Background
Thiopurine‐related adverse events such as leukopenia, liver dysfunction and pancreatitis are associated with variants in the NUDT15 gene. Loss‐of‐function (low or no enzyme activity) ...alleles are more common in Asian and Hispanic populations. The prevalence of these variants in the Australian inflammatory bowel disease (IBD) population has not yet been reported.
Aim
To evaluate the presence of NUDT15 loss‐of‐function alleles *2,*3,*9 in the Australian IBD population.
Methods
The NUDT15 screening cohort included 423 IBD patients from Brisbane, Australia. Study patients were recruited by: (i) retrospective review of clinical charts for thiopurine‐related severe adverse events; (ii) pathology data (white blood cell (WBC) and neutrophil counts). NUDT15 genotyping was performed using polymerase chain reaction (PCR)‐high‐resolution melt (HRM), TaqMan genotyping and Sanger sequencing.
Results
NUDT15 mutation R139C (allele *3) was identified in 8 of 423 (1.9%) IBD patients. Seven of eight patients were R139C heterozygous (C/T) and one patient was R139C homozygous (T/T). One of the C/T group and the T/T patient developed thiopurine‐induced myelosuppression (TIM) within 60 days of dosing. One patient in the C/T group developed TIM after 60 days of thiopurine dosing. The remaining five patients in the C/T group did not show TIM; however, other thiopurine‐related events could not be ruled out and therefore careful monitoring over a long period is recommended.
Conclusions
This is the first study to report the frequency of NUDT15 haplotypes *2,*3,*9 in an Australian IBD population. The most common variant detected was the R139C mutation. PCR and Sanger sequencing are efficient and cost‐effective approaches for NUDT15 genotyping.
Intraocular pressure (IOP) is currently the sole modifiable risk factor for primary open-angle glaucoma (POAG), one of the leading causes of blindness worldwide
. Both IOP and POAG are highly ...heritable
. We report a combined analysis of participants from the UK Biobank (n = 103,914) and previously published data from the International Glaucoma Genetic Consortium (n = 29,578)
that identified 101 statistically independent genome-wide-significant SNPs for IOP, 85 of which have not been previously reported
. We examined these SNPs in 11,018 glaucoma cases and 126,069 controls, and 53 SNPs showed evidence of association. Gene-based tests implicated an additional 22 independent genes associated with IOP. We derived an allele score based on the IOP loci and loci influencing optic nerve head morphology. In 1,734 people with advanced glaucoma and 2,938 controls, participants in the top decile of the allele score were at increased risk (odds ratio (OR) = 5.6; 95% confidence interval (CI): 4.1-7.6) of glaucoma relative to the bottom decile.
The inflammatory bowel diseases (IBDs) are a group of heterogeneous disorders characterized by acute and chronic inflammatory changes in the small or large bowel, or in both. Increasing incidence and ...prevalence figures for IBD both in the developed and developing world indicate that environmental factors are at least as significant in IBD as genetic susceptibility. Of these, diet and the host microbiota are likely to play important but as yet poorly defined roles. The major constituents of a standard “Western” diet may contribute to, or protect against, intestinal inflammation via several mechanisms. These include the effects of insulin resistance and short‐chain fatty acids such as butyrate, modification of intestinal permeability, the antiinflammatory role of polyunsaturated fatty acids, and the effect of sulfur compounds from protein on host microbiota. This detailed review critically assesses the evidence for the role of diet in the development of IBD and examines the evidence for obesity as a contributing factor to IBD pathogenesis. Particular attention is focused on methodological issues including suitability of cases and controls, confounders such as smoking, and total energy expenditure. Inflamm Bowel Dis 2010
Background and Aims
Many patients presenting with an acute severe ulcerative colitis to a regional hospital are transferred to a metropolitan hospital for specialised care. This study aimed to ...evaluate the outcomes and characteristics of these patients.
Method
A retrospective observational cohort study was conducted to examine the 30‐day colectomy rate using prospectively collected data on 69 consecutive index cases of acute severe ulcerative colitis transferred from regional hospitals to our metropolitan hospital meeting Truelove and Witts criteria. Those that avoided colectomy were followed out to 1 year to examine outcomes.
