scholarly journals Association of Selenoprotein and Selenium Pathway Genotypes with Risk of Colorectal Cancer and Interaction with Selenium Status

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 935 ◽  
Author(s):  
Veronika Fedirko ◽  
Mazda Jenab ◽  
Catherine Méplan ◽  
Jeb S. Jones ◽  
Wanzhe Zhu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Multiple Testing ◽  
Transforming Growth Factor ◽  
Statistical Significance ◽  
Nucleotide Polymorphisms ◽  
Tgf Beta ◽  
Significance Threshold ◽  
Individual Snps ◽  
Pathway Analyses ◽  
Se Status

Selenoprotein genetic variations and suboptimal selenium (Se) levels may contribute to the risk of colorectal cancer (CRC) development. We examined the association between CRC risk and genotype for single nucleotide polymorphisms (SNPs) in selenoprotein and Se metabolic pathway genes. Illumina Goldengate assays were designed and resulted in the genotyping of 1040 variants in 154 genes from 1420 cases and 1421 controls within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Multivariable logistic regression revealed an association of 144 individual SNPs from 63 Se pathway genes with CRC risk. However, regarding the selenoprotein genes, only TXNRD1 rs11111979 retained borderline statistical significance after adjustment for correlated tests (PACT = 0.10; PACT significance threshold was P < 0.1). SNPs in Wingless/Integrated (Wnt) and Transforming growth factor (TGF) beta-signaling genes (FRZB, SMAD3, SMAD7) from pathways affected by Se intake were also associated with CRC risk after multiple testing adjustments. Interactions with Se status (using existing serum Se and Selenoprotein P data) were tested at the SNP, gene, and pathway levels. Pathway analyses using the modified Adaptive Rank Truncated Product method suggested that genes and gene x Se status interactions in antioxidant, apoptosis, and TGF-beta signaling pathways may be associated with CRC risk. This study suggests that SNPs in the Se pathway alone or in combination with suboptimal Se status may contribute to CRC development.

scholarly journals COL4A2 is associated with lacunar ischemic stroke and deep ICH

Neurology ◽  
2017 ◽  
Vol 89 (17) ◽  
pp. 1829-1839 ◽  
Author(s):  
Kristiina Rannikmäe ◽  
Vhinoth Sivakumaran ◽  
Henry Millar ◽  
Rainer Malik ◽  
Christopher D. Anderson ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Multiple Testing ◽  
Small Vessel Disease ◽  
Statistical Significance ◽  
European Ancestry ◽  
Nucleotide Polymorphisms ◽  
Common Variants ◽  
Genetic Determinants ◽  
Vessel Disease ◽  
Significance Threshold

Objective:To determine whether common variants in familial cerebral small vessel disease (SVD) genes confer risk of sporadic cerebral SVD.Methods:We meta-analyzed genotype data from individuals of European ancestry to determine associations of common single nucleotide polymorphisms (SNPs) in 6 familial cerebral SVD genes (COL4A1, COL4A2, NOTCH3, HTRA1, TREX1, and CECR1) with intracerebral hemorrhage (ICH) (deep, lobar, all; 1,878 cases, 2,830 controls) and ischemic stroke (IS) (lacunar, cardioembolic, large vessel disease, all; 19,569 cases, 37,853 controls). We applied data quality filters and set statistical significance thresholds accounting for linkage disequilibrium and multiple testing.Results:A locus in COL4A2 was associated (significance threshold p < 3.5 × 10−4) with both lacunar IS (lead SNP rs9515201: odds ratio [OR] 1.17, 95% confidence interval [CI] 1.11–1.24, p = 6.62 × 10−8) and deep ICH (lead SNP rs4771674: OR 1.28, 95% CI 1.13–1.44, p = 5.76 × 10−5). A SNP in HTRA1 was associated (significance threshold p < 5.5 × 10−4) with lacunar IS (rs79043147: OR 1.23, 95% CI 1.10–1.37, p = 1.90 × 10−4) and less robustly with deep ICH. There was no clear evidence for association of common variants in either COL4A2 or HTRA1 with non-SVD strokes or in any of the other genes with any stroke phenotype.Conclusions:These results provide evidence of shared genetic determinants and suggest common pathophysiologic mechanisms of distinct ischemic and hemorrhagic cerebral SVD stroke phenotypes, offering new insights into the causal mechanisms of cerebral SVD.

