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1.
The fatty acid translocase gene CD36 and lingual lipase influence oral sensitivity to fat in obese subjects.
Pepino, MY, Love-Gregory, L, Klein, S, Abumrad, NA
Journal of lipid research. 2012;(3):561-566
Abstract
The precise orosensory inputs engaged for dietary lipids detection in humans are unknown. We evaluated whether a common single nucleotide polymorphism (rs1761667) in the CD36 gene that reduces CD36 expression and the addition of orlistat, a lipase inhibitor, to reduce FA release from triacylglycerols (TGs), the main component of dietary fats, would attenuate fat orosensory sensitivity in humans. Twenty-one obese subjects with different rs1761667 genotypes (6 AA, 7 AG, and 8 GG) were studied on two occasions in which oleic acid and triolein orosensory detection thresholds were measured using emulsions prepared with and without orlistat. Subjects homozygous for the G-allele had 8-fold lower oral detection thresholds for oleic acid and triolein than subjects homozygous for the A allele, which associates with lower CD36 expression (P = 0.03). Thresholds for heterozygous subjects were intermediate. The addition of orlistat increased detection thresholds for triolein (log threshold = -0.3 ± 0.2 vs. 0.3 ± 0.1; P < 0.001) but not oleic acid (log threshold = -1.0 ± 0.2 vs. -0.8 ± 0.2; P > 0.2). In conclusion, this is the first experimental evidence for a role of CD36 in fat gustatory perception in humans. The data also support involvement of lingual lipase and are consistent with the concept that FA and not TG is the sensed stimulus.
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2.
Beta1-adrenoceptor polymorphism predicts flecainide action in patients with atrial fibrillation.
Nia, AM, Caglayan, E, Gassanov, N, Zimmermann, T, Aslan, O, Hellmich, M, Duru, F, Erdmann, E, Rosenkranz, S, Er, F
PloS one. 2010;(7):e11421
Abstract
BACKGROUND Antiarrhythmic action of flecainide is based on sodium channel blockade. Beta(1)-adrenoceptor (beta(1)AR) activation induces sodium channel inhibition, too. The aim of the present study was to evaluate the impact of different beta(1)AR genotypes on antiarrhythmic action of flecainide in patients with structural heart disease and atrial fibrillation. METHODOLOGY/PRINCIPAL FINDINGS In 145 subjects, 87 with atrial fibrillation, genotyping was performed to identify the individual beta(1)AR Arg389Gly and Ser49Gly polymorphism. Resting heart rate during atrial fibrillation and success of flecainide-induced cardioversion were correlated with beta(1)AR genotype. The overall cardioversion rate with flecainide was 39%. The Arg389Arg genotype was associated with the highest cardioversion rate (55.5%; OR 3.30; 95% CI; 1.34-8.13; p = 0.003) compared to patients with Arg389Gly (29.5%; OR 0.44; 95% CI; 0.18-1.06; p = 0.066) and Gly389Gly (14%; OR 0.24; 95% CI 0.03-2.07; p = 0.17) variants. The single Ser49Gly polymorphism did not influence the conversion rate. In combination, patients with Arg389Gly-Ser49Gly genotype displayed the lowest conversion rate with 20.8% (OR 0.31; 95% CI; 0.10-0.93; p = 0.03). In patients with Arg389Arg variants the heart rate during atrial fibrillation was significantly higher (110+/-2.7 bpm; p = 0.03 vs. other variants) compared to Arg389Gly (104.8+/-2.4 bpm) and Gly389Gly (96.9+/-5.8 bpm) carriers. The Arg389Gly-Ser49Gly genotype was more common in patients with atrial fibrillation compared to patients without atrial fibrillation (27.6% vs. 5.2%; HR 6.98; 95% CI; 1.99-24.46; p<0.001). CONCLUSIONS The beta(1)AR Arg389Arg genotype is associated with increased flecainide potency and higher heart rate during atrial fibrillation. The Arg389Gly-Ser49Gly genotype might be of predictive value for atrial fibrillation.