Results
The 30‐day colectomy rate was 46.4% (32/69) in regional transfer patients. Rescue therapy was administered to 65% (45/69) of patients after transfer to our metropolitan hospital. Colectomy was avoided in 55% of these patients at 30 days. Colectomy free status was maintained in 78% (29/39) of these patients. Mortality was 0% at 30 days and 1 year.
Conclusion
Over 50% of the patients failing therapy in a regional centre and requiring transfer avoided short term colectomy with co‐ordinated referral for rescue therapy in a tertiary metropolitan inflammatory bowel disease unit. These patients would have ultimately required colectomy in their regional hospital without intervention.
As custom arrays are cheaper than generic GWAS arrays, larger sample size is achievable for gene discovery. Custom arrays can tag more variants through denser genotyping of SNPs at associated loci, ...but at the cost of losing genome-wide coverage. Balancing this trade-off is important for maximizing experimental designs. We quantified both the gain in captured SNP-heritability at known candidate regions and the loss due to imperfect genome-wide coverage for inflammatory bowel disease using immunochip (iChip) and imputed GWAS data on 61,251 and 38.550 samples, respectively. For Crohn's disease (CD), the iChip and GWAS data explained 19 and 26% of variation in liability, respectively, and SNPs in the densely genotyped iChip regions explained 13% of the SNP-heritability for both the iChip and GWAS data. For ulcerative colitis (UC), the iChip and GWAS data explained 15 and 19% of variation in liability, respectively, and the dense iChip regions explained 10 and 9% of the SNP-heritability in the iChip and the GWAS data. From bivariate analyses, estimates of the genetic correlation in risk between CD and UC were 0.75 (SE 0.017) and 0.62 (SE 0.042) for the iChip and GWAS data, respectively. We also quantified the SNP-heritability of genomic regions that did or did not contain the previous 163 GWAS hits for CD and UC, and SNP-heritability of the overlapping loci between the densely genotyped iChip regions and the 163 GWAS hits. For both diseases, over different genomic partitioning, the densely genotyped regions on the iChip tagged at least as much variation in liability as in the corresponding regions in the GWAS data, however a certain amount of tagged SNP-heritability in the GWAS data was lost using the iChip due to the low coverage at unselected regions. These results imply that custom arrays with a GWAS backbone will facilitate more gene discovery, both at associated and novel loci.
Anti-microbial signaling pathways are normally triggered by innate immune receptors when detecting pathogenic microbes to provide protective immunity. Here we show that the inflammasome sensor Nlrp1 ...aggravates DSS-induced experimental mouse colitis by limiting beneficial, butyrate-producing Clostridiales in the gut. The colitis-protective effects of Nlrp1 deficiency are thus reversed by vancomycin treatment, but recapitulated with butyrate supplementation in wild-type mice. Moreover, an activating mutation in Nlrp1a increases IL-18 and IFNγ production, and decreases colonic butyrate to exacerbate colitis. We also show that, in patients with ulcerative colitis, increased NLRP1 in inflamed regions of the colon is associated with increased IFN-γ. In this context, NLRP1, IL-18 or IFN-γ expression negatively correlates with the abundance of Clostridiales in human rectal mucosal biopsies. Our data identify the NLRP1 inflammasome to be a key negative regulator of protective, butyrate-producing commensals, which therefore promotes inflammatory bowel disease.
Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank ...participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 × 10
). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.
Background and Aim: Anti‐tumor‐necrosis‐factor‐alpha (anti‐TNF‐α) medications are effective in inflammatory bowel disease (IBD), but have an increased risk of tuberculosis (TB) and serious ...infections. The aim of this study was to examine the Australian/New Zealand experience of serious infections and TB in IBD patients receiving anti‐TNF‐α therapy from 1999–2009.
Methods: Serious infections, defined as ‘requiring hospital admission’ and TB cases in patients receiving, or within 3 months following, anti‐TNF‐α therapy were analyzed across Australia and New Zealand. Patient demographics, IBD medications, duration of anti‐TNF‐α therapy, and infection details were collected.