scholarly journals Associations of Two Obesity-Related Single-Nucleotide Polymorphisms with Adiponectin in Chinese Children

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Lijun Wu ◽  
Liwang Gao ◽  
Xiaoyuan Zhao ◽  
Meixian Zhang ◽  
Jianxin Wu ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Multiple Testing ◽  
Association Studies ◽  
Statistical Significance ◽  
Additive Model ◽  
Recessive Model ◽  
Chinese Children ◽  
Genome Wide Association Studies ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Purpose. Genome-wide association studies have found two obesity-related single-nucleotide polymorphisms (SNPs), rs17782313 near the melanocortin-4 receptor (MC4R) gene and rs6265 near the brain-derived neurotrophic factor (BDNF) gene, but the associations of both SNPs with other obesity-related traits are not fully described, especially in children. The aim of the present study is to investigate the associations between the SNPs and adiponectin that has a regulatory role in glucose and lipid metabolism. Methods. We examined the associations of the SNPs with adiponectin in Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. A total of 3503 children participated in the study. Results. The SNP rs6265 was significantly associated with adiponectin under an additive model (P=0.02 and 0.024, resp.) after adjustment for age, gender, and BMI or obesity statuses. The SNP rs17782313 was significantly associated with low adiponectin under a recessive model. No statistical significance was found between the two SNPs and low adiponectin after correction for multiple testing. Conclusion. We demonstrate for the first time that the SNP rs17782313 near MC4R and the SNP rs6265 near BDNF are associated with adiponectin in Chinese children. These novel findings provide important evidence that adiponectin possibly mediates MC4R and BDNF involved in obesity.

scholarly journals The Haplotype of the TGFβ1 Gene Associated with Cerebral Infarction in Chinese

2012 ◽  
Vol 39 (5) ◽  
pp. 626-631 ◽  
Author(s):  
Hong-miao Tao ◽  
Guo-zhong Chen ◽  
Gan-ping Cheng ◽  
Xiao-yun Shan
Keyword(s):  
Cerebral Infarction ◽  
Chinese Population ◽  
Transforming Growth Factor ◽  
Additive Model ◽  
Chinese Patients ◽  
Amplification Refractory Mutation System ◽  
Strong Linkage Disequilibrium ◽  
Nucleotide Polymorphisms ◽  
Individual Snps ◽  
Increased Risk

Background:Transforming growth factor beta1 (TGFβ1) is a multifunctional cytokine involved in inflammation and pathogenesis of atherosclerosis. The aim of the present study was to investigate the relationship between human TGFβ1 gene +869T>C (rs1800470), -509C>T (rs1800469) single nucleotide polymorphisms (SNPs) and haplotypes and cerebral infarction (CI) in a Chinese population.Methods:The genetic association study was performed in 450 Chinese patients (306 male and 144 female) with CI and 450 control subjects (326 male and 124 female). TGFβ1 gene +869T>C and -509C>T polymorphisms were identified with amplification refractory mutation system polymerase chain reaction and DNA sequencing method.Results:The individual SNPs analysis showed the +869T and -509C in an additive model (+869T vs +869C; -509 C vs T), +869TT genotype in a recessive model (TT vs TC+CC) and 509CC genotype in a dominant model (CC+ CT vs TT) were identified to be related to CI (P<0.05). +869T>C and -509C>T SNPs were in strong linkage disequilibrium (d'=0.87, R2=0.75). Haplotype analysis showed that +869C/-509T haplotype was associated with a significant decreased risk of CI (OR= 0.86, 95%CI, 0.70-0.92; P=0.007). Furthermore,+869T/-509C haplotype was associated with a significant increased risk of CI (OR=1.31, 95%CI, 1.10-2.03; P=0.019).Conclusions:The results of this study indicate that polymorphisms and the haplotypes in the TGFβ1 gene might be genetic markers for CI in the Chinese population.

