Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease.
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ABSTRACT:
SUBMITTER: Prieto-Perez R
PROVIDER: S-EPMC4783957 | biostudies-literature | 2016 Feb
REPOSITORIES: biostudies-literature
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Project description:The use of biological drugs has improved outcomes in pediatric inflammatory bowel disease (IBD). Prediction of the response to biological drugs would be extremely useful in IBD, and even more so in children, who are still growing physically and psychologically. Specific clinical, biochemical, and genetic parameters are considered predictive of response to biological drugs, although few studies have been carried out in children with IBD. In this review, we present current evidence on biological treatments used in pediatric IBD and the available biomarkers of response. We examine demographics, clinical characteristics, biomarkers (genetic, genomic, and cellular), and microbiota.
| S-EPMC8617733 | biostudies-literature
Project description:AimTo study the association of apolipoprotein E (APOE) polymorphisms with the susceptibility of inflammatory bowel disease (IBD) in Saudi patients.MethodsAPOE genotyping was performed to evaluate the allele and genotype frequencies in 378 Saudi subjects including IBD patients with ulcerative colitis (n = 84) or Crohn's disease (n = 94) and matched controls (n = 200) using polymerase chain reaction and reverse-hybridization techniques.ResultsThe frequencies of the APOE ε2 allele and ε2/ε3 and ε2/ε4 genotypes were significantly higher in IBD patients than in controls (P < 0.05), suggesting that the ε2 allele and its heterozygous genotypes may increase the susceptibility to IBD. On the contrary, the frequencies of the ε3 allele and ε3/ε3 genotype were lower in IBD patients as compared to controls, suggesting a protective effect of APOE ε3 for IBD. The prevalence of the ε4 allele was also higher in the patient group compared to controls, suggesting that the ε4 allele may also increase the risk of IBD. Our results also indicated that the APOE ε4 allele was associated with an early age of IBD onset. No effect of gender or type of IBD (familial or sporadic) on the frequency distribution of APOE alleles and genotypes was noticed in this study.ConclusionAPOE polymorphism is associated with risk of developing IBD and early age of onset in Saudi patients, though further studies with a large-size population are warranted.
| S-EPMC4299342 | biostudies-literature
Project description:Inflammation is the driving force in inflammatory bowel disease (IBD) and its link to oxidative stress and carcinogenesis has long been accepted. The antioxidant system of the intestinal mucosa in IBD is compromised resulting in increased oxidative injury. This defective antioxidant system may be the result of genetic variants in antioxidant genes, which can represent susceptibility factors for IBD, namely Crohn's disease (CD) and ulcerative colitis (UC). Single nucleotide polymorphisms (SNPs) in the antioxidant genes SOD2 (rs4880) and GPX1 (rs1050450) were genotyped in a Portuguese population comprising 436 Crohn's disease and 367 ulcerative colitis patients, and 434 healthy controls. We found that the AA genotype in GPX1 is associated with ulcerative colitis (OR = 1.93, adjusted P-value = 0.037). Moreover, we found nominal significant associations between SOD2 and Crohn's disease susceptibility and disease subphenotypes but these did not withstand the correction for multiple testing. These findings indicate a possible link between disease phenotypes and antioxidant genes. These results suggest a potential role for antioxidant genes in IBD pathogenesis and should be considered in future association studies.
| S-EPMC5215755 | biostudies-literature
Project description:BackgroundMyeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immunity, playing a major role in orchestrating innate and adaptive immune responses. Microglia are the resident myeloid cells of the central nervous system, and many Alzheimer's disease (AD) risk loci are found in or near genes that are highly or sometimes uniquely expressed in myeloid cells. Similarly, inflammatory bowel disease (IBD) loci are also enriched for genes expressed by myeloid cells. However, the extent to which there is overlap between the effects of AD and IBD susceptibility loci in myeloid cells remains poorly described, and the substantial IBD genetic maps may help to accelerate AD research.MethodsHere, we leveraged summary statistics from large-scale genome-wide association studies (GWAS) to investigate the causal effect of IBD (including ulcerative colitis and Crohn's disease) variants on AD and AD endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD risk variants enrichment in two different myeloid cell subtypes.ResultsOur results showed that, while PTK2B is implicated in both diseases and both sets of risk loci are enriched for myeloid genes, AD and IBD susceptibility loci largely implicate distinct sets of genes and pathways. AD loci are significantly more enriched for microglial eQTLs than IBD. We also found that genetically determined IBD is associated with a lower risk of AD, which may driven by a negative effect on the accumulation of neurofibrillary tangles (beta=-1.04, p=0.013). In addition, IBD displayed a significant positive genetic correlation with psychiatric disorders and multiple sclerosis, while AD showed a significant positive genetic correlation with amyotrophic lateral sclerosis.ConclusionTo our knowledge, this is the first study to systematically contrast the genetic association between IBD and AD, our findings highlight a possible genetically protective effect of IBD on AD even if the majority of effects on myeloid cell gene expression by the two sets of disease variants are distinct. Thus, IBD myeloid studies may not help to accelerate AD functional studies, but our observation reinforces the role of myeloid cells in the accumulation of tau proteinopathy and provides a new avenue for discovering a protective factor.
