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Single-nucleotide Polymorphisms (single-nucleotide + polymorphism)
Kinds of Single-nucleotide Polymorphisms Selected AbstractsSingle-Nucleotide Polymorphisms in Corticotropin Releasing Hormone Receptor 1 Gene (CRHR1) Are Associated With Quantitative Trait of Event-Related Potential and Alcohol DependenceALCOHOLISM, Issue 6 2010Andrew C. H. Chen Background:, Endophenotypes reflect more proximal effects of genes than diagnostic categories, hence providing a more powerful strategy in searching for genes involved in complex psychiatric disorders. There is strong evidence suggesting the P3 amplitude of the event-related potential (ERP) as an endophenotype for the risk of alcoholism and other disinhibitory disorders. Recent studies demonstrated a crucial role of corticotropin releasing hormone receptor 1 (CRHR1) in the environmental stress response and ethanol self-administration in animal models. The aim of the present study was to test the potential associations between single-nucleotide polymorphisms (SNPs) in the CRHR1 gene and the quantitative trait, P3 amplitude during the processing of visual target signals in an oddball paradigm, as well as alcohol dependence diagnosis. Methods:, We analyzed a sample from the Collaborative Study on the Genetics of Alcoholism (COGA) comprising 1049 Caucasian subjects from 209 families (including 472 alcohol-dependent individuals). Quantitative transmission disequilibrium test (QTDT) and family-based association test (FBAT) were used to test the association, and false discovery rate (FDR) was applied to correct for multiple comparisons. Results:, Significant associations (p < 0.05) were found between the P3 amplitude and alcohol dependence with multiple SNPs in the CRHR1 gene. Conclusions:, Our results suggest that CRHR1 may be involved in modulating the P3 component of the ERP during information processing and in vulnerability to alcoholism. These findings underscore the utility of electrophysiology and the endophenotype approach in the genetic study of psychiatric disorders. [source] Asthma and atopy are associated with chromosome 17q21 markers in Chinese childrenALLERGY, Issue 4 2009T. F. Leung Background:, Single-nucleotide polymorphism (SNP)-based genome-wide association study revealed that markers on chromosome 17q21 were linked to childhood asthma but not atopy in Caucasians, with the strongest signal being detected for the SNP rs7216389 in the ORMDL3 gene. Such association was unknown in Chinese. This study delineated the allele and genotype frequencies of 10 SNPs at chromosome 17q21, and investigated the relationship between these SNPs and asthma and plasma IgE in southern Chinese children. Methods:, Asthmatic children and non-allergic controls were recruited from pediatric clinics. Their plasma total and aeroallergen-specific IgE concentrations were measured by immunoassay. Ten SNPs on 17q21 region were genotyped by multiplex SNaPshotÔ, and their genotype associations with asthma traits analyzed using multivariate regression. Results:, 315 patients and 192 controls were enrolled. The allele frequency for C allele of rs7216389 varied significantly from 0.232 in our controls, 0.389 in Han Chinese to 0.536 in Caucasians. Asthma diagnosis was associated with rs11650680 and five other SNPs including rs7216389 (P = 0.019,0.034), whereas atopy was associated only with rs11650680 (P = 0.0004). Linear regression revealed the covariates for plasma total IgE to be significant for rs11650680 (P = 0.008,0.0002). Haplotypic associations were found with atopy and increased plasma total IgE, with the respective odds ratios and 95% confidence intervals for TTTCCGTT haplotype to be 0.21 and 0.09,0.52 (P = 0.0002) and 0.41 and 0.18,0.90 (P = 0.025). Conclusion:, Childhood asthma and atopy are associated with chromosome 17q21 in Chinese, but such association may involve genes other than ORMDL3 in this region. [source] Functional analysis of the osteoarthritis susceptibility,associated GDF5 regulatory polymorphismARTHRITIS & RHEUMATISM, Issue 7 2009Rainer J. Egli Objective Single-nucleotide polymorphism (SNP) rs143383 (T to C) in the 5,-untranslated region (5,-UTR) of GDF5 has recently been reported to be associated with osteoarthritis (OA) susceptibility, with lower expression of the risk-associated T allele observed in vitro and in vivo. The in vivo studies were performed on cartilage tissue from OA patients. The present study was undertaken to expand the analysis of the effect of this SNP on GDF5 allelic expression to more joint tissue types, to investigate for cis and trans factors that interact with the SNP, and to examine novel cis -acting GDF5 regulatory polymorphisms. Methods Tissue samples were collected from OA patients undergoing joint replacement of the hip or knee. Nucleic acid was extracted, and, using rs143383 and an assay that discriminates and quantifies allelic expression, the relative amount of GDF5 expression from the T and C alleles was measured. Additional common variants in the GDF5 transcript sequence were interrogated as potential regulatory elements using allelic expression and luciferase reporter assays, and electrophoretic mobility shift assays were used to search for trans factors binding to rs143383. Results We observed a consistent allelic expression imbalance of GDF5 in all tissues tested, implying that the functional effect mediated by rs143383 on GDF5 expression is joint-wide. We identified a second polymorphism, located in the 3,-UTR of GDF5, that influenced allelic expression of the gene independent of rs143383. Finally, we observed differential binding of deformed epidermal autoregulatory factor 1 (DEAF-1) to the 2 alleles of rs143383. Conclusion These findings show that the OA susceptibility mediated by polymorphism in GDF5 is not restricted to cartilage, emphasizing the need to consider the disease as involving the whole joint. The existence of an additional cis -acting regulatory polymorphism highlights the complexity of the regulation of expression of this important OA susceptibility locus. DEAF-1 is a trans -acting factor that merits further investigation as a potential tool for modulating GDF5 expression. [source] A novel promoter polymorphism in the gene encoding complement component 5 receptor 1 on