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Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease.

ABSTRACT: Tumor necrosis factor (TNF) alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th) 17 pathway.

SUBMITTER: Prieto-Perez R

PROVIDER: S-EPMC4783957 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease.

Prieto-Pérez Rocío R Almoguera Berta B Cabaleiro Teresa T Hakonarson Hakon H Abad-Santos Francisco F

International journal of molecular sciences 20160206 2

Tumor necrosis factor (TNF) alpha is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained shoul ...[more]

PMID: 26861312

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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.

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.

Dataset Information

Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease.

Publications

Association between Genetic Polymorphisms and Response to Anti-TNFs in Patients with Inflammatory Bowel Disease.

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