| S-EPMC10153331 | biostudies-literature
Project description:OBJECTIVES:In patients with inflammatory bowel disease (IBD) using biological therapy, non-adherence leads to anti-drug antibody formation and reduced effectiveness. Little is known about the optimal level of adherence in IBD patients on biologic therapy. We aimed to identify the association between adherence and disease flare and determine an optimal level of adherence. METHODS:We analyzed claims data for IBD patients prescribed adalimumab (ADA) and certolizumab (CZP) from the Truven Health MarketScan Commercial Claims and Encounters database from 2009 to 2013. Adherence was calculated using the medication possession ratio (MPR) from initiation until flare occurrence. A disease flare was defined as any hospitalization or new steroid prescription>90-days after drug initiation. The optimal MPR was determined using log-rank testing. The association between the optimal MPR and flare was assessed using multivariable Cox-Proportional hazards ratio. RESULTS:There were 6,048 patients who were prescribed ADA (n=5,325) or CZP (n=723) for IBD. The average age was 41 years (±15) and 54% were female. The optimal MPR identified was 0.86 for ADA and 0.87 for CZP; 24% of the patients were below this level. Adjusting for age, gender, and concomitant medications at initiation, patients who were adherent above these levels had a 25% lower risk of flare for ADA (HR: 0.75, 95%CI: 0.67-0.83, P<0.01) and 41% lower risk for CZP (HR: 0.59, 95%CI: 0.46-0.76, P<0.01). CONCLUSIONS:Patients who delay refills >2 days on average every 2 weeks of their subcutaneous biologics have significantly increased risk of flare. Further studies to improve adherence among those patients who consistently delay medication use are necessary.
| S-EPMC5931803 | biostudies-literature
Project description:Cigarette smoking is a well-established environmental risk factor for Crohn's disease (CD) and ulcerative colitis (UC). The exact mechanism of its effect remains unexplained. Genetic polymorphisms in metabolizing enzymes may influence susceptibility to the effect of smoking and shed light on its mechanism of action.We used a prospective cohort of patients with CD, UC, and healthy controls. Smoking status was defined as current, former, or never smoking. Patients were genotyped for polymorphisms in CYP2A6, glutathione transferase enzymes (GSTP1 and GSTM1), NAD(P)H quinone oxidoreductase (NQO), and heme oxygenase 1 using a Sequenom platform. Multivariate logistic regression models with CD or UC as the outcome, stratified by genotype, were developed and interaction P-values calculated.Our study included 634 patients with CD, 401 with UC, and 337 healthy controls. Ever smokers had an increased risk of CD (odds ratio = 3.88, 95% confidence interval = 2.35-6.39) compared with nonsmokers among patients with AG/AA genotypes at CYP2A6. However, ever smoking was not associated with CD among patients with the AA genotype (Pinteraction = 0.001). Former smoking was associated with an increased risk for UC only in the presence of GG/AG genotypes for GSTP1 but not in those with the AA genotype (Pinteraction = 0.012). Polymorphisms at the NQO and HMOX loci did not demonstrate a statistically significant interaction with smoking and risk of CD or UC.Genetic polymorphisms in metabolizing enzymes may influence the association between smoking and CD and UC. Further studies of gene-environment interaction in inflammatory bowel disease are warranted.
| S-EPMC4113010 | biostudies-literature
Project description:To date, the utility of single genetic markers to improve disease risk assessment still explains only a small proportion of genetic variance for many complex diseases. This missing heritability may be explained by additional variants with weak effects. To discover and incorporate these additional genetic factors, statistical and computational methods must be evaluated and developed. We develop a multi-locus genetic risk score (GRS) based approach to analyze genes in NADPH oxidase complex which may result in susceptibility to development of inflammatory bowel disease (IBD). We find the complex is highly associated with IBD (P = 7.86 × 10(-14)) using the GRS-based association method. Similar results are also shown in permutation analysis (P = 6.65 × 10(-11)). Likelihood ratio test shows that the single nucleotide polymorphisms (SNPs) in the complex without nominal signals have significant contribution to the overall genetic effect within the complex (P = 0.015). Our results show that the multi-locus GRS association model can improve the genetic risk assessment on IBD by taking into account both confirmed and as yet unconfirmed disease susceptibility variants.
