Polymorphism

I can't get no (epistemic) satisfaction: Why the hard problem of consciousness entails a hard problem of explanation

by Brian Earp

Earp, B. D. (2012). I can’t get no (epistemic) satisfaction: Why the hard problem of consciousness entails a hard problem of explanation. Dialogues in Philosophy, Mental and Neuro Sciences, in press.

Daniel Dennett (1996) has disputed David Chalmers’ (1995) assertion that there is a “hard problem of consciousness”... more Daniel Dennett (1996) has disputed David Chalmers’ (1995) assertion that there is a “hard problem of consciousness” worth solving in the philosophy of mind. In this paper I defend Chalmers against Dennett on this point: I argue that there is a hard problem of consciousness, that it is distinct in kind from the so-called easy problems, and that it is vital for the sake of honest and productive research in the cognitive sciences to be clear about the difference. But I have my own rebuke for Chalmers on the point of explanation. Chalmers (1995, 1996) proposes to “solve” the hard problem of consciousness by positing qualia as fundamental features of the universe, alongside such ontological basics as mass and space-time. But this is an inadequate solution: to posit, I will urge, is not to explain. To bolster this view, I borrow from an account of explanation by which it must provide “epistemic satisfaction” to be considered successful (Rowlands, 2001; Campbell, 2009), and show that Chalmers’ proposal fails on this account. I conclude that research in the science of consciousness cannot move forward without greater conceptual clarity in the field.

MDM2 SNP309 does not confer an increased risk to oral squamous cell carcinoma but may modulate the age of disease onset

by Rosnah Binti Zain

The MDM2 SNP309 has been associated with increased expression of the protein which could suppress p53 function, and... more The MDM2 SNP309 has been associated with increased expression of the protein which could suppress p53 function, and has been shown to modulate risk to cancer. We have previously shown that overexpression of MDM2 is a common event in oral cancers. In the present study, we determined the association between the MDM2 SNP309 polymorphism and oral cancer in 207 oral cancer patients and 116 normal subjects. We genotyped the MDM2 SNP309 by PCR-RFLP. Logistic regression was adapted to calculate odds ratios for MDM2 SNP309 polymorphism from univariate and multivariable adjusted models. Our results suggest that MDM2 SNP309 does not confer increased risk to oral cancer (OR = 1.55, 95% CI = 0.77-3.11). However, the GG/TG genotype was associated with later disease onset in women above 55 years of age. Collectively, our data suggests that MDM2 SNP309 may modulate the risk to oral cancer and is a modifier of the age at oral cancer onset in women above the age of 55 years.

GSTM1, GSTT1 and CYP1A1 polymorphisms and risk of oral cancer: a case-control study in Jakarta, Indonesia.

by Rosnah Binti Zain

Purpose: to investigate genetic polymorphisms in GSTM1, GSTT1 and CYP1A1 and the association with the risk of oral... more Purpose: to investigate genetic polymorphisms in GSTM1, GSTT1 and CYP1A1 and the association with the risk of oral cancer in the Jakarta population. Method: A total of 81 cases and 162 controls matched for age and sex were selected from 5 hospitals in Jakarta. Sociodemographic data using questionnaires were obtained and peripheral blood samples were collected with informed consent for PCR-RFLP assay. Conditional logistic regression analysis was performed to obtain the association between the risk of oral cancer and GSTM1, GSTT1 and CYP1A1 polymorphisms. Results: GSTM1 and GSTT1 null were slightly overrepresented among cases (60.5% and 45.7% respectively) compared to controls (55.6% and 41.4% respectively), but no statistically significant differences were observed. In contrast, the distribution of CYP1A1 polymorphism was higher among controls compared to cases (52.5 % versus 42.4 %). The odds ratio of null GSTM1 and GSTT1 genotypes was slightly higher compared to wild type genotypes (OR 1.19, 95% CI 0.70-2.02 and OR 1.19, 95% CI 0.72-2.05 respectively). Furthermore, the presence of CYP1A1 polymorphism did not increase the risk of oral cancer (OR 0.70, 95% 0.39-1.25). Conclusion: Genetic polymorphisms of GSTM1, GSTT1 and CYP1A1 may not be risk factors for oral cancer in the Jakarta population.

