ABSTRACT
Clinically differentiating between autoimmune and neurodegenerative disorders can often pose a diagnostic challenge. The differential diagnosis of rapidly progressing neurological and cognitive symptoms includes central nervous system tumours, cerebral vasculitis, and inflammatory, autoimmune, or paraneoplastic encephalopathies. Rarer neurodegenerative diseases such as Creutzfeldt-Jakob disease should also be considered. Detection of treatable causes, such as autoimmune disorders, remains important when potentially occurring in conjunction with Creutzfeldt-Jakob disease. The following report describes a rare case in which autoimmune encephalopathy and prion disease were considered as possible comorbidities.
Subject(s)
Anti-N-Methyl-D-Aspartate Receptor Encephalitis , Brain Diseases , Creutzfeldt-Jakob Syndrome , Hashimoto Disease , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/complications , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/diagnosis , Anti-N-Methyl-D-Aspartate Receptor Encephalitis/therapy , Autoantibodies , Creutzfeldt-Jakob Syndrome/complications , Creutzfeldt-Jakob Syndrome/diagnosis , Hashimoto Disease/complications , Hashimoto Disease/diagnosis , HumansABSTRACT
The use of natural fibres for components subjected to higher mechanical requirements tends to be limited by the high price of high-quality semi-finished products. Therefore, the present study deals with the development of more cost-effective staple fibre yarns made from flax tow. In the subsequent processing stage, the yarns were processed into quasi-unidirectional (UD) fabrics. The results of the fibre characterisation along the process chain have shown that no significant mechanical fibre damage occurs after slivers' production. Fibres prepared from yarns and fabrics show comparable characteristics. The yarns were processed to composites by pultrusion to verify the reinforcement effect. The mechanical properties were comparable to those of composites made from a high-quality UD flax roving. The fabrics were industrially processed into composite laminates using a vacuum infusion and an autoclave injection process (vacuum injection method in an autoclave). While impact strength compared to a reference laminate based on the UD flax roving was achieved, tensile and flexural properties were not reached. An analysis showed that the staple fibre yarns in the fabric show an undulation, leading to a reorientation of the fibres and lower characteristic values, which show 86-92% of the laminate made from the flax roving. Hybrid laminates with outer glass and inner flax layers were manufactured for the intended development of a leaf spring for the bogie of a narrow-gauge railroad as a demonstrator. The hybrid composites display excellent mechanical properties and showed clear advantages over a pure glass fibre-reinforced composite in lightweight construction potential, particularly flexural stiffness.
ABSTRACT
Introduction: Recent studies have suggested gender disparities in neurologic outcome after cardiac arrest (CA). However, the relation between gender and cognitive outcome has been rarely examined. Here we investigated whether sex is associated with cognitive outcome after CA events.Methods: A retrospective analysis was conducted using data collected at our institution from January 2006 to May 2017. Patients were included if they had a documented CA and were able to participate in structured neuropsychological testing. Cognitive status was assessed at about 2.1 month after CA and included tests of attention as well as short and long-term memory. Gender was used as the main predictor of outcome and was studied in relation to age, depressive mood, therapeutic hypothermia (TH), and other potential confounders.Results: Males were more likely to show favorable cognitive outcome in both univariate and multivariate analyses. Women were more likely to exhibit depressive mood. Patients who underwent TH (31% of the patients) did not show any gender differences in benefits from the treatment. Among males and females, no significant differences between age groups could be observed.Conclusions: Male sex was associated with favorable cognitive outcome after CA which could not be attributed to baseline characteristics.