scholarly journals Vitamin D-Related Genes, Blood Vitamin D Levels and Colorectal Cancer Risk in Western European Populations

Nutrients ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1954 ◽  
Author(s):  
Veronika Fedirko ◽  
Hannah Mandle ◽  
Wanzhe Zhu ◽  
David Hughes ◽  
Afshan Siddiq ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Vitamin D ◽  
Multiple Testing ◽  
A Priori ◽  
Nucleotide Polymorphisms ◽  
Multiple Testing Correction ◽  
Vitamin D Metabolism ◽  
Gene Pathway ◽  
Vitamin D Levels ◽  
Large Populations

Higher circulating 25-hydroxyvitamin D levels (25(OH)D) have been found to be associated with lower risk for colorectal cancer (CRC) in prospective studies. Whether this association is modified by genetic variation in genes related to vitamin D metabolism and action has not been well studied in humans. We investigated 1307 functional and tagging single-nucleotide polymorphisms (SNPs; individually, and by gene/pathway) in 86 vitamin D-related genes in 1420 incident CRC cases matched to controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. We also evaluated the association between these SNPs and circulating 25(OH)D in a subset of controls. We confirmed previously reported CRC risk associations between SNPs in the VDR, GC, and CYP27B1 genes. We also identified additional associations with 25(OH)D, as well as CRC risk, and several potentially novel SNPs in genes related to vitamin D transport and action (LRP2, CUBN, NCOA7, and HDAC9). However, none of these SNPs were statistically significant after Benjamini–Hochberg (BH) multiple testing correction. When assessed by a priori defined functional pathways, tumor growth factor β (TGFβ) signaling was associated with CRC risk (P ≤ 0.001), with most statistically significant genes being SMAD7 (PBH = 0.008) and SMAD3 (PBH = 0.008), and 18 SNPs in the vitamin D receptor (VDR) binding sites (P = 0.036). The 25(OH)D-gene pathway analysis suggested that genetic variants in the genes related to VDR complex formation and transcriptional activity are associated with CRC depending on 25(OH)D levels (interaction P = 0.041). Additional studies in large populations and consortia, especially with measured circulating 25(OH)D, are needed to confirm our findings.

Association analysis of polymorphisms in genes related to sunitinib pharmacokinetics.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4580-4580
Author(s):  
Meta Diekstra ◽  
Heinz Josef Klümpen ◽  
Martijn P. J. K. Lolkema ◽  
Huixin Yu ◽  
Jacqueline S.L. Kloth ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Plasma Concentrations ◽  
Significant Snps ◽  
Population Pharmacokinetic ◽  
Nucleotide Polymorphisms ◽  
Replication Studies ◽  
Significance Threshold ◽  
Potential Association ◽  
Individual Snps ◽  
Genes Encoding