Genetic polymorphisms and risk of oral cancer

by Rosnah Binti Zain

Objectives: This study was done to investigate the role of single nucleotide polymorphisms(SNPs) within genes of phase... more Objectives: This study was done to investigate the role of single nucleotide polymorphisms(SNPs) within genes of phase I (CYP1A1) and phase II (GSTM1, GSTT1,GSTP1) of the xenobiotic metabolism and its association with oral cancer risk.Methods: An unmatched case-control study was conducted using 207 newly diagnosed oral cancer patients and 117 non-cancer subjects selected from the OCRCC database. Peripheral blood was obtained from consented individuals and the CYP1A1, GSTM1, GSTT1 and GSTP1 genotypes were determined using polymerase chain reaction (PCR) and restriction enzyme digestion (RFLP). Simple and multiple logistic regression yielding odds ratio (OR and aOR) were employed to measure the association between genetic polymorphisms and risk of oral cancer. Results: In comparing cases and controls for CYP1A1, GSTM1 and GSTT1 polymorphism, the OR was 0.84 (95 CI 0.534 - 1.330), 0.99 (95 CI 0.627 - 1.554) and 0.87 (95 CI 0.541 - 1.388) respectively. However, the adjusted OR for GSTP1 polymorphism, as compared to the wild-type, was 0.43 (95 CI 0.221 - 0.837). It was noted that polymorphism of GSTP1 conferred a 57 reduction in risk of oral cancer as compared to individuals with the GSTP1 wild type genotype. Meanwhile individuals with combination of betel quid chewing habit and/or GSTP1 polymorphism has 1.6 times the risk of oral cancer although it was not statistically significant (95 CI 0.974 - 2.635). Conclusions: Analysis suggested that polymorphism of GSTP1 seems to have protective effect on the risk of oral cancer

CYP1A1, GSTM1 and GSTT1 polymorphisms and oral cancer – Correlation with patients’ status at 2-year, age of onset, nodal status, tumor size and stage

by Rosnah Binti Zain

Altered expression of xenobiotic enzymes such as CYP1A1, GSTM1 and GSTT1 has been reported in some malignant tumors... more Altered expression of xenobiotic enzymes such as CYP1A1, GSTM1 and GSTT1 has been reported in some malignant tumors including oral cancer. However, the correlation between these enzymes and clinicopathologic parameters has not been well documented. The aim of this study was to investigate the associations between CYP1A1, GSTM1 and GSTT1 polymorphisms with patients’ status at 2-year, age of onset, nodal status, tumor size and disease stage. A total of 195 oral cancer patients were included in this study. Peripheral blood was obtained from consented individuals and CYP1A1, GSTM1 and GSTT1 genotypes were determined using PCR and restriction enzyme digestion. Chi-square test and simple logistic regression yielding odds ratio (OR) was employed for comparison of all parameters except for age of onset where t-test was used. Patients with GSTM1/GSTT1 polymorphism were associated with almost triple increased risk of mortality at 2-year after the first being diagnosed (OR 2.79, 95% CI 1.22–6.36). Mean age of onset was higher in those with GSTT1 null (60.82 ± 10.61 years) and GSTM1/GSTT1 polymorphism genotype (59.48 ± 11.30 years) compared to lower mean age of onset for those with GSTT1 non-null (58.15 ± 11.97 years) and GSTM1/GSTT1 wild-type genotype and these observations were not significant. There was also no significant difference between CYP1A1 and GSTM1 polymorphisms and age of onset. Positive nodes are associated with high CYP1A1 polymorphism, GSTM1 null and GSTM1/GSTT1 polymorphism (59.7%, 56.5% and 72.6%, respectively) and low GSTT1 null (29.0%). For tumor size of more than 2 cm, there was higher percentage of GSTT1 null genotype (92.7%) as compared to those with tumor size of less than 2 cm (p = 0.035). Polymorphisms of all three genes were higher in late stage compared to early stage disease. However, statistically, these observations were not significant. In conclusion, no association was observed between CYP1A1 and GSTM1 polymorphisms and all clinicopathologic parameters studied. This study also showed that for GSTM1/GSTT1 and GSTT1 polymorphisms, association was seen with patients’ status at 2-year and tumor size respectively, indicating that the GST genotypes may be important indicators for the patients’ status and tumor size in oral cancer.

