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Multiple Variants (multiple + variants)
Selected AbstractsFunctional profiling of uncommon VCAM1 promoter polymorphisms prevalent in African American populations,,HUMAN MUTATION, Issue 8 2007Gila Idelman Abstract Multiple variants of the vascular adhesion molecule-1 (VCAM1) promoter show increased nucleotide heterozygosity in the African American population. Using a novel transfection-based transcriptional pathway profiling method, we show that select uncommon variants are functionally hyperactive. Eight candidate VCAM1 promoter haplotypes comprising 13 previously identified SNPs were assessed for response to known mitogens. Activity was correlated with bioinformatic analysis of hyper- and hyporesponsive variants to identify the gain or loss of haplotype-specific transcription factor binding site (TFBS). Using this approach, a low frequency regulatory allele (c.,540A>G; dbSNP rs3783605:A>G), found in a hyperactive VCAM1 promoter haplotype, was shown to create a candidate binding site for ETS2 that was confirmed in vivo by chromatin immunoprecipitation. This report provides the first functional evaluation of VCAM1 promoter polymorphisms and establishes a hypothetical foundation for investigation of their role in the pathogenesis of VCAM1 -associated diseases that disproportionately afflict African Americans, including thromboembolic diseases, asthma, and multiple myeloma. Hum Mutat 28(8), 824,829, 2007. Published 2007, Wiley-Liss, Inc. [source] Chromosome 8q24 risk variants in hereditary and non-hereditary prostate cancer patients,THE PROSTATE, Issue 5 2008Jielin Sun Abstract Background Multiple variants in three regions at 8q24 are consistently found to be associated with prostate cancer (PCa) risk in population-based association studies. The role that these variants may play in familial prostate cancer risk has not been extensively investigated. Methods We evaluated 12 SNPs at three 8q24 regions using population-based association and family-based linkage and association methods in hereditary PCa (HPC) probands and their families, non-HPC patients, and unaffected screened controls, all recruited at Johns Hopkins Hospital. Results For multiple variants in Region 1 (e.g., rs1447295) and Region 2 (e.g., rs16901979), we found statistically significantly higher frequencies of previously identified risk alleles and genotypes in HPC probands than in unaffected controls. Furthermore, in Region 2 the risk alleles were statistically significantly more frequent in HPC probands than in non-HPC patients. Family-based transmission tests found risk alleles of SNPs in Region 2, but not in Regions 1 and 3, were significantly over-transmitted to affected men in these families. We found little evidence supporting PCa linkage at 8q24 in 168 HPC families, in part explained by the observation of multiple, different risk allele-containing haplotypes segregating in the vast majority of these families. Conclusions Our study further supports the presence of PCa susceptibility loci at 8q24, particular at Region 2, and also provides evidence that these SNPs play an important role in familial prostate cancer. Large family-based studies are needed to confirm our novel findings. Prostate 68: 489,497, 2008. © 2008 Wiley-Liss, Inc. [source] Clinical Genetics & Human Genome Variation: The 2008 Human Genome Variation Society Scientific MeetingHUMAN MUTATION, Issue 5 2009William S. Oetting Abstract The annual scientific meeting of the Human Genome Variation Society (HGVS) was held on 11 November 2008, in Philadelphia, PA. The major theme of this meeting was "Clinical Genetics & Human Genome Variation." For complex diseases, it is becoming evident that the contribution of most associated genetic variants to the disease process is small and, most likely, multiple variants are required to explain the predisposition and variation that is observed. As genome-wide association studies (GWASs) identify variants that are associated with a disease, there is a need to determine if the associated variants are causative, or simply in genetic disequilibrium with the true functional variant. New methods are being devised to help classify these genetic variants as either functional or nonfunctional. As study populations increase in size, there is also a need for better-constructed databases that can bring together the different genetic variants being identified, including SNPs, copy number variants (CNVs), and methylation differences, environmental risk factors, and the clinical information needed to construct useful phenotypes. These topics and others were discussed in this year's meeting. Hum Mutat 30, 852,856, 2009. © 2009 Wiley-Liss, Inc. [source] Tumour immunology, vaccination and escape strategiesINTERNATIONAL JOURNAL OF IMMUNOGENETICS, Issue 3 2003A. García-Lora Summary Our increasing knowledge of the mechanisms by which tumour cells escape immune effector cells is helping to establish new approaches to therapeutic vaccination against tumour development. One of the escape mechanisms used by tumour cells is the generation of multiple variants with different HLA phenotypes. These MHC class I phenotypic alterations play a key role in the tumour,host scenario, as they are crucial molecules for antigen presentation to T cells and modulation of natural killer (NK) cell activity. This review presents evidence indicating that tumours develop sophisticated MHC phenotypes that allow them to escape immune surveillance. We evaluate the importance of these alterations in terms