4580 Background: Sunitinib is approved as systemic therapy for mRCC, GIST and pNET. Interpatient variability in the pharmacokinetics (PK) of sunitinib is high, which may have serious consequences for efficacy and toxicity of the drug. The objective of this study was to evaluate whether polymorphisms in candidate genes involved in sunitinib metabolism are related to the PK of sunitinib and its active metabolite SU12662. Methods: In this multicenter study, steady state sunitinib plasma concentrations and genotypes were prospectively obtained from 115 patients. Single nucleotide polymorphisms (SNPs) and haplotypes in 8 genes encoding CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3, and PORwere evaluated as covariates in a population pharmacokinetic model describing both sunitinib and SU12662 PK using NONMEM. First, candidate genotypes/haplotypes were individually tested for a potential association with sunitinib or SU12662 clearance. Next, potential significant SNPs (p<0.05) were simultaneously included in a multivariate model and tested by backward elimination with a significance threshold of p<0.0005. Results: Four out of 37 screened genotypes (from 14 different SNPs) were related to sunitinib clearance (CYP3A4*22 CC and CT, CYP3A5*3 GG, and ABCB1 (2677 TT)). CYP3A5*3 AG genotype was associated with clearance of SU12662. In the multivariate analysis, none of the SNPs reached the predefined significance threshold of p<0.0005. Nevertheless, CYP3A4*22T allele carriers showed a 22.5% decreased clearance of sunitinib (p<0.01). Conclusions: Our data suggest that individual SNPs or haplotypes in CYP1A1, CYP3A4, CYP3A5, ABCB1, ABCG2, NR1I2, NR1I3 and POR are not clearly associated with sunitinib or SU12662 clearance. Several (environmental) factors may also influence the PK of sunitinib. Interestingly, the recently identified CYP3A4*22 SNP potentially has an impact on drug exposure. Replication studies in larger groups of patients are needed to verify the role of CYP3A4*22 for sunitinib clearance.

Association between multiple sclerosis risk-associated SNPs and relapse and disability – a prospective cohort study

2013 ◽  
Vol 20 (3) ◽  
pp. 313-321 ◽  
Author(s):  
Rui Lin ◽  
Bruce V Taylor ◽  
Steve Simpson ◽  
Jac Charlesworth ◽  
Anne-Louise Ponsonby ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Vitamin D ◽  
Dose Response ◽  
Prospective Cohort ◽  
Multiple Testing ◽  
Clinical Course ◽  
Statistical Significance ◽  
Nucleotide Polymorphisms ◽  
Risk Effects ◽  
Genetic Predictors

Background: The modulating effects of the multiple sclerosis (MS) risk-associated single-nucleotide polymorphisms (SNPs) on MS clinical course are not well established. Objectives: The objective of this paper is to investigate whether known MS risk-associated SNPs were associated with clinical course, and whether these SNPs modified the 25(OH)D-relapse association. Methods: Using a prospective cohort of 141 participants with relapsing–remitting MS and genotype data followed between 2002 and 2005, genotype-vitamin D interactions and the genetic predictors of relapse were assessed using survival analysis, and genetic predictors of 25(OH)D and disability progression were evaluated by multilevel mixed-effects linear regression. Results: While no SNP reached statistical significance after multiple testing, five SNPs were associated with relapse, with significant cumulative genotype risk effects and two demonstrated significant allele dose-response. Two SNPs altered the 25(OH)D-relapse association with significant allele dose-response. Five SNPs modified levels of 25(OH)D, with significant cumulative genotype ‘risk’ effect, and three demonstrated significant allele dose-response. We found no consistent evidence for an association between any SNPs and disability. Conclusions: Our study provides evidence for an association between known MS risk-associated SNPs and relapse. Our findings indicate gene-environment interactions may be an important mechanism on MS clinical course, and provide support for the role of vitamin D in MS relapse.

scholarly journals Haplotype-based eQTL mapping finds evidence for complex gene regulatory regions poorly tagged by marginal SNPs

2018 ◽  
Author(s):  
Robert Brown ◽  
Sriram Sankararaman ◽  
Bogdan Pasaniuc
Keyword(s):  
Gene Expression ◽  
Multiple Testing ◽  
Additive Model ◽  
Effect Sizes ◽  
Independent Effect ◽  
Nucleotide Polymorphisms ◽  
Multiple Snps ◽  
Significance Threshold ◽  
Association Data ◽  
Zero Effect