Subject(s)
Cardiopulmonary Resuscitation , Heart Arrest , Hypothermia, Induced , Cognition , Female , Heart Arrest/complications , Heart Arrest/therapy , Humans , Male , Retrospective Studies , Sex Factors , Treatment OutcomeABSTRACT
PURPOSE: The treatment of oral cancer requires an effective rehabilitation strategy such as an early intensive rehabilitation (EIR) program. MATERIALS AND METHODS: The medical records and data of 41 patients who participated in an EIR program and 20 control group patients were analyzed. These patients all underwent surgical resection of the primary tumor followed by microsurgical reconstruction using free flaps. The length of stay (LOS) at the acute care hospital was compared between the two groups. Four indexes were used to evaluate the effectiveness of the EIR program. RESULTS: EIR patients stayed an average of 11.6 fewer days at the acute care hospital. All indexes showed significant improvements (p < 0.001). The Barthel Index (BI) and the Early Intensive Rehabilitation Barthel Index (EIR-BI) improved by 36.0 and 103.6 points, respectively. At discharge, the Bogenhausener Dysphagia Score (BODS) had improved to a score of 11.0 compared to the 13.9 at admission. EIR patients had a Work Ability Index (WAI) score of 25.7. CONCLUSION: Length of stay at the acute care hospital can be reduced using early intensive rehabilitation if patients are transferred to an intensive rehabilitation clinic early.
Subject(s)
Hospitals, Rehabilitation/statistics & numerical data , Length of Stay/statistics & numerical data , Mouth Neoplasms/rehabilitation , Mouth Neoplasms/therapy , Recovery of Function , Adult , Aged , Aged, 80 and over , Female , Free Tissue Flaps , Humans , Male , Middle Aged , Patient Discharge , Rehabilitation Centers , Statistics, Nonparametric , Surveys and Questionnaires , Treatment OutcomeABSTRACT
Spasticity is a symptom occurring in many neurological conditions including stroke, multiple sclerosis, hypoxic brain damage, traumatic brain injury, tumours and heredodegenerative diseases. It affects large numbers of patients and may cause major disability. So far, spasticity has merely been described as part of the upper motor neurone syndrome or defined in a narrowed neurophysiological sense. This consensus organised by IAB-Interdisciplinary Working Group Movement Disorders wants to provide a brief and practical new definition of spasticity-for the first time-based on its various forms of muscle hyperactivity as described in the current movement disorders terminology. We propose the following new definition system: Spasticity describes involuntary muscle hyperactivity in the presence of central paresis. The involuntary muscle hyperactivity can consist of various forms of muscle hyperactivity: spasticity sensu strictu describes involuntary muscle hyperactivity triggered by rapid passive joint movements, rigidity involuntary muscle hyperactivity triggered by slow passive joint movements, dystonia spontaneous involuntary muscle hyperactivity and spasms complex involuntary movements usually triggered by sensory or acoustic stimuli. Spasticity can be described by a documentation system grouped along clinical picture (axis 1), aetiology (axis 2), localisation (axis 3) and additional central nervous system deficits (axis 4). Our new definition allows distinction of spasticity components accessible to BT therapy and those inaccessible. The documentation sheet presented provides essential information for planning of BT therapy.
Subject(s)
Botulinum Toxins/therapeutic use , Muscle Spasticity/diagnosis , Muscle Spasticity/drug therapy , Neurotoxins/therapeutic use , Humans , Movement Disorders/drug therapyABSTRACT
Previous reports have investigated the impact of age on D-Dimer testing in elderly individuals with suspected deep vein thrombosis (DVT), but data on the age-related diagnostic value of D-dimer in a sample covering a broad age range are limited. The present study determined age-specifically the diagnostic accuracy of D-dimer and compared it to C-reactive protein (CRP), a marker of inflammation, in 500 patients with suspected DVT from the VTEval project (NCT02156401). Sensitivity of D-dimer was lower in patients < 60 years in comparison to patients ≥ 60 years (∆-16.8%), whereas specificity was 27.9% higher. Lowest levels of sensitivity were detected for female sex, unprovoked DVT, low thrombotic burden, and distal DVT. A fixed D-dimer threshold of 0.25 mg/L FEU resulted in elevated sensitivity for patients < 60 with a reduction of false negatives by 40.0% for proximal DVT and by 50.0% for distal DVT. In patients < 60 years, D-dimer and CRP demonstrated comparable diagnostic performance for both proximal and distal DVT (p > 0.05). In conclusion, these data outline a clinically-relevant limitation of D-dimer testing among younger patients with suspected DVT indicating a necessity for age-adapted cut-off values. Further research is required to decrypt the role of inflammation in the pathophysiology and diagnosis of venous thrombosis.