chromosome 19q13.3 is not associated with asthma and atopy in three independent populationsCLINICAL & EXPERIMENTAL ALLERGY, Issue 5 2004K. C. Barnes Summary Background The inflammatory functions of complement component 5 (C5) are mediated by its receptor, C5R1, which is expressed on bronchial, epithelial, vascular endothelial and smooth muscle cells. A susceptibility locus for murine allergen-induced airway hyper-responsiveness was identified in a region syntenic to human chromosome 19q13, where linkage to asthma has been demonstrated and where the gene encoding C5R1 is localized. Objective The aim of this study was to screen for novel polymorphisms in the C5R1 gene and to determine whether any identified polymorphisms are associated with asthma and/or atopy and whether they are functional. Methods Single-nucleotide polymorphism (SNP) detection in the gene encoding C5R1 was performed by direct sequencing. Genotyping was performed in three populations characterized for asthma and/or atopy: (1) 823 German children from The Multicenter Allergy Study; (2) 146 individuals from Tangier Island, Virginia, a Caucasian isolate; and (3) asthma case,parent trios selected from 134 families (N=783) in Barbados. Functional studies were performed to evaluate differences between the wild-type and the variant alleles. Results We identified a novel SNP in the promoter region of C5R1 at position ,245 (T/C). Frequency of the ,245C allele was similar in the German (31.5%) and Tangier Island (36.3%) populations, but higher in the Afro-Caribbean population (53.0%; P=0.0039 to <0.0001). We observed no significant associations between the ,245 polymorphism and asthma or atopy phenotypes. Upon examination of the functional consequences of the ,245T/C polymorphism, we did not observe any change in promoter activity. Conclusion This new marker may provide a valuable tool to assess the risk for C5a-associated disorders, but it does not appear to be associated with asthma and/or atopy. [source] The PIP5K2A and RGS4 genes are differentially associated with deficit and non-deficit schizophreniaGENES, BRAIN AND BEHAVIOR, Issue 2 2007S. C. Bakker Several putative schizophrenia susceptibility genes have recently been reported, but it is not clear whether these genes are associated with schizophrenia in general or with specific disease subtypes. In a previous study, we found an association of the neuregulin 1 (NRG1) gene with non-deficit schizophrenia only. We now report an association study of four schizophrenia candidate genes in patients with and without deficit schizophrenia, which is characterized by severe and enduring negative symptoms. Single-nucleotide polymorphisms (SNPs) were genotyped in the DTNBP1 (dysbindin), G72/G30 and RGS4 genes, and the relatively unknown PIP5K2A gene, which is located in a region of linkage with both schizophrenia and bipolar disorder. The sample consisted of 273 Dutch schizophrenia patients, 146 of whom were diagnosed with deficit schizophrenia and 580 controls. The strongest evidence for association was found for the A-allele of SNP rs10828317 in the PIP5K2A gene, which was associated with both clinical subtypes (P = 0.0004 in the entire group; non-deficit P = 0.016, deficit P = 0.002). Interestingly, this SNP leads to a change in protein composition. In RGS4, the G-allele of the previously reported SNP RGS4-1 (single and as part of haplotypes with SNP RGS4-18) was associated with non-deficit schizophrenia (P = 0.03) but not with deficit schizophrenia (P = 0.79). SNPs in the DTNBP1 and G72/G30 genes were not significantly associated in any group. In conclusion, our data provide further evidence that specific genes may be involved in different schizophrenia subtypes and suggest that the PIP5K2A gene deserves further study as a general susceptibility gene for schizophrenia. [source] Single-nucleotide polymorphisms in the IL-4 and IL-13 promoter region in aggressive periodontitisJOURNAL OF CLINICAL PERIODONTOLOGY, Issue 6 2007J. R. Gonzales Abstract Introduction: IL-4 and IL-13 polymorphisms have been shown to influence the susceptibility to systemic diseases. In this study, possible associations between the IL-4 ,590 C,T, IL-4 ,34 C,T, IL-13 ,1112 C,T and IL-13 ,1512 A,C promoter polymorphisms were investigated in subjects with generalized aggressive periodontitis (AgP) compared with healthy individuals. Material and Methods: Fifty-eight patients with diagnosis of generalized AgP and 51 matched healthy controls participated in the study. Blood samples were collected and DNA isolated. Molecular analyses were performed by PCR-RFLP in a blind fashion. Genotype and allele frequencies among study groups were compared using Fisher's exact test (, value: 0.05). Pearson's ,2 test was used for analysis of Hardy,Weinberg equilibrium. Results: The frequency of the IL-4 ,590 T/T and IL-4 ,34 T/T genotypes differed significantly between groups (p=0.05, 0.02, respectively), although the allele frequencies were similar. There was a higher frequency of the IL-4 ,590 T/T and IL-4 ,34 T/T genotypes in patients with AgP compared with controls. The genotype and allele frequencies of the IL-13 polymorphisms did not differ between groups. Conclusions: This study demonstrated an association between the IL-4 ,590 T/T and IL-4 ,34 T/T genotypes and AgP. Further research is necessary to prove if there is an association of these polymorphisms with AgP, and if the polymorphisms have a functional effect. [source] Single-nucleotide polymorphisms and mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent depressive disorderJOURNAL OF PINEAL RESEARCH, Issue 4 2010Piotr Ga, ecki Abstract:, Depressive disorder (DD) is characterised by disturbances in blood melatonin concentration. It is well known that melatonin is involved in the control of circadian rhythms, sleep included. The use of melatonin and its analogues has been found to be effective in depression therapy. Melatonin synthesis is a multistage process, where the last stage is catalysed by acetylserotonin methyltransferase (ASMT), the reported rate-limiting melatonin synthesis enzyme. Taking into account the significance of genetic factors in depression development, the gene for ASMT may become an interesting focus for studies in patients with recurrent DD. The goal of the study was to