Smad7 and Colorectal Carcinogenesis: A Double-Edged Sword

Colorectal carcinogenesis is a complex process in which many immune and non-immune cells and a huge number of mediators are involved. Among these latter factors, Smad7, an inhibitor of the transforming growth factor (TGF)-β1 signaling that has been involved in the amplification of the inflammatory process sustaining chronic intestinal inflammation, is supposed to make a valid contribution to the growth and survival of colorectal cancer (CRC) cells. Smad7 is over-expressed by tumoral cells in both sporadic CRC and colitis-associated CRC, where it sustains neoplastic processes through activation of either TGFβ-dependent or non-dependent pathways. Consistently, genome-wide association studies have identified single nucleotide polymorphisms of the Smad7 gene associated with CRC and shown that either amplification or deletion of the Smad7 gene associates with a poor prognosis or better outcome, respectively. On the other hand, there is evidence that over-expression of Smad7 in immune cells infiltrating the inflamed gut of patients with inflammatory bowel disease can elicit anti-tumor responses, with the down-stream effect of attenuating CRC cell growth. Taken together, these observations suggest a double role of Smad7 in colorectal carcinogenesis, which probably depends on the cell subset and the biological context analyzed. In this review, we summarize the available evidences about the role of Smad7 in both sporadic and colitis-associated CRC.

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Analysis of Candidate Genes in Occurrence and Growth of Colorectal Adenomas

Journal of Oncology ◽

10.1155/2009/306786 ◽

2009 ◽

Vol 2009 ◽

pp. 1-9 ◽

Cited By ~ 2

Author(s):

Sylviane Olschwang ◽

Déwi Vernerey ◽

Vanessa Cottet ◽

Alexandre Pariente ◽

Bernard Nalet ◽

...

Keyword(s):

Association Studies ◽

Geographic Origin ◽

Colorectal Adenomas ◽

Colorectal Carcinogenesis ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Colorectal Tumorigenesis ◽

Exact Test ◽

Biologically Relevant ◽

Set Up

Predisposition to sporadic colorectal tumours is influenced by genes with minor phenotypic effects. A case-control study was set up on 295 patients treated for a large adenoma matched with polyp-free individuals on gender, age, and geographic origin in a 1 : 2 proportion. A second group of 302 patients treated for a small adenoma was also characterized to distinguish effects on adenoma occurrence and growth. We focussed the study on 38 single nucleotide polymorphisms (SNPs) encompassing 14 genes involved in colorectal carcinogenesis. Effect of SNPs was tested using unconditional logistic regression. Comparisons were made for haplotypes within a given gene and for biologically relevant genes combinations using the combination test. TheAPCp.Glu1317Gly variant appeared to influence the adenoma growth (P=.04, exact test) but not its occurrence. This result needs to be replicated and genome-wide association studies may be necessary to fully identify low-penetrance alleles involved in early stages of colorectal tumorigenesis.

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The Role of SNP Interactions when Determining Independence of Novel Signals in Genetic Association Studies—An Application to ARG1 and Bronchodilator Response

Journal of Personalized Medicine ◽

10.3390/jpm11020145 ◽

2021 ◽

Vol 11 (2) ◽

pp. 145

Author(s):

Ryan Walsh ◽

Kirsten Voorhies ◽

Merry-Lynn McDonald ◽

Michael McGeachie ◽

Joanne E. Sordillo ◽

...

Keyword(s):

Genetic Association ◽

Association Studies ◽

Critical Role ◽

Genetic Association Studies ◽

Genome Wide Association Studies ◽

The Novel ◽

Simulation Studies ◽

Nucleotide Polymorphisms ◽

Bronchodilator Response

Genome-wide association studies (GWAS) play a critical role in identifying many loci for common diseases and traits. There has been a rapid increase in the number of GWAS over the past decade. As additional GWAS are being conducted, it is unclear whether a novel signal associated with the trait of interest is independent of single nucleotide polymorphisms (SNPs) in the same region that has been previously associated with the trait of interest. The general approach to determining whether the novel association is independent of previous signals is to examine the association of the novel SNP with the trait of interest conditional on the previously identified SNP and/or calculate linkage disequilibrium (LD) between the two SNPs. However, the role of epistasis and SNP by SNP interactions are rarely considered. Through simulation studies, we examined the role of SNP by SNP interactions when determining the independence of two genetic association signals. We have created an R package on Github called gxgRC to generate these simulation studies based on user input. In genetic association studies of asthma, we considered the role of SNP by SNP interactions when determining independence of signals for SNPs in the ARG1 gene and bronchodilator response.