Combined effects of isothiocyanates (ITCs) intake, glutathione S-transferases (GSTs) polymorphism and risk habits on oral squamous cell carcinoma (OSCC) associated with earlier age of disease onset

by Rosnah Binti Zain

Introduction: ITCs found in cruciferous vegetables has been reported to reduce cancer risk by inducing phase II... more Introduction: ITCs found in cruciferous vegetables has been reported to reduce cancer risk by inducing phase II conjugating enzymes, in particular GSTs. Interestingly, these enzymes also metabolize ITCs therefore; the protective effects of ITCs would depend on the activity of GSTs. This study aimed to determine association between dietary ITCs, GSTs polymorphisms and risk habits (cigarette smoking, alcohol drinking and betel-quid chewing) with oral cancer.Method: Included in this study were 115 OSCC patients and 116 healthy subjects. Information on ITC intake from cruciferous vegetables was collected via a semi-quantitative FFQ. Peripheral blood lymphocytes were obtained for genotyping of GSTM1, GSTT1 and GSTP1 using PCR multiplex and PCR-RFLP. Chi-square and logistic regression were performed to determine the association of ITC and GSTs polymorphism and risk of oral cancer.Results: When dietary ITC was categorized into high (greater than/equal to median) and low (less than median) intake, ITC consumption was higher among cases (51.3%) than controls. However, it was not statistically significant (p = 0.645). Discussion: Odd ratios analysis showed no significant association between ITC intake, GSTM1, GSTT1 or GSTP1 genotypes with oral cancer risk. However, GSTP1 wild-type was associated with later disease onset in women above 55 years of age (p = 0.017). Among men above 45 years of age, there was a significant 17-year difference in the age of OSCC onset between those with GSTP1 wild-type ? low ITC intake and GSTP1 polymorphism ? high ITC intake (p < 0.001). Similarly further analysis stratified by risk habits (drinking and chewing), showed that GSTP1 polymorphism ? high ITC intake was associated with earlier disease onset (p < 0.001). This study suggests that combinatory effects between dietary ITCs, GSTP1 polymorphism and risk habits may be associated with risk of oral cancer and modulate the age of disease onset.

Aldehyde dehydrogenase 2 (ALDH2) and glutathione S-transferase M1 (GSTM1) polymorphisms in relation to oral cancer risk among Malaysians

by Rosnah Binti Zain

Introduction: ALDH2 is an enzyme involved in major oxidative pathway of alcohol metabolism while GSTM1 is a... more Introduction: ALDH2 is an enzyme involved in major oxidative pathway of alcohol metabolism while GSTM1 is a drug-metabolizing enzyme of acetaldehyde. It has been reported that the mutant ALDH2 allele and the absence of GSTM1 contributes to increased oral cancer risk due to reduced acetaldehyde metabolism. This study aims to determine ALDH2 and GSTM1 polymorphisms and its association with oral cancer risk. Method: An unmatched case-control study was conducted using 163 oral cancer patients and 87 non-cancer subjects selected from the OCRCC database. ALDH2 and GSTM1 genotypes were determined using PCR-RFLP from peripheral blood. Multiple logistic regression was employed to assess association between polymorphisms and oral cancer risk. Results: Most common risk habit was betel-quid chewing (44.0%), followed by smoking (30.4%) and alcohol drinking (29.6%). The prevalence of ALDH2 polymorphism is only 5.7%, while GSTM1 null is seen in 51.2%. Alcohol drinking and the combination of ALDH2 polymorphism and alcohol consumption is significantly associated with increased risk of oral cancer (p < 0.001). Discussion: In this population, although the prevalence of alcohol consumption is low compared to other populations, alcohol drinking has been found to significantly increase oral cancer risk, even after adjusting for confounding factors (age, gender and ethnic) (aOR 6.8, 95% CI 2.6, 18.1). The prevalence of ALDH2 polymorphism was found to be much lower compared to other Asian population such as the Japanese and Taiwanese. In relation to oral cancer risk, no significant association was seen for both the polymorphisms of ALDH2 and GSTM1. However, when analysis was done for the combination of ALDH2 polymorphism and alcohol consumption, those who concurrently exhibit ALDH2 polymorphism and consumed alcohol was found to be 6 times more likely to develop oral cancer (aOR 6.6, 95% CI 2.4, 17.9). No such association was observed for the combination of GSTM1 polymorphism and alcohol consumption. In conclusion, alcohol consumption is a significant independent risk factor for oral cancer among Malaysians while ALDH2 polymorphism together with the habit of alcohol drinking also confers an increased risk for oral cancer.