evaluate two single-nucleotide polymorphisms (SNPs) (rs4446909; rs5989681) of the ASMT gene, as well as mRNA expression for ASMT in recurrent DD-affected patients. We genotyped two polymorphisms in a group of 181 recurrent DD patients and in 149 control subjects. The study was performed using the polymerase chain reaction/restriction fragment length polymorphism method. The distribution of genotypes in both studied SNPs in the ASMT gene differed significantly between DD and healthy subjects. The presence of AA genotype of rs4446909 polymorphism and of GG genotype of rs5989681 polymorphism was associated with lower risk for having recurrent DD. In turn, patients with depression were characterised by reduced mRNA expression for ASMT. In addition, ASMT transcript level in both recurrent DD patients and in healthy subjects depended significantly on genotype distributions in both polymorphisms. In conclusion, our results suggest the ASMT gene as a susceptibility gene for recurrent DD. [source] Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 2 2010Di Feng Objective Genetic variants of the interferon (IFN) regulatory factor 5 gene (IRF5) are associated with susceptibility to systemic lupus erythematosus (SLE). The contribution of these variants to IRF-5 expression in primary blood cells of SLE patients has not been addressed, nor has the role of type I IFNs. The aim of this study was to determine the association between increased IRF-5 expression and the IRF5 risk haplotype in SLE patients. Methods IRF-5 transcript and protein levels in 44 Swedish patients with SLE and 16 healthy controls were measured by quantitative real-time polymerase chain reaction, minigene assay, and flow cytometry. Single-nucleotide polymorphisms rs2004640, rs10954213, and rs10488631 and the CGGGG insertion/deletion were genotyped in these patients. Genotypes of these polymorphisms defined both a common risk haplotype and a common protective haplotype. Results IRF-5 expression and alternative splicing were significantly up-regulated in SLE patients compared with healthy donors. Enhanced transcript and protein levels were associated with the risk haplotype of IRF5; rs10488631 displayed the only significant independent association that correlated with increased transcription from the noncoding first exon 1C. Minigene experiments demonstrated an important role for rs2004640 and the CGGGG insertion/deletion, along with type I IFNs, in regulating IRF5 expression. Conclusion This study provides the first formal proof that IRF-5 expression and alternative splicing are significantly up-regulated in primary blood cells of patients with SLE. Furthermore, the risk haplotype is associated with enhanced IRF-5 transcript and protein expression in patients with SLE. [source] Variation at the ANP32A gene is associated with risk of hip osteoarthritis in womenARTHRITIS & RHEUMATISM, Issue 7 2009Ana M. Valdes Objective The ANP32A gene encodes a tumor suppressor molecule that plays a regulatory role in apoptosis and interferes with canonical Wnt signaling in vitro. We undertook this study to test whether genetic variation at ANP32A was associated with osteoarthritis (OA) in women. Methods Single-nucleotide polymorphisms (SNPs) in the ANP32A gene were genotyped in 438 control women, 425 women with total knee replacements (TKRs), and 537 women with total hip replacements (THRs) from the Nottingham case,control study as well as in 820 women from the population-based Chingford Study cohort for whom hip and knee radiographs were available. The most highly associated SNP was further tested in women from the Rotterdam Study (131 with THRs, 633 with knee OA, and 1,567 controls) and the TwinsUK Study cohort (67 with THRs, 43 with TKRs, and 358 controls), for a total of 2,170 patients with OA and 2,849 controls. Results The ANP32A transcript was abundantly expressed in normal and OA articular cartilage. Three SNPs in the ANP32A gene were significantly associated in Nottingham patients with hip OA, but not knee OA. One of these (rs7164503) was associated with hip and knee OA in the Chingford Study cohort and with THR in the TwinsUK Study cohort, but the association was not statistically significant in the Rotterdam Study. When we combined hip data from all 4 cohorts, we found that the minor allele of rs7164503 was associated with a significantly lower risk of hip OA (Mantel-Haenszel odds ratio 0.67 [95% confidence interval 0.53,0.84], P < 3.8 × 10,4) and that a similar trend was observed for knee OA (Mantel-Haenszel odds ratio 0.87 [95% confidence interval 0.73,1.01], P < 0.055). Conclusion Our results provide evidence suggesting that ANP32A is involved in the pathogenesis of OA of the hip. [source] Association of adrenergic receptor gene polymorphisms with different fibromyalgia syndrome domainsARTHRITIS & RHEUMATISM, Issue 7 2009Gilberto Vargas-Alarcón Objective Fibromyalgia (FM) patients have signs of relentless sympathetic hyperactivity associated with hyporeactivity to stress. Adrenergic receptors (ARs) are parts of the sympathetic nervous system that are fundamental for maintenance of homeostasis. We undertook this study to correlate ,-AR and ,-AR gene polymorphisms with the presence of FM and with different domains of the FM syndrome as measured by the Fibromyalgia Impact Questionnaire (FIQ). Methods We studied 78 Mexican FM patients and 48 age-matched controls as well as 78 Spanish FM patients and 71 controls. All subjects studied were women. Single-nucleotide polymorphisms (SNPs) of ,1A -AR (rs574584, rs1383914, rs1048101, and rs573542), ,2 -AR (rs1042713 and rs1042714), and ,3 -AR (rs4994) were analyzed by 5, exonuclease TaqMan polymerase chain reaction. Polymorphic haplotypes were constructed after linkage disequilibrium analysis. Results The ,2 -AR AC haplotype was a risk factor for the presence of FM. This haplotype had an increased frequency in Mexican patients compared with Mexican controls (42.1% versus 30.5%; P = 0.04). Similarly, 50.4% of Spanish patients had this haplotype compared with 40.0% of Spanish controls (P = 0.05). In Spanish patients, the ,1A -AR SNP rs1383914 was associated with the presence of FM (P = 0.01), and the ,1A -AR SNP rs1048101 was linked with FIQ disability (P = 0.02). Mexican patients with the rs574584 GG genotype presented the highest