Subject(s)
Fibrin Fibrinogen Degradation Products , Inflammation/complications , Venous Thrombosis/blood , Venous Thrombosis/etiology , Age Factors , Aged , Biomarkers , C-Reactive Protein , Female , Humans , Male , Middle Aged , ROC Curve , Reproducibility of Results , Sensitivity and Specificity , Venous Thrombosis/diagnosisABSTRACT
INTRODUCTION: Venous thromboembolism (VTE) with its two manifestations deep vein thrombosis (DVT) and pulmonary embolism (PE) is a major public health problem. The VTEval Project aims to investigate numerous research questions on diagnosis, clinical management, treatment and prognosis of VTE, which have remained uncertain to date. METHODS AND ANALYSIS: The VTEval Project consists of three observational, prospective cohort studies on VTE comprising cohorts of individuals with a clinical suspicion of acute PE (with or without DVT), with a clinical suspicion of acute DVT (without symptomatic PE) and with an incidental diagnosis of VTE (PE or DVT). The VTEval Project expects to enrol a total of approximately 2000 individuals with subsequent active and passive follow-up investigations over a time period of 5â years per participant. Time points for active follow-up investigations are at months 3, 6, 12, 24 and 36 after diagnosis (depending on the disease cohort); passive follow-up investigations via registry offices and the cancer registry are performed 48 and 60â months after diagnosis for all participants. Primary short-term outcome is defined by overall mortality (PE-related death and all other causes of death), primary long-term outcome by symptomatic VTE (PE-related death, recurrence of non-fatal PE or DVT). The VTEval Project includes three 'all-comer' studies and involves the standardised acquisition of high-quality data, covering the systematic assessment of VTE including symptoms, risk profile, psychosocial, environmental and lifestyle factors as well as clinical and subclinical disease, and it builds up a large state-of-the-art biorepository containing various materials from serial blood samplings. ETHICS AND DISSEMINATION: The VTEval Project has been approved by the local data safety commissioner and the responsible ethics committee (reference no. 837.320.12 (8421-F)). Trial results will be published in peer-reviewed journals and presented at national and international scientific meetings. TRIAL REGISTRATION NUMBER: NCT02156401.
Subject(s)
Pulmonary Embolism/diagnosis , Pulmonary Embolism/therapy , Venous Thromboembolism/diagnosis , Venous Thromboembolism/therapy , Venous Thrombosis/diagnosis , Venous Thrombosis/therapy , Biological Specimen Banks , Biomarkers , Female , Follow-Up Studies , Humans , Life Style , Male , Prospective Studies , Research Design , Risk Assessment , Risk Factors , Treatment Outcome , Venous Thromboembolism/etiology , Venous Thromboembolism/psychologyABSTRACT
BACKGROUND: Observational studies have consistently associated obesity with colorectal cancer risk. Because both traits are genetically determined and share some metabolic biomarkers, we hypothesized that obesity-related polymorphisms could also influence the risk of developing colorectal cancer. METHODS: We conducted a comprehensive population-based case-control study in 1,792 German colorectal cancer cases and 1,805 controls to explore associations between 28 obesogenic variants identified through genome-wide association studies (GWAS) and colorectal cancer risk. We also evaluated interactions between polymorphisms and body mass index (BMI), type II diabetes (T2D), and gender. RESULTS: No evidence of association between obesogenic variants and colorectal cancer risk was observed after correction for multiple testing. There was only a remarkable interaction between the LTArs1041981 polymorphism and gender, which modified the risk of colorectal cancer [Pinteraction = 0.002; males: odds ratio (OR), 1.14; 95% confidence intervals (CI), 1.00-1.30 vs. females: OR, 0.83; 95% CI, 0.71-0.97]. CONCLUSIONS: Our findings showed that obesogenic variants are not a major pathogenetic risk factor for colorectal cancer. IMPACT: This comprehensive population-based case-control study does not provide evidence of a shared genetic component between obesity and colorectal cancer.