AbstractMotivationExpression quantitative trait loci (eQTLs), variations in the genome that impact gene expression, are identified through eQTL studies that test for a relationship between single nucleotide polymorphisms (SNPs) and gene expression levels. These studies typically assume an underlying additive model. Non-additive tests have been proposed, but are limited due to the increase in the multiple testing burden and are potentially biased by filtering criteria that relies on marginal association data. Here we propose using combinations of short haplotypes instead of SNPs as predictors for gene expression. Essentially, this method looks for genomic regions where haplotypes have different effect sizes. The differences in effect can be due to multiple genetic architectures such as a single SNP, a burden of rare SNPs, multiple SNPs with independent effect or multiple SNPs with an interaction effect occurring on the same haplotype.ResultsSimulations show that when haplotypes, rather than SNPs, are assigned non-zero effect sizes, our method has increased power compared to the marginal SNP method. In the GEUVADIS gene expression data, our method finds 101 more eGenes than the marginal method (5,202 vs. 5,101). The methods do not have full overlap in the eGenes that they find. Of the 5,202 eGenes found by our method, 707 are not found by the marginal method—even though it has a lower significance threshold. This indicates that many genes have regulatory architectures that are not well tagged by marginal SNPs and demonstrates the need to better model alternative archi-tectures.

scholarly journals Transforming growth factor-beta and matrix protein expression in acute and chronic rejection of human renal allografts.

1995 ◽  
Vol 6 (2) ◽  
pp. 286-294
Author(s):  
F S Shihab ◽  
T Yamamoto ◽  
C C Nast ◽  
A H Cohen ◽  
N A Noble ◽  
...  
Keyword(s):  
Growth Factor ◽  
Acute Rejection ◽  
Transforming Growth Factor Beta ◽  
Chronic Rejection ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Statistical Significance ◽  
Tgf Beta ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pai 1

Because the increased tissue expression of TGF-beta underlies fibrosis in many diseases, it was hypothesized that sustained elevated transforming growth factor (TGF)-beta overexpression might be responsible for fibrosis in chronic rejection of the renal allograft. To test this hypothesis, biopsies were obtained from 5 patients with acute rejection, 5 patients with chronic rejection, 10 normal individuals, and 10 patients with kidney disease. The tissues were examined by immunofluorescence for the three TGF-beta isoforms (1, 2, and 3) and the two matrix proteins induced by TGF-beta that serve as markers of fibrosis: fibronectin extradomain A positive (EDA+) and plasminogen activator inhibitor-1 (PAI-1). The tubulointerstitium from all cases of acute rejection and chronic rejection showed highly significant increases in immunostaining for the three TGF-beta isoforms (P < 0.001), fibronectin EDA+ (P < 0.005), and PAI-1 (P < 0.001). In the glomeruli, only TGF-beta 1 expression achieved statistical significance (P < 0.005) in acute rejection, whereas in chronic rejection, all three TGF-beta isoforms (p < 0.001) in addition to fibronectin EDA+ (p < 0.001) and PAI-1 (p < 0.001) were elevated. There was both cellular and matrix staining of the TGF-beta isoforms. In striking contrast, control kidney tissues were negative or only weakly positive. Because TGF-beta was present both in acute and in chronic rejection but not in control tissues and because acute rejection episodes are a good predictor for chronic rejection, these results suggest that TGF-beta may play a role in the pathogenesis of fibrosis in chronic rejection.

Role of stomatin-like protein 2 in colorectal cancer tumorigenesis via alteration of TGF-β1/Smad4 signaling

2015 ◽  
Vol 3 (1) ◽  
pp. 365-377
Keyword(s):  
Colorectal Cancer ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Diagnostic Value ◽  
Tumor Promoter ◽  
Immunohistochemical Method ◽  
Tgf Beta ◽  
The Us ◽  
Hematoxylin And Eosin