FIQ score compared with Mexican patients with other genotypes (P = 0.01), and in Mexicans SNP rs574584 was associated with FIQ morning stiffness (P = 0.04) and with FIQ tiredness upon awakening (P = 0.02). Conclusion AR gene polymorphisms are related to the risk of developing FM and are also linked to different domains of the FM syndrome. [source] Identification of a novel susceptibility locus for juvenile idiopathic arthritis by genome-wide association analysisARTHRITIS & RHEUMATISM, Issue 1 2009Anne Hinks Objective Juvenile idiopathic arthritis (JIA) is a chronic rheumatic disease of childhood. Two well-established genetic factors known to contribute to JIA susceptibility, HLA and PTPN22, account for less than half of the genetic susceptibility to disease; therefore, additional genetic factors have yet to be identified. The purpose of this study was to perform a systematic search of the genome to identify novel susceptibility loci for JIA. Methods A genome-wide association study using Affymetrix GeneChip 100K arrays was performed in a discovery cohort (279 cases and 184 controls). Single-nucleotide polymorphisms (SNPs) showing the most significant differences between cases and controls were then genotyped in a validation sample of cases (n = 321) and controls, combined with control data from the 1958 UK birth cohort (n = 2,024). In one region in which association was confirmed, fine-mapping was performed (654 cases and 1,847 controls). Results Of the 112 SNPs that were significantly associated with JIA in the discovery cohort, 6 SNPs were associated with JIA in the independent validation cohort. The most strongly associated SNP mapped to the HLA region, while the second strongest association was with a SNP within the VTCN1 gene. Fine-mapping of that gene was performed, and 10 SNPs were found to be associated with JIA. Conclusion This study is the first to successfully apply a SNP-based genome-wide association approach to the investigation of JIA. The replicated association with markers in the VTCN1 gene defined an additional susceptibility locus for JIA and implicates a novel pathway in the pathogenesis of this chronic disease of childhood. [source] Low prevalence of progranulin mutations in Finnish patients with frontotemporal lobar degenerationEUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2009J. Krüger Background and purpose:, Mutations in the progranulin (PGRN) gene have recently been associated with frontotemporal lobar degeneration (FTLD). The frequency of these mutations varies between populations. The aim of this study was to determine mutations and genetic variations of the PGRN gene in Finnish patients with FTLD and FTLD with associated motor neuron disease (FTLD-MND). Subjects and methods:, All exons of the PGRN gene were sequenced from 69 Finnish patients with FTLD. The FTLD-MND phenotype was present in 13 of the 69 patients. Results:, No pathogenic PGRN mutations were identified in the cohort. Eleven sequence variations were detected, of which IVS8 + 15C>T, IVS4-51_-52insAGTC and IVS11 + 25G>A have not been reported previously. At least one single-nucleotide polymorphism (SNP) of PGRN was detected in 83% of patients. Conclusions:, We conclude that mutations in PGRN are rare among Finnish patients with FTLD and FTLD-MND. However, SNPs were frequent suggesting high genetic variability of the PGRN gene. [source] Single QTL mapping and nucleotide-level resolution of a physiologic trait in wine Saccharomyces cerevisiae strainsFEMS YEAST RESEARCH, Issue 6 2007Philippe Marullo Abstract Natural Saccharomyces cerevisiae yeast strains exhibit very large genotypic and phenotypic diversity. However, the link between phenotype variation and genetic determinism is still difficult to identify, especially in wild populations. Using genome hybridization on DNA microarrays, it is now possible to identify single-feature polymorphisms among divergent yeast strains. This tool offers the possibility of applying quantitative genetics to wild yeast strains. In this instance, we studied the genetic basis for variations in acetic acid production using progeny derived from two strains from grape must isolates. The trait was quantified during alcoholic fermentation of the two strains and 108 segregants derived from their crossing. A genetic map of 2212 markers was generated using oligonucleotide microarrays, and a major quantitative trait locus (QTL) was mapped with high significance. Further investigations showed that this QTL was due to a nonsynonymous single-nucleotide polymorphism that targeted the catalytic core of asparaginase type I (ASP1) and abolished its activity. This QTL was only effective when asparagine was used as a major nitrogen source. Our results link nitrogen assimilation and CO2 production rate to acetic acid production, as well as, on a broader scale, illustrating the specific problem of quantitative genetics when working with nonlaboratory microorganisms. [source] Temporal lobe grey matter volume in schizophrenia is associated with a genetic polymorphism influencing glycogen synthase kinase 3-, activityGENES, BRAIN AND BEHAVIOR, Issue 4 2010F. Benedetti At the crossroad of multiple pathways regulating trophism and metabolism, glycogen synthase kinase (GSK)3 is considered a key factor in influencing the susceptibility of neurons to harmful stimuli (neuronal resilience) and is a target for several psychiatric drugs that directly inhibit it or increase its inhibitory phosphorylation. Inhibition of GSK3 prevents apoptosis and could protect against the neuropathological processes associated with psychiatric disorders. A GSK3- ,promoter single-nucleotide polymorphism (rs334558) influences transcriptional strength, and the less active form was associated with less detrimental clinical features of mood disorders. Here we studied the effect of rs334558 on grey matter volumes (voxel-based morphometry) of 57 patients affected by chronic schizophrenia. Carriers of the less active C allele variant showed significantly higher brain volumes in an area encompassing posterior regions of right middle and superior temporal gyrus, within the boundaries of Brodmann area 21. The temporal lobe is the brain parenchymal region with the most consistently documented morphometric abnormalities in schizophrenia, and neuropathological