| S-EPMC3662393 | biostudies-literature
Project description:BackgroundRecent evidence suggests that the IL-33/IL1RL1 axis plays a critical role in several autoimmune and inflammatory disorders; however, its mechanistic role in inflammatory bowel disease (IBD) has not been clearly defined. We investigated the contribution of IL-33 and IL1RL1 polymorphisms to IBD risk, and possible correlations with phenotype in an Italian cohort of adult and pediatric patients.MethodsWe evaluated the association of six SNPs in IL-33 and IL1RL1 genes, in 805 Crohn's disease (CD), 816 ulcerative colitis (UC), and 752 controls, using Taqman. IL-33 and IL1RL1 mRNA expression was also analyzed.ResultsSignificant allele and genotype associations with IL-33 rs3939286 were found in CD (P = 0.004; P = 0.035) and UC patients (P = 0.002; P = 0.038). After stratifying the cohort for age at diagnosis, the differences remained significant only in the IBD adult-onset. Significant associations were also obtained in CD patients with two IL1RL1 polymorphisms (rs13015714 and rs2058660, P<0.015). By combining homo- and heterozygous carriers of the rs13015714 risk allele, differences were still significant for both CD adult- and pediatric-onset. Upon genotype-phenotype evaluation, an increased frequency of extensive colitis in adult UC (P = 0.019) and in steroid-responsive pediatric patients (P = 0.024) carrying the IL-33 rs3939286 risk genotype, was observed. mRNA expression of IL-33 and IL1RL1 in inflamed IBD biopsy samples was significantly increased.ConclusionsCommon IL-33 and IL1RL1 polymorphisms contribute to the risk of IBD in an Italian cohort of adult and pediatric patients, with some influence on sub-phenotypes.
| S-EPMC3636262 | biostudies-literature
Project description:Parkinson's disease and inflammatory bowel disease have been increasingly associated, implying shared pathophysiology. To explore biological explanations for the reported connection, we leveraged summary statistics of updated genome-wide association studies and characterized the genetic overlap between the two diseases. Aggregated genetic association data were available for 37 688 cases versus 981 372 controls for Parkinson's disease and 25 042 cases versus 34 915 controls for inflammatory bowel disease. Genetic correlation was estimated with the high-definition likelihood method. Genetic variants with joint association to both diseases were identified by conditional false discovery rate framework and further annotated to reveal shared loci, genes, and enriched pathways. For both Crohn's disease and ulcerative colitis, the two main subtypes of inflammatory bowel disease, we detected weak but statistically significant genetic correlations with Parkinson's disease (Crohn's disease: rg = 0.06, P = 0.01; ulcerative colitis: rg = 0.06, P = 0.03). A total of 1290 variants in 27 independent genomic loci were detected to associate with Parkinson's disease and Crohn's disease at conjunctional false discovery rate under 0.01 and 1359 variants in 15 loci were pleiotropic to Parkinson's disease and ulcerative colitis. Among the identified pleiotropic loci, 23 are novel and have never been associated with both phenotypes. A mixture of loci conferring either same or opposing genetic effects on two phenotypes was also observed. Positional and expression quantitative trait loci mapping prioritized 296 and 253 genes for Parkinson's disease with Crohn's disease and ulcerative colitis, respectively, among which only <10% are differentially expressed in both colon and substantia nigra. These genes were identified to overrepresent in pathways regulating gene expression and post-translational modification beyond several immune-related pathways enriched by major histocompatibility complex genes. In conclusion, we found robust evidence for a genetic link between Parkinson's disease and inflammatory bowel disease. The identified genetic overlap is complex at the locus and gene levels, indicating the presence of both synergistic and antagonistic pleiotropy. At the functional level, our findings implied a role of immune-centered mechanisms in the reported gut-brain connection.
| S-EPMC9847552 | biostudies-literature
Project description:IntroductionStudies suggest that nonsteroidal anti-inflammatory drugs (NSAID) may contribute to inflammatory bowel disease (IBD) exacerbations. We examined whether variation in the likelihood of IBD exacerbations is attributable to NSAID.MethodsIn a cohort of patients with IBD (2004-2015), we used 3 analytic methods to examine the likelihood of an exacerbation after an NSAID exposure. First, we matched patients by propensity for NSAID use and examined the association between NSAID exposure and IBD exacerbation using an adjusted Cox proportional hazards model. To assess for residual confounding, we estimated a previous event rate ratio and used a self-controlled case series analysis to further explore the relationship between NSAID and IBD exacerbations.ResultsWe identified 15,705 (44.8%) and 19,326 (55.2%) IBD patients with and without an NSAID exposure, respectively. Findings from the Cox proportional hazards model suggested an association between NSAID and IBD exacerbation (hazard ratio 1.24; 95% confidence interval 1.16-1.33). However, the likelihood of an IBD exacerbation in the NSAID-exposed arm preceding NSAID exposure was similar (hazard ratio 1.30; 95% confidence interval 1.21-1.39). A self-controlled case series analysis of 3,968 patients who had both an NSAID exposure and IBD exacerbation demonstrated similar exacerbation rates in the 1 year preceding exposure, 2-6 weeks postexposure, and 6 weeks to 6 months postexposure, but a higher incidence in 0-2 weeks postexposure, suggesting potential confounding by reverse causality.DiscussionWhile we see an association between NSAID and IBD exacerbations using traditional methods, further analysis suggests this may be secondary to residual bias. These findings may reassure patients and clinicians considering NSAID as a nonopioid pain management option.
| S-EPMC9714642 | biostudies-literature