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death in the US, resulting in over a half-million deaths annually. Stomatin-like protein 2 (SLP-2) is a novel member of the stomatin superfamily and is found in several types of human tumors. However, whether it is expressed in human CRC is unknown. Recently, the importance of SMAD4, a downstream regulator in the TGF-beta signaling pathway, in colorectal cancer has been highlighted.TGF-beta signaling occurs through Smads 2/3/4, which translocate to the nucleus to regulate transcription; TGF-beta has tumor-suppressive effects in some tumor models and pro-metastatic effects in others. In patients with colorectal cancer (CRC), mutations or reduced levels of Smad4 have been correlated with reduced survival. A total of 93 patients with CRC was examined. In the present study, we aimed to explore the diagnostic value of SLP-2 in patients with CRC and to investigate whether CRC expression is regulated by transforming growth factor-β (TGF-β)/SMAD4 signaling. The expression of SLP-2 mRNA and protein was examined by immunohistochemistry (IHC) and qPCR, respectively. A standard immunohistochemical method was applied to stain the slides for hematoxylin and eosin (H&E), Tunnel, Phospho-Smad, E-cadherin, and β-catenin. Our data, revealed for the first time the role of SLP-2 overexpression CRC through downregulation of Smad4. Thus, the loss of Smad4 in colorectal cancer appears to switch TGF-β from tumor suppressor to a tumor promoter, and this group of patients could potentially benefit from SLP-2 inhibitor therapy. Furthermore; present study suggest that SLP-2 may be considered as a useful diagnostic marker for metastatic CRC.

Predictive value of VEGF gene polymorphisms in metastatic colorectal cancer patients treated with a bevacizumab-based chemotherapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14512-e14512
Author(s):  
Paola Ulivi ◽  
Giorgia Marisi ◽  
Emanuela Scarpi ◽  
Alessandro Passardi ◽  
Angela Ragazzini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Direct Sequencing ◽  
Statistical Significance ◽  
Objective Response ◽  
Case Series ◽  
Predictive Marker ◽  
Treated Group ◽  
Phase Iii ◽  
Nucleotide Polymorphisms

e14512 Background: Bevacizumab (B) + chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer (mCRC). However, molecular predictors of B efficacy have still not been identified. In this study we verified the role of specific VEGF polymorphisms as predictive markers of the efficacy of B in mCRC patients. Methods: One hundred and forty-nine patients enrolled onto the phase III prospective multicentric randomized “Italian Trial in Advanced Colorectal Cancer (ITACa)” trial were considered for this study. Seventy-four patients received FOLFIRI or FOLFOX plus B and 75 patients received only CT. A peripheral blood sample was collected from each patients and submitted to genomic DNA extraction. Five single nucleotide polymorphisms (SNPs) were analyzed by direct sequencing: VEGF -2578 C/A, -1498 C/T, -1154 G/A, -634 G/C, +936 C/T. All candidate genotypes were evaluated for a potential correlation with objective response rate (ORR) (Chi-square test). Results: In the B-treated group, the presence of VEGF -2578 AA, -634 GG or -1498 CC polymorphisms was associated with a better ORR compared to the other genotypes. In particular, of the 17 patients carrying the VEGF -2578 AA genotype, 14 (82.4%) showed a response, whereas only 30 (54.6%) of the 55 patients carrying -2578 CC or CA responded to therapy (p=0.05). Similarly, of 30 patients with VEGF -634 GG, 23 (76.7%) responded to therapy, whereas only 21 (50%) of the 42 patients with VEGF -634 GC or CC were responders (p=0.03). Moreover, 13 (81.3%) of the 16 patients carrying VEGF -1498 CC were responders, whereas of the 56 patients with VEGF -1498 CT or TT, only 31 (55.4%) showed a response (p=0.07). No differences in terms of ORR were observed in patients receiving only chemotherapy. However, as a result of the low power of the interaction test, the relation between ORR and treatment was very close to statistical significance for VEGF -2578 only (p=0.07). Conclusions: VEGF -2578 C/A seems to be a potential predictive marker for B-based CT in mCRC patients. Further studies on larger case series are now needed to confirm this finding.

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