processes in these regions develop soon at the beginning of the illness. These results support the interest for GSK3- ,as a factor affecting neuropathology in major behavioural disorders, such as schizophrenia, and thus as a possible target for treatment. [source] Behavioral and neurochemical phenotyping of Homer1 mutant mice: possible relevance to schizophreniaGENES, BRAIN AND BEHAVIOR, Issue 5 2005K. K. Szumlinski Homer proteins are involved in the functional assembly of postsynaptic density proteins at glutamatergic synapses and are implicated in learning, memory and drug addiction. Here, we report that Homer1 -knockout (Homer1 -KO) mice exhibit behavioral and neurochemical abnormalities that are consistent with the animal models of schizophrenia. Relative to wild-type mice, Homer1 -KO mice exhibited deficits in radial arm maze performance, impaired prepulse inhibition, enhanced ,behavioral despair', increased anxiety in a novel objects test, enhanced reactivity to novel environments, decreased instrumental responding for sucrose and enhanced MK-801- and methamphetamine-stimulated motor behavior. No-net-flux in vivo microdialysis revealed a decrease in extracellular glutamate content in the nucleus accumbens and an increase in the prefrontal cortex. Moreover, in Homer1 -KO mice, cocaine did not stimulate a rise in frontal cortex extracellular glutamate levels, suggesting hypofrontality. These behavioral and neurochemical data derived from Homer1 mutant mice are consistent with the recent association of schizophrenia with a single-nucleotide polymorphism in the Homer1 gene and suggest that the regulation of extracellular levels of glutamate within limbo-corticostriatal structures by Homer1 gene products may be involved in the pathogenesis of this neuropsychiatric disorder. [source] D324N single-nucleotide polymorphism in the FLT3 gene is associated with higher risk of myeloid leukemiasGENES, CHROMOSOMES AND CANCER, Issue 4 2006Susanne Schnittger Mutations within the FLT3 gene are of growing importance for classification, risk assessment, and therapeutic targeting of acute myeloid leukemia (AML). We analyzed 656 AML patients for a recently described single-nucleotide polymorphism (SNP) in the third immunoglobulin-like domain of the extracellular region of FLT3. The FLT3 D324N variant was present in 42 cases (6.4%), but it was not associated with a specific AML subtype and did not show an elevated leukocyte count, as do other FLT3 mutations. In remission samples, a 50% ratio of the normal to the D324N variant was detectable. Stably expressed in IL-3 dependent Ba/F3 cells, the D324N variant did not confer receptor autophosphorylation, factor independent growth, or increased resistance to apoptotic cell death in response to varying doses of FLT3 ligand. In 400 healthy donors, the FLT3 D324N variant was detected in 6 cases (1.5%) and segregated in a family. Thus, it was shown to be a polymorphism with a lower frequency in healthy controls than in patients with AML (P < 0.001). In addition, 21 of 234 CML (9.0%) and 7 of 155 ALL (4.5%) cases carried the FLT3 D324N. Our data suggest that the FLT3 D324N variant might be associated with a predisposition to different subtypes of leukemia. © 2005 Wiley-Liss, Inc. [source] Comparison of single-nucleotide polymorphisms and microsatellite markers for linkage analysis in the COGA and simulated data sets for Genetic Analysis Workshop 14: Presentation Groups 1, 2, and 3GENETIC EPIDEMIOLOGY, Issue S1 2005Marsha A. Wilcox Abstract The papers in presentation groups 1,3 of Genetic Analysis Workshop 14 (GAW14) compared microsatellite (MS) markers and single-nucleotide polymorphism (SNP) markers for a variety of factors, using multiple methods in both data sets provided to GAW participants. Group 1 focused on data provided from the Collaborative Study on the Genetics of Alcoholism (COGA). Group 2 focused on data simulated for the workshop. Group 3 contained analyses of both data sets. Issues examined included: information content, signal strength, localization of the signal, use of haplotype blocks, population structure, power, type I error, control of type I error, the effect of linkage disequilibrium, and computational challenges. There were several broad resulting observations. 1) Information content was higher for dense SNP marker panels than for MS panels, and dense SNP markers sets appeared to provide slightly higher linkage scores and slightly higher power to detect linkage than MS markers. 2) Dense SNP panels also gave higher type I errors, suggesting that increased test thresholds may be needed to maintain the correct error rate. 3) Dense SNP panels provided better trait localization, but only in the COGA data, in which the MS markers were relatively loosely spaced. 4) The strength of linkage signals did not vary with the density of SNP panels, once the marker density was ,1 SNP/cM. 5) Analyses with SNPs were computationally challenging, and identified areas where improvements in analysis tools will be necessary to make analysis practical for widespread use. Genet. Epidemiol. 29:(Suppl. 1): S7,S28, 2005. © 2005 Wiley-Liss, Inc. [source] Linkage mapping methods applied to the COGA data set: Presentation Group 4 of Genetic Analysis Workshop 14GENETIC EPIDEMIOLOGY, Issue S1 2005E. Warwick Daw Abstract Presentation Group 4 participants analyzed the Collaborative Study on the Genetics of Alcoholism data provided for Genetic Analysis Workshop 14. This group examined various aspects of linkage analysis and related issues. Seven papers included linkage analyses, while the eighth calculated identity-by-descent (IBD) probabilities. Six papers analyzed linkage to an alcoholism phenotype: ALDX1 (four papers), ALDX2 (one paper), or a combination both (one paper). Methods used included Bayesian variable selection coupled with Haseman-Elston regression, recursive partitioning to identify phenotype and covariate groupings that interact with evidence for linkage, nonparametric linkage regression modeling, affected sib-pair linkage analysis with discordant sib-pair controls, simulation-based homozygosity mapping in a single pedigree, and application of a propensity score to collapse covariates in a general conditional logistic model. Alcoholism linkage was found with ,2 of these approaches on