was also confirmed on multivariate analysis ( P = .007). The G2677T SNP was not associated with UC or CD. These 2 SNPs lie in linkage disequilibrium in our population (D', .8-.9; r 2 , .7-.8). Two-locus haplotypes showed both positive (3435T/G2677 haplotype: P = .03; OR, 1.44) and negative (C3435/2677T haplotype: P = .002; OR, .35) associations with UC. Homozygotes for the haplotype 3435T/G2677 were significantly increased in UC ( P = .017; OR, 8.88; 95% CI, 1.10-71.45). CONCLUSIONS: Allelic variations of the MDR1 gene determine disease extent as well as susceptibility to UC in the Scottish population. The present data strongly implicate the C3435T SNP, although the 2-locus haplotype data underline the need for further detailed haplotypic studies.

Adolescent↗
PubMed2005

The hedgehog signalling pathway in the gastrointestinal tract: implications for development, homeostasis, and disease.

The hedgehog signalling pathway is critical to normal mammalian gastrointestinal development. Through epithelial-mesenchymal interactions, hedgehog signalling ensures appropriate axial patterning of the embryonic gut. Congenital abnormalities, including malrotations, anorectal malformations, and tracheoesophageal fistula are associated with germ-line mutations/deletion of genes encoding hedgehog signalling components in man and present in genetically engineered animal models. In adults, there is evidence that the pathway plays a role in maintaining stem cell populations in the stomach and directing epithelial cell differentiation in the intestine. Recent data implicate hedgehog signalling in the formation and maintenance of a number of malignancies, including those of the upper gastrointestinal (GI) tract and pancreas, in which abrogation of the pathway offers a novel therapeutic approach in animal models. Most recently, evidence in vitro indicates that there is a recapitulation of embryonic hedgehog signalling in acute epithelial injury and chronic inflammation, a finding with key implications for inflammatory disorders of the intestine, such as inflammatory bowel diseases. This pathway may provide an important link between chronic inflammation and cancer. We summarize the available evidence demonstrating that this developmental pathway has continuing roles in adult homeostasis and is dysregulated in malignancy and inflammation of the gastrointestinal tract.

Animals↗
PubMed2005

The contribution of OCTN1/2 variants within the IBD5 locus to disease susceptibility and severity in Crohn's disease.

BACKGROUND & AIMS: Recent data suggest that polymorphisms in the organic cation transporter (OCTN) genes OCTN1 (SLC22A4) and OCTN2 (SLC22A5) represent disease-causing mutations within the IBD5 locus (chromosome 5q31). We investigated associations with disease susceptibility, phenotype, and evidence for epistasis with CARD15 in 679 patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: A total of 374 patients with CD, 305 patients with UC, and 294 healthy controls (HCs) were studied. Genotyping for single nucleotide polymorphisms IGR2096, IGR2198, and IGR2230, OCTN1 variant (SLC22A4 1672C-->T), and OCTN2 variant (SLC22A5 -207G-->C) was performed using the TaqMan system. RESULTS: The IBD5 OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D', >0.959). IGR2198 variant allele frequency (49.1% vs 40.8%; P = .0046) and homozygosity (21% vs 14.8%; P = .044) were associated with CD versus HCs. Variant allelic frequency of OCTN1 (53.6% vs 43%; P = .0008) and OCTN2 (56.1% vs 48.4%; P = .0092) polymorphisms and homozygosity for the OCTN1/2-TC haplotype (28.4% vs 16%; P = .0042) were associated with CD versus HCs. IGR2198 homozygosity and TC homozygosity were associated with stricturing/penetrating disease at follow-up (P = .011 and P = .011, respectively) and disease progression (P = .038 and P = .049, respectively) on univariate analysis and with need for surgery on multivariate analysis (P = .016 and P = .004, respectively). In the absence of the IBD5 risk haplotype, no association of OCTN1/2 variants with CD was detected. No associations were seen with UC. CONCLUSIONS: The IBD5 locus influences susceptibility, progression, and need for surgery in CD. However, the contribution of OCTN1/2 variants is not independent of the IBD5 haplotype; a causative role for these genes remains plausible but is not yet proven. Further genetic, functional, and expression data are now required.

Adult↗
PubMed2005

Infliximab use in Crohn's disease: impact on health care resources in the UK.