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The role of polymorphic ERAP1 in autoinflammatory disease

Bioscience Reports ◽

10.1042/bsr20171503 ◽

2018 ◽

Vol 38 (4) ◽

Cited By ~ 15

Author(s):

Emma Reeves ◽

Edward James

Keyword(s):

Single Nucleotide Polymorphisms ◽

Autoinflammatory Disease ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Single Nucleotide ◽

Cell Functions ◽

The Impact

Autoimmune and autoinflammatory conditions represent a group of disorders characterized by self-directed tissue damage due to aberrant changes in innate and adaptive immune responses. These disorders possess widely varying clinical phenotypes and etiology; however, they share a number of similarities in genetic associations and environmental influences. Whilst the pathogenic mechanisms of disease remain poorly understood, genome wide association studies (GWAS) have implicated a number of genetic loci that are shared between several autoimmune and autoinflammatory conditions. Association of particular HLA alleles with disease susceptibility represents one of the strongest genetic associations. Furthermore, recent GWAS findings reveal strong associations with single nucleotide polymorphisms in the endoplasmic reticulum aminopeptidase 1 (ERAP1) gene and susceptibility to a number of these HLA-associated conditions. ERAP1 plays a major role in regulating the repertoire of peptides presented on HLA class I alleles at the cell surface, with the presence of single nucleotide polymorphisms in ERAP1 having a significant impact on peptide processing function and the repertoire of peptides presented. The impact of this dysfunctional peptide generation on CD8+ T-cell responses has been proposed as a mechanism of pathogenesis diseases where HLA and ERAP1 are associated. More recently, studies have highlighted a role for ERAP1 in innate immune-mediated pathways involved in inflammatory responses. Here, we discuss the role of polymorphic ERAP1 in various immune cell functions, and in the context of autoimmune and autoinflammatory disease pathogenesis.

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Association Analysis of Genetic Variants with Type 2 Diabetes in a Mongolian Population in China

Journal of Diabetes Research ◽

10.1155/2015/613236 ◽

2015 ◽

Vol 2015 ◽

pp. 1-7 ◽

Cited By ~ 11

Author(s):

Haihua Bai ◽

Haiping Liu ◽

Suyalatu Suyalatu ◽

Xiaosen Guo ◽

Shandan Chu ◽

...

Keyword(s):

Type 2 Diabetes ◽

Large Scale ◽

Risk Allele ◽

Association Studies ◽

Northern China ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Genome Wide

The large scale genome wide association studies (GWAS) have identified approximately 80 single nucleotide polymorphisms (SNPs) conferring susceptibility to type 2 diabetes (T2D). However, most of these loci have not been replicated in diverse populations and much genetic heterogeneity has been observed across ethnic groups. We tested 28 SNPs previously found to be associated with T2D by GWAS in a Mongolian sample of Northern China (497 diagnosed with T2D and 469 controls) for association with T2D and diabetes related quantitative traits. We replicated T2D association of 11 SNPs, namely, rs7578326 (IRS1), rs1531343 (HMGA2), rs8042680 (PRC1), rs7578597 (THADA), rs1333051 (CDKN2), rs6723108 (TMEM163), rs163182 and rs2237897 (KCNQ1), rs1387153 (MTNR1B), rs243021 (BCL11A), and rs10229583 (PAX4) in our sample. Further, we showed that risk allele of the strongest T2D associated SNP in our sample, rs757832 (IRS1), is associated with increased level of TG. We observed substantial difference of T2D risk allele frequency between the Mongolian sample and the 1000G Caucasian sample for a few SNPs, including rs6723108 (TMEM163) whose risk allele reaches near fixation in the Mongolian sample. Further study of genetic architecture of these variants in susceptibility of T2D is needed to understand the role of these variants in heterogeneous populations.

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TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation

Molecular Neurodegeneration ◽

10.1186/s13024-021-00436-5 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Lorenza Magno ◽

Tom D. Bunney ◽

Emma Mead ◽

Fredrik Svensson ◽

Magda N. Bictash

Keyword(s):

Immune Cells ◽

Association Studies ◽

Innate Immune ◽

Genome Wide Association Studies ◽

Gene Products ◽

The Past ◽

Genome Wide ◽

The Brain ◽

Insight Into

AbstractThe central role of the resident innate immune cells of the brain (microglia) in neurodegeneration has become clear over the past few years largely through genome-wide association studies (GWAS), and has rapidly become an active area of research. However, a mechanistic understanding (gene to function) has lagged behind. That is now beginning to change, as exemplified by a number of recent exciting and important reports that provide insight into the function of two key gene products – TREM2 (Triggering Receptor Expressed On Myeloid Cells 2) and PLCγ2 (Phospholipase C gamma2) – in microglia, and their role in neurodegenerative disorders. In this review we explore and discuss these recent advances and the opportunities that they may provide for the development of new therapies.