chromosomes 2, 4, 6, 7, 9, 14, and 21. The remaining linkage paper compared the utility of several single-nucleotide polymorphism (SNP) and microsatellite marker maps for Monte Carlo Markov chain combined oligogenic segregation and linkage analysis, and analyzed one of the electrophysiological endophenotypes, ttth1, on chromosome 7. Linkage was found with all marker sets. The last paper compared the multipoint IBD information content of several SNP sets and the microsatellite set, and found that while all SNP sets examined contained more information than the microsatellite set, most of the information contained in the SNP sets was captured by a subset of the SNP markers with ,1-cM marker spacing. From these papers, we highlight three points: a 1-cM SNP map seems to capture most of the linkage information, so denser maps do not appear necessary; careful and appropriate use of covariates can aid linkage analysis; and sources of increased gene-sharing between relatives should be accounted for in analyses. Genet. Epidemiol. 29(Suppl. 1):S29,S34, 2005. © 2005 Wiley-Liss, Inc. [source] A common variant in the patatin-like phospholipase 3 gene (PNPLA3) is associated with fatty liver disease in obese children and adolescents,,HEPATOLOGY, Issue 4 2010Nicola Santoro The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene (PNPLA3) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3(rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype (P = 0.005). Although the expression of PNPLA3, PNPLA2, PPAR,2(peroxisome proliferator-activated receptor gamma 2), SREBP1c(sterol regulatory element binding protein 1c), and ACACA(acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin (LEP)(P = 0.03) and sirtuin 1 (SIRT1) expression (P = 0.04). Conclusion: A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size. (HEPATOLOGY 2010.) [source] Variation in enterovirus receptor genesJOURNAL OF MEDICAL VIROLOGY, Issue 1 2003Åse Karttunen Abstract The increased incidence of a enterovirus infections observed in patients with type 1 diabetes preceding the development of the clinical disease could be partially explained by variation in the genes coding for enterovirus receptors. We carried out sequence analysis of the most common enterovirus receptor molecules in 21 diabetic children and 20 healthy adults. DNA was isolated from the leukocytes, and gene regions known to code for virus-recognizing domains in major enterovirus receptors were amplified and sequenced. Heterozygous single-nucleotide polymorphism (SNP), Ala 67 (GCG),,,Thr (ACG), was detected in the poliovirus receptor gene in four individuals in the diabetes group, but not in the control group. However, serological studies could not confirm that this substitution would convey different susceptibility to poliovirus infection. A heterozygous SNP, Lys 29 (AAG),,,Met (ATG), was found in the intracellular adhesion molecule-1 (ICAM-1) (receptor for rhinoviruses and some coxsackie A viruses) in one individual in both groups. A silent SNP in the ,2 integrin subunit gene (echovirus 1 receptor) was frequently found in both groups, a silent heterozygotic SNP in coxsackievirus-adenovirus receptor (coxsackie B virus receptor) gene was seen in one individual in the diabetes group, whereas no variation was found in the DAF (echovirus receptor) and ,3 integrin subunit sequences (receptor for coxsackievirus A9) studied. In conclusion, both synonymous and nonsynonymous sequence variability of genes coding for enterovirus and rhinovirus receptors was shown to occur, but no pattern directly specific for type 1 diabetes was found. J. Med. Virol. 70:99,108, 2003. © 2003 Wiley-Liss, Inc. [source] Initial Evidence of an Association Between OPRM1 and Adolescent Alcohol MisuseALCOHOLISM, Issue 1 2010Robert Miranda Background:, Considerable research efforts have attempted to identify genes associated with alcoholism among adults, yet few studies have examined adolescents. Identifying genes associated with alcohol misuse in youth is important given that the relative contribution of genetic and environmental influences on alcoholism varies across development. The purpose of this study was to examine the association between a polymorphism of the ,-opioid receptor gene (OPRM1) and alcohol misuse in a sample of youth and to test whether heightened sensitivity to the reinforcing effects of alcohol mediated this relationship. Methods:, Adolescents (n = 187; mean age = 15.4 years; 47.6% female) were genotyped for A118G (rs1799971), a single-nucleotide polymorphism (SNP) of the OPRM1 gene, and assessed for alcohol use disorder (AUD) diagnoses and other psychopathology. Alcohol misuse was also measured continuously to maximize detection of drinking problems in youth. Drinking motives were used to capture the extent to which youth consumed alcohol to enhance positive affect. Results:, AUD groups differed significantly in terms of allelic distributions of the A118G SNP, such that 51.9% of youth with an AUD carried at least one copy of the G allele compared to 16.3% of non-AUD controls. Those who carried the G allele endorsed drinking to enhance positive affect more strongly than those who were homozygous for the A allele and drinking to enhance positive affect mediated the association between OPRM1 and alcohol-related problems. Conclusions:, These data build on findings from adult studies and provide the first evidence that a polymorphism of the OPRM1 receptor gene is associated with the development of early-onset alcohol-related problems during adolescence, in part, by heightening sensitivity to the reinforcing effects of alcohol. [source] A single-nucleotide polymorphism in the 5,-untranslated region of the hPER2 gene is associated with diurnal preferenceJOURNAL OF SLEEP RESEARCH, Issue 3 2005JAYSHAN D. CARPEN Summary The PERIOD2 (PER2) gene is a key component of the molecular mechanism that generates circadian rhythms in mammals. A missense mutation in the human PER2 gene has previously been linked to advanced sleep phase syndrome (ASPS). We have investigated three other single-nucleotide polymorphisms in the hPER2 gene, one downstream of the transcription start site (C,1228T), one in exon 2 in the 5,-untranslated region (5,-UTR) (C111G), and one missense mutation (G3853A) causing a glycine to glutamine substitution