of the potential development of therapeutic approaches to immune vaccination. [source] Multiple mucinous and lipomatous variant of eccrine angiomatous hamartoma associated with spindle cell hemangioma: a novel collision tumor?JOURNAL OF CUTANEOUS PATHOLOGY, Issue 4 2006Hae-Woong Lee In most cases, EAH arises as a single lesion; however, multiple variants have been reported. We report a 35-year-old female patient with multiple, sudoriparous, subcutaneous nodules on the right foot, which showed typical histopathological findings of EAH, and vascular components of the tumor consisted of thin-walled dilated vascular spaces intermixed with spindle cells and some histiocytoid endothelial cells representing spindle cell hemangioma (SCH). To our knowledge, the co-existence of EAH with SCH is a novel finding and not yet described. [source] Chromosome 8q24 risk variants in hereditary and non-hereditary prostate cancer patients,THE PROSTATE, Issue 5 2008Jielin Sun Abstract Background Multiple variants in three regions at 8q24 are consistently found to be associated with prostate cancer (PCa) risk in population-based association studies. The role that these variants may play in familial prostate cancer risk has not been extensively investigated. Methods We evaluated 12 SNPs at three 8q24 regions using population-based association and family-based linkage and association methods in hereditary PCa (HPC) probands and their families, non-HPC patients, and unaffected screened controls, all recruited at Johns Hopkins Hospital. Results For multiple variants in Region 1 (e.g., rs1447295) and Region 2 (e.g., rs16901979), we found statistically significantly higher frequencies of previously identified risk alleles and genotypes in HPC probands than in unaffected controls. Furthermore, in Region 2 the risk alleles were statistically significantly more frequent in HPC probands than in non-HPC patients. Family-based transmission tests found risk alleles of SNPs in Region 2, but not in Regions 1 and 3, were significantly over-transmitted to affected men in these families. We found little evidence supporting PCa linkage at 8q24 in 168 HPC families, in part explained by the observation of multiple, different risk allele-containing haplotypes segregating in the vast majority of these families. Conclusions Our study further supports the presence of PCa susceptibility loci at 8q24, particular at Region 2, and also provides evidence that these SNPs play an important role in familial prostate cancer. Large family-based studies are needed to confirm our novel findings. Prostate 68: 489,497, 2008. © 2008 Wiley-Liss, Inc. [source] Detailed characterization of the porcine MC4R gene in relation to fatness and growthANIMAL GENETICS, Issue 4 2009B. Fan Summary In contrast to the human MC4R gene, where multiple variants have been described, several of which are associated with appetite and obesity, few MC4R variants have been reported in the pig. The most interesting polymorphism reported to date in the pig is p.Asp298Asn, which is significantly associated with variation in growth and fatness traits in most breeds and crosses. However, some reports have seemingly failed to confirm this association. The discrepancy of p.Asp298Asn associations in some pig populations suggested that further discovery of SNPs in MC4R would be useful. Utilizing the recently released pig genome sequence information, we obtained the whole MC4R genome sequence and detected five additional SNPs, a variable (CA)n repeat and a C indel in the ISU Berkshire × Yorkshire pig resource family. Linkage disequilibrium (LD) analysis revealed that the additional five SNPs were not in strong LD with p.Asp298Asn, but single marker association analysis indicated that they were significantly (P < 0.05) associated with fatness measures and very highly significantly (P < 0.0001) associated with average daily gain on test (ADGTEST). Three major haplotypes were identified and the subsequent association analyses suggested that the two non-synonymous SNPs had different effects, e.g. p.Arg236His influenced back fat and growth on test while p.Asp298Asn was primarily associated with variation in growth rate in this population. An interaction effect between these two SNPs was found for ADGTEST, which may partly explain some of the previous discrepancies reported for MC4R in different pig populations. Examination of the p.Arg236His polymorphism in populations where the effect of p.Asp298Asn is limited is warranted. [source] SNP Haplotypes in the Angiotensin I-Converting Enzyme (ACE) Gene: Analysis of Nigerian Family Data Using Gamete Competition ModelsANNALS OF HUMAN GENETICS, Issue 2 2005C. A. McKenzie Summary Gamete competition models were used to explore the relationships between 13 ACE gene polymorphisms and plasma ACE concentration in a set of Nigerian families. Several markers in the 5, and 3, regions of the gene were significantly associated with ACE concentration (P < 10 -4). Multi-locus genotypes comprising different combinations of markers from the 5, UTR and the 3, region of the gene were also analysed; in addition to G2350A, in the 3, region, two markers from the 5, UTR (A-5466C and A-240T) were found to be associated with ACE concentration. These results are consistent with reports that have suggested the presence of at least two ACE-linked QTLs, and demonstrate the utility of gamete competition models in the exploratory investigation of the relationship between a quantitative trait and multiple variants in a small genomic region. [source] | |||||||||||||