39) Concomitant Polymorphs of the Antihyperlipoproteinemic Bezafibrate

by Dr Andreas Lemmerer aka Crystal Magician

Andreas Lemmerer, Nikoletta B. Bathori, Catharine Esterhuysen, Susan A. Bourne and Mino R. Caira, Crystal Growth & Design (2009), 9, 2646-2655.

The two polymorphic forms alpha and beta of the active pharmaceutical ingredient... more The two polymorphic forms alpha and beta of the active pharmaceutical ingredient 2-[4-[2-(4-chlorobenzamide)ethyl]-phenoxy]-2-methylpropanoic acid (bezafibrate) have been reinvestigated and fully characterized by optical microscopy, infrared spectroscopy, differential scanning calorimetry, thermal gravimetric analysis, variable temperature X-ray powder diffraction, and single crystal X-ray diffraction. Form alpha is obtained from ethanol, whereas form beta can be grown from a 2-butanone solution provided that stoichiometric quantities of iso-nicotinamide are present. Without iso-nicotinamide, both forms grow concomitantly from a 2-butanone solution. The two forms are related enantiotropically, with form beta converting to form alpha at 160.7 °C. Form beta is the more stable form at room temperature and at temperatures below the transition temperature of 160.7 °C. The two polymorphs arise from conformational differences which result in vastly different hydrogen bonding interactions and subsequent crystal packing in the solid state. The crystal habits of the two forms reflect the different solid-state packing observed by single crystal X-ray diffraction. Computational modelling calculations on the energy of the conformations have been carried out in the solid state and compared to those energy minima calculated in the gas phase.

Discovery of Three Polymorphs of 7-Fluoroisatin Reveals Challenges In Using Computational Crystal Structure Prediction As a Complement to Experimental Screening

by Sharmarke Mohamed

Final Manuscript: Co-authored with Sarah Barnett, Sally Price, Derek Tocher and Collaborators from ISIS

A combined computational and experimental polymorph search was undertaken to establish the crystal forms of... more A combined computational and experimental polymorph search was undertaken to establish the crystal forms of 7-fluoroisatin, a simple molecule with no reported crystal structures, to evaluate the value of crystal structure prediction studies as an aid to solid form discovery. Three polymorphs were found in a manual crystallisation screen, as well as two solvates. Form I (P21/c, Z′ = 1), found from the majority of solvent evaporation experiments, corresponded to the most stable form in the computational search of Z′ = 1 structures. Form III (P21/a, Z′ = 2) is probably a metastable form, which was only found concomitantly with form I, and has the same dimeric R(8) hydrogen bonding motif as form I and the majority of the computed low energy structures. However, the most thermodynamically stable polymorph, form II (P[1 with combining macron], Z′ = 2), has an expanded four molecule R(18) hydrogen bonding motif, which could not have been found within the routine computational study. The computed relative energies of the three forms are not in accord with experimental results. Thus, the experimental finding of three crystalline polymorphs of 7-fluoroisatin illustrates the many challenges for computational screening to be a tool for the experimental crystal engineer, in contrast to the results for an analogous investigation of 5-fluoroisatin.

Strong Association of 677 C>T Substitution in the MTHFR Gene with Male Infertility - A Study on an Indian Population and a Meta-Analysis

by Madhukar Dama

Background
Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine... more Background
Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme of folate and methionine metabolism, making it crucial for DNA synthesis and methylation. The objective of this study was to analyze MTHFR gene 677C>T polymorphism in infertile male individuals from North India, followed by a meta-analysis on our data and published studies.

Methodology/Principal Findings
We undertook genotyping on a total of 837 individuals including well characterized infertile (N = 522) and confirmed fertile (N = 315) individuals. The SNP was typed by direct DNA sequencing. Chi square test was done for statistical analysis. Published studies were searched using appropriate keywords. Source of data collection for meta-analysis included ‘Pubmed’, ‘Ovid’ and ‘Google Scholar’. Those studies analyzing 677C>T polymorphism in male infertility and presenting all relevant data were included in meta-analysis. The genotype data for infertile subjects and fertile controls was extracted from each study. Chi square test was done to obtain odds ratio (OR) and p-value. Meta-analysis was performed using Comprehensive Meta-analysis software (Version 2). The frequency of mutant (T) allele (p = 0.0025) and genotypes (CT+TT) (p = 0.0187) was significantly higher in infertile individuals in comparison to fertile controls in our case-control study. The overall summary estimate (OR) for allele and genotype meta-analysis were 1.304 (p = 0.000), 1.310 (p = 0.000), respectively, establishing significant association of 677C>T polymorphism with male infertility.