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3.
BDNF gene is a risk factor for schizophrenia in a Scottish population.
Neves-Pereira, M, Cheung, JK, Pasdar, A, Zhang, F, Breen, G, Yates, P, Sinclair, M, Crombie, C, Walker, N, St Clair, DM
Molecular psychiatry. 2005;(2):208-12
Abstract
Schizophrenia is a severe psychiatric disease with a strong genetic component. Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of schizophrenia and bipolar (BP) disorders. The present study has examined two polymorphisms in linkage disequilibrium in the BDNF gene, which have been variously reported as associated with schizophrenia and BP. In our study, 321 probands with a primary diagnosis of schizophrenia or schizoaffective disorder, and 263 with a diagnosis of bipolar affective disorder, were examined together with 350 controls drawn from the same geographical region of Scotland. The val66met single-nucleotide polymorphism (SNP) showed significant (P = 0.005) association for valine (allele G) with schizophrenia but not bipolar disorder. Haplotype analysis of val/met SNP and a dinucleotide repeat polymorphism in the putative promoter region revealed highly significant (P < 1 x 10(-8)) under-representation of the methionine or met-1 haplotype in the schizophrenic but not the BP population. We conclude that, although the val66met polymorphism has been reported to alter gene function, the risk may depend upon the haplotypic background on which the val/met variant is carried.
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4.
SNPs and haplotypes in the S100B gene reveal association with schizophrenia.
Liu, J, Shi, Y, Tang, J, Guo, T, Li, X, Yang, Y, Chen, Q, Zhao, X, He, G, Feng, G, et al
Biochemical and biophysical research communications. 2005;(1):335-41
Abstract
The S100B gene locates in 21q22.3 and produces neurotrophin mainly in astrocytes of CNS which can act as an extensive marker of glial cell integrity. The synaptic destabilization hypothesis (GGF/SD) suggests that the functional deficiency of growth factors like S100B is involved in the etiology of schizophrenia and the S100B serum concentration is reported to be significantly increased in patients with acute schizophrenia and decreased in chronic schizophrenia patients. To validate the association between S100B and schizophrenia, 384 cases and 401 controls, all Chinese Han subjects, were recruited. Four SNPs V1 (-960C>G), V2 (-111C>T), V3 (2757C>G, rs1051169), and V4 (5748C>T, rs9722) were studied. And haplotype V3-V4 (G-C) showed a significant association with schizophrenia. Our study showed an association between schizophrenia and a possible susceptible haplotype V3-V4 (G-C) which possesses a genetic tendency for increased S100B expression. Our results suggest that S100B could be a susceptible gene for schizophrenia and provide indirect evidence for the GGF/SD hypothesis.
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5.
A common PCSK9 haplotype, encompassing the E670G coding single nucleotide polymorphism, is a novel genetic marker for plasma low-density lipoprotein cholesterol levels and severity of coronary atherosclerosis.