OBJECTIVE: To quantify the impact of infliximab therapy on health care resource utilization in the UK. METHODS: A retrospective audit was undertaken at seven centres in the UK, which reviewed patient notes for a period of 6 months before and 6 months after an initial infliximab infusion. Details of hospital admissions, outpatient visits, operations, diagnostic procedures, drug usage, and overall efficacy were collected. Results were compared for the two 6 month study periods. RESULTS: A total of 205 patients (62% female, median age 33 years) with moderate/severe Crohn's disease were audited. The majority of patients had chronic active disease (62%) and most received one infusion initially (72%). Clinicians rated 74% of responses as good to excellent and patients 72%. Most patients had concomitant immunosuppression (pre: 75%, post: 75%). Approximately half of the patients (45%) stopped taking steroids, with a further 34% having a dosage reduction. A fall of 1093 inpatient days was seen (1435 vs. 342) in the 6 months following infliximab administration. There were seven fewer operations, 33 fewer examinations under anaesthetic, and 99 fewer diagnostic procedures. Outpatient visits were similar pre- versus post- (555 vs. 534). The total reduction in direct costs amounted to an estimated pounds 591,006. Three hundred and fifty-three infliximab infusions were administered at an estimated cost of pounds 562,719. Thus, there was a net reduction of pounds 28,287 or pounds 137.98 per patient. CONCLUSIONS: Infliximab appears to be a potentially cost effective treatment for selected patients based on the reduced number of inpatient stays, examinations under anaesthetic, and diagnostic procedures over a 6 month period.

Adolescent↗
PubMed2005

The clinical course of ulcerative colitis after orthotopic liver transplantation for primary sclerosing cholangitis: further appraisal of immunosuppression post transplantation.

BACKGROUND AND AIMS: The course of ulcerative colitis (UC) following orthotopic liver transplantation (OLT) for primary sclerosing cholangitis (PSC) is unclear. We documented the nationwide experience of the course of UC, before and after OLT for PSC. METHODS AND RESULTS: A total of 470 liver transplants were performed for 413 patients between 1992 and 2003, in the Scottish Liver Transplantation Unit, UK. Twenty-six patients had co-existing UC/PSC. Of these, data from 20 patients were studied over a median period of 11.9 years before OLT and 4.4 years after OLT; of the others, four patients required colectomy prior to OLT, one died within 7 days of transplant, and one developed UC after transplant. A significantly higher relapse rate (number of relapses/year of follow-up) was seen after OLT (median 1.0 versus 0.3; interquartile range, 0.10-1.42 and 0.01-0.40, respectively; P = 0.007). The corticosteroids requirement (number of courses/year of follow-up) after OLT was also significantly higher (0.40 versus 0.10; interquartile range, 0.51-1.13 and 0.05-0.12, respectively; P = 0.003). Twenty per cent of patients (4/20) became corticosteroid dependent after OLT. Thirty-five per cent of patients (7/20) underwent colectomy after OLT: three for severe disease and four for neoplasia/dysplasia. Five patients (19%) developed neoplasia following OLT. CONCLUSION: Despite immunosuppression, UC follows a more aggressive clinical course after OLT and is associated with a high rate of neoplasia.

Adult↗
PubMed2005

Genotype-phenotype analysis in childhood-onset Crohn's disease: NOD2/CARD15 variants consistently predict phenotypic characteristics of severe disease.

INTRODUCTION: The incidence of early-onset CD in Scotland is among the highest worldwide. Three single nucleotide polymorphisms (SNPs) R702W, G908R and Leu1007finsC in the NOD2/CARD15 gene predispose to adult CD. We investigated the contribution of these variants to disease susceptibility and phenotype in the Scottish early-onset IBD population. PATIENTS AND METHODS: 906 individuals including 247 Scottish IBD patients aged <16 years at diagnosis, 414 parents and 245 controls were genotyped. Transmission disequilibrium testing (TDT), case-control analysis and detailed genotype-phenotype analysis were performed. RESULTS: The Leu1007finsC variant was associated with susceptibility to CD by case-control (4.2% versus. 1.4%, P = 0.01) and TDT analysis (P = 0.006). The Population Attributable Risk (PAR) for the 3 NOD2/CARD15 mutations was 7.9%. Carriage of NOD2/CARD15 variants was associated with, at diagnosis: decreased albumin (31.0% versus. 9.0%, P = 0.001) and raised CRP (25% versus. 9.5%, P = 0.04) and at follow up: need for surgery (39.5% versus. 12.8%, P = 0.0002) jejunal involvement (50% versus. 18.4%, P = 0.01) jejunal and ileal involvement (50% versus. 10.7%, P = 0.009), raised CRP (57.1% and 12.8%, P = 0.0009), lower weight/height centile (75.0% versus. 20.2%, P = 0.03, 50.0% versus. 16.0%, P = 0.001 respectively) and stricturing disease (45.5% versus. 19.4%, P < 0.05). Multifactorial analysis demonstrated carriage was associated with need for surgery (P = 0.004, OR 4.9 [1.5-14.7]). CONCLUSIONS: These NOD2/CARD 15 variants in the Scottish early onset CD population have a definite, albeit relatively small contribution to CD susceptibility (PAR 7.9%) but a major impact on phenotype. In particular NOD2/CARD15 variants are strongly associated with several markers of disease severity in pediatric CD, notably need for surgery.

Adolescent↗