Subject(s)
Colorectal Neoplasms/genetics , Genome-Wide Association Study/methods , Obesity/complications , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Male , Middle Aged , Risk FactorsABSTRACT
BACKGROUND: Previous studies reported a positive association of body mass index (BMI) with microsatellite-stable (MSS) but not with microsatellite-instable (MSI-high) colorectal cancer. However, information from population-based studies conducted in representative age groups is so far limited. METHODS: We conducted a population-based case-control study (DACHS) in Southern Germany, including 1,215 patients with incident colorectal cancer and 1,891 matched controls with no upper age limit. Information on risk factors of colorectal cancer was obtained in standardized interviews. Microsatellite instability was analyzed using a mononucleotide marker panel. RESULTS: Median age among cases was 69 years, and 115 cases were classified MSI-high (9.5%). In multivariate analyses, BMI was positively associated with both risk of MSI-high colorectal cancer [per 5 kg/m(2): OR, 1.71; 95% confidence interval (CI), 1.35-2.17] and risk of MSS colorectal cancer (OR, 1.20; 95% CI, 1.07-1.33). The association with MSI-high colorectal cancer was limited to women (OR, 2.04; 95% CI, 1.50-2.77; P interaction = 0.02) and most pronounced among ever users of postmenopausal hormone replacement therapy (OR, 4.68; 95% CI, 2.36-9.30; P interaction = 0.01). In case-only analyses, BMI was more strongly associated with MSI-high colorectal cancer than with MSS colorectal cancer among women (OR, 1.84; 95% CI, 1.13-1.82; P interaction = 0.01). CONCLUSIONS: This population-based study confirms previous findings of increased risk of MSS colorectal cancer with obesity between both sexes and suggests that overweight and obesity may also be associated with increased risk of MSI-high colorectal cancer among women. IMPACT: These findings extend available data on the association of BMI and microsatellite instability in colorectal cancer and may suggest a link between overweight and obesity with sporadic MSI-high colorectal cancer in women.
Subject(s)
Body Mass Index , Colorectal Neoplasms/epidemiology , Colorectal Neoplasms/genetics , Microsatellite Instability , Obesity/epidemiology , Obesity/genetics , Adult , Aged , Aged, 80 and over , Animals , Case-Control Studies , Female , Genetic Predisposition to Disease , Germany/epidemiology , Humans , Male , Middle Aged , Risk FactorsABSTRACT
BACKGROUND: The link between colorectal cancer (CRC) and type 2 diabetes mellitus (T2D) has been extensively studied. Although it is commonly accepted that T2D is a risk factor for CRC, the underlying mechanisms are still poorly understood. RESEARCH DESIGN AND METHODS: Given that the genetic background contributes to both traits, it is conceivable that genetic variants associated with T2D may also influence the risk of CRC. We selected 26 T2D-related single-nucleotide polymorphisms (SNP) previously identified by genome-wide association studies and assessed their association with CRC and their interaction with known risk factors (gender, T2D, and body mass index) of CRC. Selected SNP were genotyped in 1798 CRC cases and 1810 controls from the population-based Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study (Germany). RESULTS: Patients carrying the TCF7L2_rs7903146_T allele had an increased risk of CRC (P(trend) = 0.02), whereas patients harboring the IL13_rs20541_T allele had a reduced risk (P(trend) = 0.02). A further analysis revealed gender-specific effects: the TCF7L2_rs7903146_T allele was associated with an increased risk of CRC in women (P(trend) = 0.003) but not in men (P(interaction) = 0.06); the LTA_rs1041981_A allele was associated with a decreased risk for CRC in women (P(trend) = 0.02), with an opposite effect in men (P(trend) = 0.05; P(interaction) = 0.002); the CDKAL1_rs7754840_C allele was associated with a decreased risk for CRC in men (P(trend) = 0.03), with no effect in women (P(interaction) = 0.03). The risk associated with the presence of T2D was modified both by IGF2BP2_rs4402960 and PPARγ_rs1801282 SNP (P(interaction) = 0.04 and 0.04, respectively). None of the findings were significant after correction for multiple comparisons. CONCLUSIONS: These findings suggest that T2D-related variants modify CRC risk independently and/or in an interactive manner according to the gender and the presence or absence of T2D.