Chen, SN, Ballantyne, CM, Gotto, AM, Tan, Y, Willerson, JT, Marian, AJ
Journal of the American College of Cardiology. 2005;(10):1611-9
Abstract
OBJECTIVES We sought to determine the effects of PCSK9 variants on plasma low-density lipoprotein cholesterol (LDL-C) levels, severity of coronary atherosclerosis, and response to statin therapy in the Lipoprotein Coronary Atherosclerosis Study (LCAS) population. BACKGROUND Mutations in PCSK9 cause autosomal-dominant hypercholesterolemia. We hypothesized that PCSK9 variants could affect plasma LDL-C in individuals with polygenic hypercholesterolemia. METHODS We sequenced all 12 exons and boundaries to detect novel polymorphisms, and genotyped 372 subjects in LCAS and 319 subjects in a second independent population for six polymorphisms, including novel leucine repeats, by fluorescently tagged markers. We reconstructed haplotypes using a Bayesian algorithm. RESULTS Permutation test results showed statistically significant differences in global haplotype distribution among the tertiles of LDL-C (odds ratio [OR]: 2.36, 95% confidence interval [CI]: 1.90 to 4.32, p = 0.005) and minimum lumen diameter of coronary lesions (OR: 1.83, 95% CI: 1.01 to 3.55, p = 0.045). Regression analysis identified haplotype 3 as an independent determinant of LDL-C levels (adjusted R2 = 2.2%, F = 9.37, p = 0.002). Haplotype structure analysis identified E670G as the determinant variant, exerting a dose effect (GG > EG > EE) and accounting for 3.5% of plasma LDL-C variability (F = 14.6, p < 0.001). Plasma total cholesterol, apolipoprotein B, and lipoprotein (a) levels were also associated with the E670G variant. Distributions of the E670G genotypes in an independent normolipidemic and the hyperlipidemic LCAS populations were significantly different (F = 7.2, p = 0.027). No significant treatment-by-genotype interactions were detected. The false positive report probability was between 2% and 8%. CONCLUSIONS Haplotype 3 encompassing the E670G variant is an independent determinant of plasma LDL-C levels and the severity of coronary atherosclerosis.
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6.
Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study.
Massat, I, Souery, D, Del-Favero, J, Nothen, M, Blackwood, D, Muir, W, Kaneva, R, Serretti, A, Lorenzi, C, Rietschel, M, et al
Molecular psychiatry. 2005;(6):598-605
Abstract
The available data from preclinical and pharmacological studies on the role of the C-O-methyl transferase (COMT) support the hypothesis that abnormal catecholamine transmission has been implicated in the pathogenesis of mood disorders (MD). We examined the relationship of a common functional polymorphism (Val108/158Met) in the COMT gene, which accounts for four-fold variation in enzyme activity, with 'early-onset' (EO) forms (less than or equal to 25 years) of MD, including patients with major depressive disorder (EO-MDD) and bipolar patients (EO-BPD), in a European multicenter case-control sample. Our sample includes 378 MDD (120 EO-MDD), 506 BPD (222 EO-BPD) and 628 controls. An association was found between the high-activity COMT Val allele, particularly the COMT Val/Val genotype and EO-MDD. These findings suggest that the COMT Val/Val genotype may be involved in EO-MDD or may be in linkage disequilibrium with a different causative polymorphism in the vicinity. The COMT gene may have complex and pleiotropic effects on susceptibility and symptomatology of neuropsychiatric disorders.
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7.
Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia.
Handoko, HY, Nyholt, DR, Hayward, NK, Nertney, DA, Hannah, DE, Windus, LC, McCormack, CM, Smith, HJ, Filippich, C, James, MR, et al
Molecular psychiatry. 2005;(6):589-97
Abstract
Several lines of evidence have implicated the catechol-O-methyltransferase (COMT) gene as a candidate for schizophrenia (SZ) susceptibility, not only because it encodes a key dopamine catabolic enzyme but also because it maps to the velocardiofacial syndrome region of chromosome 22q11 which has long been associated with SZ predisposition. The interest in COMT as a candidate SZ risk factor has led to numerous case-control and family-based studies, with the majority placing emphasis on examining a functional Val/Met polymorphism within this enzyme. Unfortunately, these studies have continually produced conflicting results. To assess the genetic contribution of other COMT variants to SZ susceptibility, we investigated three single-nucleotide polymorphisms (SNPs) (rs737865, rs4633, rs165599) in addition to the Val/Met variant (rs4680) in a highly selected sample of Australian Caucasian families containing 107 patients with SZ. The Val/Met and rs4633 variants showed nominally significant associations with SZ (P<0.05), although neither of the individual SNPs remained significant after adjusting for multiple testing (most significant P=0.1174). However, haplotype analyses showed strong evidence of an association; the most significant being the three-marker haplotype rs737865-rs4680-rs165599 (global P=0.0022), which spans more than 26 kb. Importantly, conditional analyses indicated the presence of two separate and interacting effects within this haplotype, irrespective of gender. In addition, our results indicate the Val/Met polymorphism is not disease-causing and is simply in strong linkage disequilibrium with a causative effect, which interacts with another as yet unidentified variant approximately 20 kb away. These results may help explain the inconsistent results reported on the Val/Met polymorphism and have important implications for future investigations into the role of COMT in SZ susceptibility.