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Lessons in IBD Pathogenesis from New Animal Models of Spontaneous Colitis

Canadian Journal of Gastroenterology ◽

10.1155/1995/491264 ◽

1995 ◽

Vol 9 (6) ◽

pp. 309-315 ◽

Cited By ~ 1

Author(s):

R Balfour Sartor

Keyword(s):

T Cell ◽

B Cells ◽

Animal Models ◽

Transforming Growth Factor ◽

Intestinal Inflammation ◽

Cell Subset ◽

T Cell Subsets ◽

Hla B27 ◽

Transgenic Rats ◽

Chronic Intestinal Inflammation

The recent explosion of transgenic and targeted gene deleted (knockout [KO]) rodents has yielded a number of new animal models of spontaneous, chronic intestinal inflammation that have provided novel insights into the pathogenesis of human inflammatory bowel disease (IBD). Spontaneous colitis resulting from deletion of genes encoding key immunoregulatory cytokines (interleukin [IL]-2, IL-10 and transforming growth factor [TGF]-beta) and T cell receptors (TCRs) demonstrates that an intact mucosal immune response prevents colitis. The TCR KO model incriminates B lymphocytes in spontaneous colonic inflammation – TCR KO with intact B cells causes colitis, but simultaneous deletion of T and B cells does not. This model and induction of colitis in severe combined immunodeficient (SCID) mice by constitution with one T cell subset (CD45RHhi), but prevention by addition of the CD45RBlosubset, strongly suggest that T cell subsets down-regulate inflammation in the normal, immunocompetent host. An essential role for normal luminal bacteria in induction and perpetuation of enterocolitis is provided by the absence of chronic intestinal inflammation in germ-free (sterile) IL-2 KO mice and human leukocyte antigen (HLA)-B27 transgenic rats, and attenuated inflammation in IL-2 and IL-10 KO mice raised under specific pathogen-free conditions. The fundamental role of host genetic susceptibility in chronic intestinal inflammation and systemic manifestations is established by development of spontaneous colitis and perianal inflammation in C3H/HeJ Bir substrain mice and HLA-B27 transgenic rats.

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Does Chronic Intestinal Inflammation Promote Atrial Fibrillation: A Mendelian Randomization Study With Populations of European Ancestry

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.641291 ◽

2021 ◽

Vol 8 ◽

Author(s):

LaiTe Chen ◽

ChenYang Jiang

Keyword(s):

Atrial Fibrillation ◽

Causal Inference ◽

Mendelian Randomization ◽

Intestinal Inflammation ◽

Causal Role ◽

European Ancestry ◽

Genome Wide Association Studies ◽

Weighted Median ◽

Chronic Intestinal Inflammation

Background: Inflammatory bowel disease (IBD), comprising ulcerative colitis (UC), and Crohn's disease (CD), has been reported to be associated with an increased risk of atrial fibrillation (AF). However, the causal role of the chronic intestinal inflammation (CII) in the development of AF remains controversial. We use Mendelian randomization (MR) analysis to explore the causal inference of CII on AF.Methods: A two-sample MR analysis was performed to estimate the potential causal effect of CII on AF. Statistical summaries for the associations between single nucleotide polymorphisms (SNPs) and phenotypes of CII were obtained from genome-wide association studies (GWAS) with cohorts of CD (n = 51,874), UC (n = 47,745), and IBD (n = 65,642) of European descent. The GWAS of 1,030,836 people of European ancestry, including 60,620 AF cases and 970,216 controls was collected to identify genetic variants underlying AF. The causal inference was estimated using the multiplicative random effects inverse-variance weighted method (IVW). The methods of MR-Egger, simple median, and weighted median were also employed to avoid the bias of pleiotropy effects.Results: Using three sets of SNPs (75 SNPs of CD, 60 SNPs of UC, and 95 SNPs of IBD), multiplicative random-effect IVW model estimated a universal null effect of CII on AF (CD: OR = 1.0059, 95% CI: 0.9900, 1.0220, p = 0.47; UC: OR = 1.0087, 95% CI: 0.9896, 1.0281, p = 0.38; IBD: OR = 1.0080, 95% CI: 0.9908, 1.0255, p = 0.37). Similar results were observed using the MR-Egger, simple median, weighted median methods.Conclusion: As opposing to the traditional observational studies, our two-sample MR analysis did not find enough evidence to support a causal role of either CD or UC in the development of AF.