in the predicted protein. Subjects selected from a group of 484 volunteers for extreme morning or evening preference, or intermediate diurnal preference were genotyped with regard to the three polymorphisms (n = 35 for each group). Whereas allele frequencies for the other two polymorphisms did not differ significantly between any of the groups, the 111G allele frequency was significantly higher in subjects with extreme morning preference (0.14) than in subjects with extreme evening preference (0.03) (Fisher's exact test, two-sided P value = 0.031, odds ratio = 5.67). No significant difference in 111G allele frequency was observed between either of these groups and subjects with intermediate diurnal preference. Computer prediction indicated that the C111G polymorphism, which occurs 12 bases upstream from the translation start codon, might alter the secondary structure of the transcript. The PER2 111G allele associates with morning preference and is a potential candidate allele for ASPS. [source] Association of the toll-like receptor 2 A-16934T promoter polymorphism with severe atopic dermatitisALLERGY, Issue 11 2009D.-Y. Oh Background:, Atopic dermatitis (AD) is a chronic inflammatory skin disease with a multifactorial pathogenesis and increasing incidence in the Western world. A genetically determined defective function of pattern recognition receptors such as toll-like receptors (TLRs) has been proposed as a candidate mechanism in the pathogenesis of AD. Aim:, To study the impact of genetic predisposition of five genes encoding for pattern recognition-related molecules for the phenotype of AD. Methods:, We examined nine different single-nucleotide polymorphism (SNP) frequencies in the genes encoding TLR1, -2, -4, -9 and the adapter molecule TIRAP by PCR with subsequent melting curve analysis in a case/control cohort of 136 adult AD patients and 129 age and gender matched non-atopic, healthy individuals. TLR2-expression and -function in cells from genotyped individuals were analysed. Results:, For the SNPs examined, similar genotype frequencies were found in both groups. In a subgroup of patients suffering from severe AD (SCORAD >50), a significantly increased representation of the A-allele in position ,16934 of the tlr2 gene was present (P = 0.004). Constitutive tlr2 mRNA expression in peripheral monocytes was independent of this tlr2 promoter SNP. Stimulation assays indicated that IL-6, but not TNF-, secretion following TLR2 stimulation is reduced in homozygous tlr2 -16934-A allele carriers. Conclusion:, These data indicate that TLR2 is relevant for the phenotype of severe AD in adults. [source] INFERRING PROCESSES DURING INTRODUCTION AND RANGE EXPANSION: Detecting strong positive selection in the genomeMOLECULAR ECOLOGY RESOURCES, Issue 5 2010WOLFGANG STEPHAN Abstract New statistical tests have been developed in the past decade that enable us to infer evidence of recent strong positive selection from genome-wide data on single-nucleotide polymorphism and to localize the targets of selection in the genome. Based on these tests, past demographic events that led to distortions of the site-frequency spectrum of variation can be distinguished from selection, in particular if linkage disequilibrium is taken into account. These methods have been successfully applied to species from which complete sequence information and polymorphism data are available, including Drosophila melanogaster, humans, and several plant species. To make full use of the available data, however, the tests that were primarily designed for panmictic populations need to be extended to spatially structured populations. [source] A sodium channel gene SCN9A polymorphism that increases nociceptor excitability,ANNALS OF NEUROLOGY, Issue 6 2009Mark Estacion PhD Sodium channel NaV1.7, encoded by the SCN9A gene, is preferentially expressed in nociceptive primary sensory neurons, where it amplifies small depolarizations. In studies on a family with inherited erythromelalgia associated with NaV1.7 gain-of-function mutation A863P, we identified a nonsynonymous single-nucleotide polymorphism within SCN9A in the affected proband and several unaffected family members; this polymorphism (c. 3448C&T, Single Nucleotide Polymorphisms database rs6746030, which produces the amino acid substitution R1150W in human NaV1.7 [hNaV1.7]) is present in 1.1 to 12.7% of control chromosomes, depending on ethnicity. In this study, we examined the effect of the R1150W substitution on function of the hNaV1.7 channel, and on the firing of dorsal root ganglion (DRG) neurons in which this channel is normally expressed. We show that this polymorphism depolarizes activation (7.9,11mV in different assays). Current-clamp analysis shows that the 1150W allele depolarizes (6mV) resting membrane potential and increases (,2-fold) the firing frequency in response to depolarization in DRG neurons in which it is present. Our results suggest that polymorphisms in the NaV1.7 channel may influence susceptibility to pain. Ann Neurol 2009;66:862,866 [source] Characterization of single-nucleotide polymorphism markers in the Mediterranean mussel, Mytilus galloprovincialisAQUACULTURE RESEARCH, Issue 10 2010Manuel Vera Abstract The Mediterranean mussel, Mytilus galloprovincialis, is one of the most important aquaculture species in Europe. Appropriate molecular markers are required to evaluate genetic resources and to trace genealogies in breeding programmes for improving mussel culture. Microsatellites have been commonly applied to this purpose in other species. However, Mediterranean mussel microsatellites have demonstrated high frequencies of null alleles that hamper accurate estimates of population parameters and confident parentage inferences. As alternative markers, we have characterized in silico 25 potential single-nucleotide polymorphism (SNP) markers in the Mediterranean mussel from expressed sequence tag (EST) public databases. The genotyping of SNPs was performed using a single-base extension approach. Their polymorphism was evaluated in 47 individuals from an Atlantic population. Out of the 25 potential SNPs tested, 12 were technically feasible (producing a single amplicon) and polymorphic. All were biallelic and had an unbiased heterozygosity ranging from 0.160 to 0.504. One SNP was from a