Subject(s)
Colorectal Neoplasms/genetics , Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Adult , Alleles , Case-Control Studies , Female , Genotype , Humans , Male , Risk Factors , Sex FactorsABSTRACT
ATP Binding Cassette B1 (ABCB1) is a transporter with a broad substrate specificity involved in the elimination of several carcinogens from the gut. Several polymorphic variants within the ABCB1 gene have been reported as modulators of ABCB1-mediated transport. We investigated the impact of ABCB1 genetic variants on colorectal cancer (CRC) risk. A hybrid tagging/functional approach was performed to select 28 single nucleotide polymorphisms (SNPs) that were genotyped in 1,321 Czech subjects, 699 CRC cases and 622 controls. In addition, six potentially functional SNPs were genotyped in 3,662 German subjects, 1,809 cases and 1,853 controls from the DACHS study. We found that three functional SNPs (rs1202168, rs1045642 and rs868755) were associated with CRC risk in the German population. Carriers of the rs1202168_T and rs868755_T alleles had an increased risk for CRC (P(trend)â=â0.016 and 0.029, respectively), while individuals bearing the rs1045642_C allele showed a decreased risk of CRC (P(trend)â=â0.022). We sought to replicate the most significant results in an independent case-control study of 3,803 subjects, 2,169 cases and 1,634 controls carried out in the North of Germany. None of the SNPs tested were significantly associated with CRC risk in the replication study. In conclusion, in this study of about 8,800 individuals we show that ABCB1 gene polymorphisms play at best a minor role in the susceptibility to CRC.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Polymorphism, Genetic , ATP Binding Cassette Transporter, Subfamily B , Adult , Aged , Aged, 80 and over , Alleles , Case-Control Studies , Czech Republic , Female , Genotype , Humans , Male , Middle Aged , Models, Genetic , RiskABSTRACT
Genome-wide association studies (GWAS) have identified more than a dozen loci associated with colorectal cancer (CRC) risk. Here, we examined potential effect-modification between single-nucleotide polymorphisms (SNP) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23), rs6983267 at 8q24 (MYC), rs10795668 at 10p14 (FLJ3802842), rs3802842 at 11q23 (LOC120376), rs4444235 at 14q22.2 (BMP4), rs4779584 at 15q13 (GREM1), rs9929218 at 16q22.1 (CDH1), rs4939827 at 18q21 (SMAD7), rs10411210 at 19q13.1 (RHPN2), and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/nonsteroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal P(interaction) = 1.3 × 10(-4); adjusted P = 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption.
Subject(s)
Colorectal Neoplasms/genetics , Gene-Environment Interaction , Genetic Predisposition to Disease/genetics , Diet , Genotype , Humans , Polymorphism, Single NucleotideABSTRACT
Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.
Subject(s)
Colorectal Neoplasms/genetics , Genome-Wide Association Study , Female , Genetic Predisposition to Disease , Humans , Male , Odds Ratio , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
Mucins represent major components of the mucous layer in the stomach, protecting the underlying epithelium from acid, mechanical trauma, proteases and pathogenic bacteria. Previous studies have shown an association of neoplastic transformation in the stomach with aberrant mucin levels, suggesting a potential role of genetic variation in mucin genes in the development of gastric cancer (GC). We assessed the association of genetic variation in candidate single nucleotide polymorphisms (SNPs) in mucin genes with the risk of chronic atrophic gastritis (CAG), a well-established precursor of GC in the German population-based ESTHER study. We genotyped MUC1 T31T, MUC2 L58P, MUC2 V116M, MUC5B E34G, MUC5B R51W, MUC5B rs2014486 (intronic) and MUC6 V619M for 533 serologically defined CAG cases and 1054 age- and sex-matched controls. None of the analysed SNPs was associated with CAG. However, large studies are needed to disclose or exclude potential weak associations of these SNPs with CAG risk.