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8.
Prediction of stone disease by discriminant analysis and artificial neural networks in genetic polymorphisms: a new method.
Chiang, D, Chiang, HC, Chen, WC, Tsai, FJ
BJU international. 2003;(7):661-6
Abstract
OBJECTIVE To use information from genetic polymorphisms and from patients (drinking/exercise habits) to identify their association with stone disease, the main analytical and predictive tools being discriminant analysis (DA) and artificial neural networks (ANNs). PATIENTS, SUBJECTS AND METHODS Urinary stone disease is common in Taiwan; the formation of calcium oxalate stone is reportedly associated with genetic polymorphisms but there are many of these. Genotyping requires many individuals and markers because of the complexity of gene-gene and gene-environmental factor interactions. With the development of artificial intelligence, data-mining tools like ANNs can be used to derive more from patient data in predicting disease. Thus we compared 151 patients with calcium oxalate stones and 105 healthy controls for the presence of four genetic polymorphisms; cytochrome p450c17, E-cadherin, urokinase and vascular endothelial growth factor (VEGF). Information about environmental factors, e.g. water, milk and coffee consumption, and outdoor activities, was also collected. Stepwise DA and ANNs were used as classification methods to obtain an effective discriminant model. RESULTS With only the genetic variables, DA successfully classified 64% of the participants, but when all related factors (gene and environmental factors) were considered simultaneously, stepwise DA was successful in classifying 74%. The results for DA were best when six variables (sex, VEGF, stone number, coffee, milk, outdoor activities), found by iterative selection, were used. The ANN successfully classified 89% of participants and was better than DA when considering all factors in the model. A sensitivity analysis of the input parameters for ANN was conducted after the ANN program was trained; the most important inputs affecting stone disease were genetic (VEGF), while the second and third were water and milk consumption. CONCLUSIONS While data-mining tools such as DA and ANN both provide accurate results for assessing genetic markers of calcium stone disease, the ANN provides a better prediction than the DA, especially when considering all (genetic and environmental) related factors simultaneously. This model provides a new way to study stone disease in combination with genetic polymorphisms and environmental factors.
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9.
Urokinase gene 3'-UTR T/C polymorphism is associated with urolithiasis.
Tsai, FJ, Lin, CC, Lu, HF, Chen, HY, Chen, WC
Urology. 2002;(3):458-61
Abstract
OBJECTIVES To study single nucleotide polymorphisms to investigate the possibility that urokinase is involved in the formation of urolithiasis, which, although lacking in genetic evidence, has been previously proposed. METHODS A total of 153 patients with recurrent calcium stones and 105 controls were studied. Polymerase chain reaction-based restriction analysis was used to identify the C/T polymorphism of the urokinase gene, which is mapped on the 3'-untranslated region (3'-UTR) on chromosome 10. RESULTS A significant difference was found in the distribution of the urokinase gene 3'-UTR C/T polymorphism frequency between patients with stones and normal controls (P <0.05). The odds ratio for the risk of the "T" allele in patients with stones was 3.088 (95% confidence interval 1.06 to 8.99). CONCLUSIONS The results of our study demonstrate that the urokinase gene 3'-UTR "T" allele is associated with calcium stone disease. Individuals possessing the "T" allele have a higher incidence of calcium oxalate stone disease. The results of this study provide genetic evidence that the urokinase gene may play a role in stone formation.