mitochondrial gene. The combined potential of nuclear SNPs for parentage assignment gave an exclusion probability of a false couple of parents of 0.9471. These markers will be useful for evaluating resources and tracing genealogies in genetic breeding programmes implemented to solve the main problems of mussel culture. [source] Deletion of the late cornified envelope genes, LCE3C and LCE3B, is associated with rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 5 2010Elisa Docampo Objective The risk of rheumatoid arthritis (RA) is increased in the offspring of individuals affected with various autoimmune disorders, including psoriasis. Recently, the deletion of 2 genes from the late cornified envelope (LCE) gene cluster, LCE3C and LCE3B, has been associated with psoriasis in several populations. The purpose of this study was to assess whether this polymorphic gene deletion could also be involved in susceptibility to RA. Methods We tested for association between the LCE3C_LCE3B copy number variant and a single-nucleotide polymorphism in strong linkage disequilibrium with this variant (rs4112788) and RA in 2 independent case,control data sets (197 and 400 samples from patients with RA, respectively, and 411 and 567 samples from control subjects, respectively), collected at 4 Spanish hospitals. All samples were directly typed for presence of the LCE3C_LCE3B deletion (LCE3C_LCE3B- del) by polymerase chain reaction, and association analysis was performed using the SNPassoc R package. Results An association of homozygosity for the LCE3C_LCE3B -del and rs4112788 C allele with the risk of RA was observed in the first data set and was replicated in an independent case,control set. A combined analysis showed an overall P value of 0.0012 (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.16,1.81) for association of the LCE3C_LCE3B- del. When the analysis was stratified for serologic data, we observed association in anti,cyclic citrullinated peptide (anti-CCP),positive patients (P = 0.012, OR 1.51 [95% CI 1.09,2.13]) but not in anti-CCP,negative patients. Conclusion We have identified an association between the LCE3C_LCE3B -del and RA, and we have verified a pleiotropic effect of a common genetic risk factor (LCE3C_LCE3B- del) for autoimmune diseases that is involved in both psoriasis and RA. [source] The association of a nonsynonymous single-nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese populationARTHRITIS & RHEUMATISM, Issue 2 2010Kenichi Shimane Objective Genome-wide association (GWA) studies in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) in Caucasian populations have independently identified risk variants in and near the tumor necrosis factor , (TNF,),induced protein 3 gene (TNFAIP3), which is crucial for the regulation of TNF-mediated signaling and Toll-like receptor signaling. The aim of this study was to assess the role of TNFAIP3 in the development of SLE and RA in Japanese subjects. Methods We selected 2 single-nucleotide polymorphisms (SNPs) from previous GWA studies. Rs2230926 is a nonsynonymous SNP in TNFAIP3 and is associated with SLE, while rs10499194 is an intergenic SNP associated with RA. We then performed 2 independent sets of SLE case,control comparisons (717 patients and 1,362 control subjects) and 3 sets of RA case,control comparisons (3,446 patients and 2,344 control subjects) using Japanese subjects. We genotyped SNPs using TaqMan assays. Results We observed a significant association between rs2230926 and an increased risk of SLE and RA in the Japanese population (for SLE, odds ratio [OR] 1.92, 95% confidence interval [95% CI] 1.53,2.41, P = 1.9 × 10,8; for RA, OR 1.35, 95% CI 1.18,1.56, P = 2.6 × 10,5). The intergenic SNP rs10499194 was also associated with SLE and RA, while the risk allele for RA in Caucasians was protective against the diseases in our population. Conclusion We demonstrated a significant association between the nonsynonymous variant in TNFAIP3 and the risk for SLE and RA in the Japanese population. TNFAIP3, similar to STAT4 and IRF5, may be a common genetic risk factor for SLE and RA that is shared between the Caucasian and Japanese populations. [source] The FCRL3 ,169CT promoter single-nucleotide polymorphism, which is associated with systemic lupus erythematosus in a Japanese population, predicts expression of receptor protein on CD19+ B cellsARTHRITIS & RHEUMATISM, Issue 11 2009Andrew W. Gibson PhD No abstract is available for this article. [source] Rheumatoid arthritis does not share most of the newly identified systemic lupus erythematosus genetic factorsARTHRITIS & RHEUMATISM, Issue 9 2009Marian Suarez-Gestal Objective Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) share some genetic factors such as HLA, PTPN22, STAT4, and 6q23. The aim of this study was to determine whether 9 other SLE genetic factors are also implicated in RA susceptibility. Methods A characteristic single-nucleotide polymorphism (SNP) in each of 9 genetic factors, ITGAM (rs1143679), C8orf13,BLK (rs13277113), TYK2 (rs2304256), 1q25.1 (rs10798269), PXK (rs6445975), KIAA1542 (rs4963128), MECP2 (rs17435), BANK1 (rs17266594), and LY9 (rs509749), was studied in 1,635 patients with RA and 1,906 control subjects from Spain. The rs7574865 SNP in STAT4 was also included. Analyses were conducted globally and after stratification by sex and clinical features (anti,cyclic citrullinated peptide and rheumatoid factor, shared epitope, rheumatoid nodules, radiographic changes, sicca syndrome, and pneumonitis). Results No association was observed between RA and any of the 9 newly identified SLE genetic factors. A meta-analysis using previous data was consistent with these results. In addition, there were no significant differences between individuals with and those without each of the clinical features analyzed, except the frequency of the minor allele in the C8orf13,BLK locus that was decreased in patients with sicca syndrome (14.6% versus 22.4% in controls; P = 0.003). Conclusion None of the 9 recently identified SLE risk factors showed association with RA. Therefore, common genetic factors affecting the pathogenesis of these 2 disorders seem to be limited, revealing that the genetic component contributes to the different expression of these diseases. [source] | ||||||||||||||||||||||||||||||||||