Subject(s)
Gastritis, Atrophic/genetics , Mucin-1/genetics , Mucin-2/genetics , Mucin-5B/genetics , Mucin-6/genetics , Aged , Case-Control Studies , Cohort Studies , Female , Gastritis, Atrophic/pathology , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide , Risk FactorsABSTRACT
BACKGROUND: Recent studies have reported associations of DNA repair pathway gene variants and risk of various cancers and precancerous lesions, such as chronic atrophic gastritis (CAG). METHODS: A nested case-control study within the German population-based ESTHER cohort was conducted, including 533 CAG cases and 1054 controls. Polymorphisms in eleven DNA repair genes (APEX1, ERCC1, ERCC2/XPD, PARP1 and XRCC1), in CD3EAP/ASE-1 and PPP1R13L were analysed. RESULTS: No association was disclosed for any of the analysed polymorphisms. Nor did stratified analyses according to ages < 65 and ≥ 65 years show any significant association with CAG risk. CONCLUSIONS: The results of this large German case-control study do not reveal associations of DNA repair pathway polymorphisms and risk of CAG. On the basis of a large number of CAG cases, they do not support associations of DNA repair pathway SNPs with CAG risk, but suggest the need of larger studies to disclose or exclude potential weak associations, or of studies with full coverage of candidate genes.
Subject(s)
DNA Repair/genetics , Gastritis, Atrophic/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Case-Control Studies , Female , Genotype , Genotyping Techniques , Humans , Male , Middle Aged , RiskABSTRACT
The mechanisms underlying the association of menopausal hormone therapy (MHT) with reduced colorectal cancer (CRC) risk are unknown and the identification of genetic modifiers may yield further insight. We explored the effect modification of MHT-associated CRC risk in postmenopausal women by 47 polymorphisms with known or putative functional relevance in 16 candidate genes related to hormone metabolism (COMT, CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2C19, CYP3A4, CYP17A1, GSTP, and HSD17B1), transport (ABCB1), and signaling (ESR1, ESR2, SHBG, PGR, and NR1I2). A total of 685 CRC patients and 684 healthy controls from a German population-based case-control study (DACHS) were genotyped. Multiplicative statistical interaction between polymorphisms and ever MHT use as well as duration of use was assessed using multivariate logistic regression. CRC risk associated with ever MHT use as well as with duration was significantly modified by rs1202168 in the transporter gene ABCB1 (P interaction=0.04). The MHT-associated risk reduction was not significant in homozygous non-carriers (odds ratio (OR) ever use=0.84, 95% confidence interval (CI) 0.53-1.34; OR per 5 year duration=0.94, 95% CI 0.83-1.08), while homozygous carriers of the minor T allele had a 57% lower risk with ever use of MHT (95% CI 0.21-0.88) and a 22% lower risk per 5 years of MHT use (95% CI 0.62-0.97). Significant effect modification was also observed for the ESR1_rs910416 polymorphism (P interaction=0.03 for ever use and 0.07 for duration of use), whereby the decreased risk was attenuated in homozygous carriers of the minor C allele (OR ever use=0.87, 95% CI 0.48-1.60, OR per 5 year duration=0.99, 95% CI 0.83-1.18). Results of this exploratory study provide first evidence that polymorphisms in genes related to estrogen transport and signaling may modify MHT-associated CRC risk but warrant replication in an independent population.