Conclusions/Significance
677C>T substitution associated strongly with male infertility in Indian population. Allele and genotype meta-analysis also supported its strong correlation with male infertility, thus establishing it as a risk factor.

Effects of Natural Selection and Gene Conversion on the Evolution of Human Glycophorins Coding for MNS Blood Polymorphisms in Malaria-Endemic African …

by Paolo Marcatili

Connecting the Human Variome Project to Nutrigenomics

by Chris Evelo

Jim Kaput, Chris T. Evelo, Giuditta Perozzi, Ben van Ommen and Richard Cotton (2010). Genes & Nutrition, Volume 5, Number 4, 275-283, DOI: 10.1007/s12263-010-0186-6

Nutrigenomics is the science of analyzing and understanding gene–nutrient interactions, which because of the genetic... more Nutrigenomics is the science of analyzing and understanding gene–nutrient interactions, which because of the genetic heterogeneity, varying degrees of interaction among gene products, and the environmental diversity is a complex science. Although much knowledge of human diversity has been accumulated, estimates suggest that ~90% of genetic variation has not yet been characterized. Identification of the DNA sequence variants that contribute to nutrition-related disease risk is essential for developing a better understanding of the complex causes of disease in humans, including nutrition-related disease. The Human Variome Project (HVP; http://www.humanvariomeproject.org/) is an international effort to systematically identify genes, their mutations, and their variants associated with phenotypic variability and indications of human disease or phenotype. Since nutrigenomic research uses genetic information in the design and analysis of experiments, the HVP is an essential collaborator for ongoing studies of gene–nutrient interactions. With the advent of next generation sequencing methodologies and the understanding of the undiscovered variation in human genomes, the nutrigenomic community will be generating novel sequence data and results. The guidelines and practices of the HVP can guide and harmonize these efforts.

Genetic variation in thioredoxin interacting protein (TXNIP) is associated with hypertriglyceridaemia and blood pressure in diabetes mellitus.

by Chris Evelo

M M J van Greevenbroek, V M M-J Vermeulen, E J M Feskens, C T Evelo, M Kruijshoop, B Hoebee, C J H van der Kallen, T W A de Bruin (2007). Diabet Med 24: 5. 498-504 May 

Aims  Thioredoxin interacting protein (TXNIP) is an attractive candidate gene for diabetes or diabetic dyslipidaemia,... more Aims  Thioredoxin interacting protein (TXNIP) is an attractive candidate gene for diabetes or diabetic dyslipidaemia, since TXNIP is the strongest glucose-responsive gene in pancreatic B-cells, TXNIP deficiency in a mouse model is associated with hyperlipidaemia and TXNIP is located in the 1q21-1q23 chromosomal Type 2 diabetes mellitus (DM) locus. We set out to investigate whether metabolic effects of TXNIP that were previously reported in a murine model are also relevant in human Type 2 DM.

Methods  The frequency distribution of a 3′ UTR single nucleotide polymorphism (SNP) in TXNIP was investigated in subjects with normal glucose tolerance (NGT; n = 379), impaired glucose tolerance (IGT; n = 228) and Type 2 DM (n = 230). Metabolic data were used to determine the effect of this SNP on parameters associated with lipid and glucose metabolism.

Results  The frequency of the TXNIP variation did not differ between groups, but within the group of diabetic subjects, carriers of the TXNIP-T variant had 1.6-fold higher triglyceride concentrations (P = 0.015; n = 136) and a 5.5-mmHg higher diastolic blood pressure (P = 0.02; n = 212) than homozygous carriers of the common C-allele, whereas in non-diabetic subjects fasting glucose was 0.26 mmol/l lower (P = 0.002; n = 478) in carriers of the T-allele. Moreover, a significant interaction between plasma glucose concentrations and TXNIP polymorphism on plasma triglycerides was observed (P = 0.012; n = 544).

Conclusion  This is the first report to implicate TXNIP in a human disorder of energy metabolism, Type 2 diabetes. The effect of TXNIP on triglycerides is influenced by plasma glucose concentrations, suggesting that the biological relevance of TXNIP variations may be particularly relevant in recurrent episodes of hyperglycaemia.