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Altered gene regulation as a candidate mechanism by which ciliopathy gene SDCCAG8 contributes to schizophrenia and cognitive function

Human Molecular Genetics ◽

10.1093/hmg/ddz292 ◽

2019 ◽

Vol 29 (3) ◽

pp. 407-417

Author(s):

Mairéad Flynn ◽

Laura Whitton ◽

Gary Donohoe ◽

Ciaran G Morrison ◽

Derek W Morris

Keyword(s):

Gene Regulation ◽

Association Studies ◽

Cell Signalling ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Phenotypic Analysis ◽

Genome Wide ◽

Dependent Cell ◽

Altered Gene

Abstract Mutations in genes that encode centrosomal/ciliary proteins cause severe cognitive deficits, while common single-nucleotide polymorphisms in these genes are associated with schizophrenia (SZ) and cognition in genome-wide association studies. The role of these genes in neuropsychiatric disorders is unknown. The ciliopathy gene SDCCAG8 is associated with SZ and educational attainment (EA). Genome editing of SDCCAG8 caused defects in primary ciliogenesis and cilium-dependent cell signalling. Transcriptomic analysis of SDCCAG8-deficient cells identified differentially expressed genes that are enriched in neurodevelopmental processes such as generation of neurons and synapse organization. These processes are enriched for genes associated with SZ, human intelligence (IQ) and EA. Phenotypic analysis of SDCCAG8-deficent neuronal cells revealed impaired migration and neuronal differentiation. These data implicate ciliary signalling in the aetiology of SZ and cognitive dysfunction. We found that centrosomal/ciliary genes are enriched for association with IQ, suggesting altered gene regulation as a general model for neurodevelopmental impacts of centrosomal/ciliary genes.

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The Role of ABCG2 in the Pathogenesis of Primary Hyperuricemia and Gout—An Update

International Journal of Molecular Sciences ◽

10.3390/ijms22136678 ◽

2021 ◽

Vol 22 (13) ◽

pp. 6678

Author(s):

Robert Eckenstaler ◽

Ralf A. Benndorf

Keyword(s):

Early Onset ◽

Association Studies ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Genome Wide ◽

Functional Analyses ◽

Urate Reabsorption ◽

Shed Light

Urate homeostasis in humans is a complex and highly heritable process that involves i.e., metabolic urate biosynthesis, renal urate reabsorption, as well as renal and extrarenal urate excretion. Importantly, disturbances in urate excretion are a common cause of hyperuricemia and gout. The majority of urate is eliminated by glomerular filtration in the kidney followed by an, as yet, not fully elucidated interplay of multiple transporters involved in the reabsorption or excretion of urate in the succeeding segments of the nephron. In this context, genome-wide association studies and subsequent functional analyses have identified the ATP-binding cassette (ABC) transporter ABCG2 as an important urate transporter and have highlighted the role of single nucleotide polymorphisms (SNPs) in the pathogenesis of reduced cellular urate efflux, hyperuricemia, and early-onset gout. Recent publications also suggest that ABCG2 is particularly involved in intestinal urate elimination and thus may represent an interesting new target for pharmacotherapeutic intervention in hyperuricemia and gout. In this review, we specifically address the involvement of ABCG2 in renal and extrarenal urate elimination. In addition, we will shed light on newly identified polymorphisms in ABCG2 associated with early-onset gout.

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The current review of adolescent obesity: the role of genetic factors

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0480 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Birsen Yılmaz ◽

Makbule Gezmen Karadağ

Keyword(s):

Genetic Factors ◽

Association Studies ◽

Genome Wide Association ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Heterogeneous Condition ◽

Current Review ◽

Genome Wide

AbstractObesity, a complex, multi-factor and heterogeneous condition, is thought to result from the interaction of environmental and genetic factors. Considering the result of adolescence obesity in adulthood, the role of genetic factors comes to the fore. Recently, many genome-wide association studies (GWAS) have been conducted and many loci associated with adiposity have been identified. In adolescents, the strongest association with obesity has been found in single nucleotide polymorphisms (SNP) in the FTO gene. Besides FTO, GWAS showed consistent effects between variants in MC4R, TMEM18, TNNI3K, SEC16B, GNPDA2, POMC and obesity. However, these variants may not have similar effects for all ethnic groups. Although recently genetic factors are considered to contribute to obesity, relatively little is known about the specific loci related to obesity and the mechanisms by which they cause obesity.

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