Subject(s)
Carcinoma/etiology , Colorectal Neoplasms/etiology , Estrogen Replacement Therapy/adverse effects , Gonadal Steroid Hormones/metabolism , Metabolic Networks and Pathways/genetics , Signal Transduction/genetics , Adult , Aged , Aged, 80 and over , Biological Transport/genetics , Carcinoma/genetics , Case-Control Studies , Colorectal Neoplasms/genetics , Female , Genetic Association Studies , Gonadal Steroid Hormones/genetics , Humans , Male , Middle Aged , Polymorphism, Genetic/physiology , Risk FactorsABSTRACT
BACKGROUND & AIMS: An association between gastric cancer and the rs2294008 (C>T) polymorphism in the prostate stem cell antigen (PSCA) gene has been reported for several Asian populations. We set out to determine whether such an association exists in white individuals. METHODS: We genotyped 166 relatives of gastric cancer patients, including 43 Helicobacter pylori-infected subjects with hypochlorhydria and gastric atrophy, 65 infected subjects without these abnormalities, 58 H pylori-negative relatives, and 100 population controls. Additionally, a population-based study of chronic atrophic gastritis provided 533 cases and 1054 controls. We then genotyped 2 population-based, case-control studies of upper gastrointestinal cancer: the first included 312 gastric cancer cases and 383 controls; the second included 309 gastric cancer cases, 159 esophageal cancer cases, and 211 controls. Odds ratios were computed from logistic models and adjusted for confounding variables. RESULTS: Carriage of the risk allele (T) of rs2294008 in PSCA was associated with chronic atrophic gastritis (adjusted odds ratio [OR], 1.5; 95% confidence interval [CI]: 1.1-1.9) and noncardia gastric cancer (OR, 1.9; 95% CI: 1.3-2.8). The association was strongest for the diffuse histologic type (OR, 3.2; 95% CI: 1.2-10.7). An inverse association was observed between carriage of the risk allele and gastric cardia cancer (OR, 0.5; 95% CI: 0.3-0.9), esophageal adenocarcinoma (OR, 0.5; 95% CI: 0.3-0.9), and esophageal squamous cell carcinoma (OR, 0.4; 95% CI: 0.2-0.9). CONCLUSIONS: The rs2294008 polymorphism in PSCA increases the risk of noncardia gastric cancer and its precursors in white individuals but protects against proximal cancers.
Subject(s)
Adenocarcinoma/genetics , Antigens, Neoplasm/genetics , Carcinoma, Squamous Cell/genetics , Esophageal Neoplasms/genetics , Gastrointestinal Neoplasms/genetics , Neoplasm Proteins/genetics , Polymorphism, Single Nucleotide , Adenocarcinoma/epidemiology , Carcinoma, Squamous Cell/epidemiology , Case-Control Studies , Esophageal Neoplasms/epidemiology , Female , GPI-Linked Proteins/genetics , Gastritis, Atrophic/epidemiology , Gastritis, Atrophic/genetics , Gastrointestinal Neoplasms/epidemiology , Genetic Predisposition to Disease , Helicobacter Infections/epidemiology , Helicobacter Infections/genetics , Helicobacter pylori/isolation & purification , Humans , Male , Risk , White People/geneticsABSTRACT
A recent study examined associations of tagging single nucleotide polymorphisms (tagSNPs) in 43 fatty acid metabolism-related genes and risk of colorectal cancer (CRC), showing rs8752, rs2612656 and a haplotype [comprising both of the single nucleotide polymorphisms (SNPs)] in the hydroxyprostaglandin dehydrogenase 15-(NAD) (HPGD) gene to be positively associated with CRC risk. In the present study, we attempted to replicate these single marker and haplotype associations, using 1795 CRC cases and 1805 controls from the German Darmkrebs: Chancen der Verhütung durch Screening study (DACHS). In addition to rs8752 and rs2612656, HPGD tagSNPs rs9312555, rs17360144 and rs7349744 were genotyped for haplotype analyses. Except for a marginally significant inverse association of HPGD rs8752 with CRC risk [odds ratio (OR) = 0.85; 95% confidence interval (CI) = 0.74, 0.98; P = 0.03], none of the analyzed tagSNPs showed any association with CRC. Subset analyses for colon and rectal cancers yielded similar, yet non-significant risk estimates at all five loci. Also, none of the haplotypes was found to be associated with CRC, colon or rectal cancers. However, rs8752 was significantly associated with a decreased risk of CRC among individuals with a body mass index < 30 (OR = 0.82, 95% CI = 0.70, 0.95, P = 0.01) as well as among smokers (OR = 0.74, 95% CI = 0.61, 0.90, P = 0.003). Yet, our data do not support the previously reported associations of HPGD tagSNPs and risk of CRC.