Results: A total of 5562 IBD patients were managed across the centers. Of these, 489 (16.8%) Crohn's disease and 137 (5.2%) ulcerative colitis patients received anti‐TNF‐α therapy. There were three cases of latent TB that received prophylaxis prior to anti‐TNF‐α therapy. No cases of active TB were reported. Fourteen (2.2%) serious infections occurred. Seven occurred in patients receiving anti‐TNF‐α therapy for less than 6 months, including two cases of primary Varicella zoster (VZV), two cases of Pneumocystis jiroveci pneumonia, two cases of Staphylococcus aureus bacteremia, and one severe flu‐like illness. Six patients were taking additional immunosuppressive medications. The other seven infections occurred after 6 months (mean 32.6 ± 24.3 months) and included one case of primary VZV, one flu‐like illness, and five bacterial infections. All infections resolved with treatment.
Conclusion: TB is a very rare complication of anti‐TNF‐α therapy in Australia and New Zealand. Serious infections are uncommon but early opportunistic infections with Pneumocystis jiroveci pneumonia suggest a need for vigilance in patients on multiple immunosuppressive medications. VZV vaccination prior to immunosuppressive therapy should be considered in VZV‐naïve patients.
Predicting risk of disease from genotypes is being increasingly proposed for a variety of diagnostic and prognostic purposes. Genome-wide association studies (GWAS) have identified a large number of ...genome-wide significant susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC), two subtypes of inflammatory bowel disease (IBD). Recent studies have demonstrated that including only loci that are significantly associated with disease in the prediction model has low predictive power and that power can substantially be improved using a polygenic approach.
We performed a comprehensive analysis of risk prediction models using large case-control cohorts genotyped for 909,763 GWAS SNPs or 123,437 SNPs on the custom designed Immunochip using four prediction methods (polygenic score, best linear genomic prediction, elastic-net regularization and a Bayesian mixture model). We used the area under the curve (AUC) to assess prediction performance for discovery populations with different sample sizes and number of SNPs within cross-validation.
On average, the Bayesian mixture approach had the best prediction performance. Using cross-validation we found little differences in prediction performance between GWAS and Immunochip, despite the GWAS array providing a 10 times larger effective genome-wide coverage. The prediction performance using Immunochip is largely due to the power of the initial GWAS for its marker selection and its low cost that enabled larger sample sizes. The predictive ability of the genomic risk score based on Immunochip was replicated in external data, with AUC of 0.75 for CD and 0.70 for UC. CD patients with higher risk scores demonstrated clinical characteristics typically associated with a more severe disease course including ileal location and earlier age at diagnosis.
Our analyses demonstrate that the power of genomic risk prediction for IBD is mainly due to strongly associated SNPs with considerable effect sizes. Additional SNPs that are only tagged by high-density GWAS arrays and low or rare-variants over-represented in the high-density region on the Immunochip contribute little to prediction accuracy. Although a quantitative assessment of IBD risk for an individual is not currently possible, we show sufficient power of genomic risk scores to stratify IBD risk among individuals at diagnosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Epithelial damage and loss of intestinal barrier function are hallmark pathologies of the mucosal inflammation associated with conditions such as inflammatory bowel disease. In order to resolve ...inflammation and restore intestinal integrity the mucosa must rapidly and effectively repair the epithelial barrier. Epithelial wound healing is a highly complex and co-ordinated process and the factors involved in initiating intestinal epithelial healing are poorly defined. In order for restitution to be successful there must be a balance between epithelial cell migration, proliferation, and differentiation within and adjacent to the inflamed area. Endogenous, compensatory epithelial signaling pathways are activated by the changes in oxygen tensions that accompany inflammation. These signaling pathways induce the activation of key transcription factors, governing anti-apoptotic, and proliferative processes resulting in epithelial cell survival, proliferation, and differentiation at the site of mucosal inflammation. In this review, we will discuss the primary processes involved in epithelial restitution with a focus on the role of hypoxia-inducible factor and epithelial integrins as mediators of epithelial repair following inflammatory injury at the mucosal surface.
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