Subject(s)
Colorectal Neoplasms/genetics , Hydroxyprostaglandin Dehydrogenases/genetics , Polymorphism, Single Nucleotide , Adult , Aged , Aged, 80 and over , Case-Control Studies , Colorectal Neoplasms/etiology , Female , Haplotypes , Humans , Male , Middle Aged , Odds Ratio , RiskABSTRACT
It is well known that approximately 90% of colorectal cancer (CRC) cases originate from the constitutive activation of the canonical Wnt signaling pathway. There is increasing evidence that genetic variation both in Wnt and apoptotic pathway genes affects CRC susceptibility and progression. This population-based case-control study, including 1795 CRC cases and 1805 controls, investigates the association between common, putative functional polymorphisms in DNFA5, HIF1A, NDRG1, PYGO1, SFRP2, SFRP4, WISP1 and WISP3 genes and CRC risk. We found no evidence for an association between the selected allelic variants and risk of CRC. Subsite analyses, however, revealed a significant association of HIF1A c.*191T>C with rectal cancer risk [odds ratio (OR) = 1.25, 95% confidence interval (CI), 1.03-1.51, P = 0.03] comparing minor allele carriers with major allele homozygotes. In addition, homozygosity for the minor allele of SFRP4 P320T was significantly associated with rectal cancer risk (OR = 1.37, 95% CI, 1.06-1.79, P = 0.02) and early-stage CRC (OR = 1.33, 95% CI, 1.05-1.69, P = 0.02). This study does not support the hypothesis that Wnt signaling- and apoptosis-related polymorphisms contribute to CRC risk. However, our results provide evidence that CRC subsets may be affected. If confirmed, this knowledge may be used to assess individual susceptibility and to target potential measures of cancer prevention.
Subject(s)
Cell Death/genetics , Colorectal Neoplasms/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Wnt Proteins/genetics , Adult , Aged , Aged, 80 and over , Amino Acid Substitution , Apoptosis/genetics , Carrier State , Case-Control Studies , Colorectal Neoplasms/pathology , Female , Genetic Variation , Germany , Homozygote , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Male , Middle Aged , Neoplasm Staging , Odds Ratio , Proto-Oncogene Proteins/genetics , Risk Factors , Signal Transduction , White People/genetics , Wnt Proteins/physiologyABSTRACT
Chronic inflammation is an established risk factor for colorectal cancer (CRC), and polymorphisms in genes regulating inflammatory processes appear to alter the risk for neoplasia and the efficacy of nonsteroidal anti-inflammatory drugs in CRC chemoprevention. We examined the association between selected inflammation gene polymorphisms and CRC risk. In a large population-based case-control study with 1,795 CRC cases and 1,805 controls from the German DACHS study, we evaluated 5 putative functional inflammatory pathway polymorphisms in PRODH, PTGS1 and UBD genes. PTGS1 G213G was significantly associated with an increased CRC risk [odds ratio (OR), 1.19; 95% confidence interval (CI), 1.03-1.39; p = 0.02] comparing minor allele carriers with major allele homozygotes. This risk estimate was consistent across locations and stages of CRC (range of ORs, 1.15-1.20). Carriage of the minor allele of UBD I68T was significantly associated with advanced stages of CRC and with CRC below 65 years of age (OR, 1.23; 95% CI, 1.04-1.45; p = 0.02 and OR, 1.32; 95% CI, 1.05-1.67; p = 0.02, respectively). Our results support a role of variants in inflammatory pathway genes in CRC susceptibility and progression.