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Common SNPs (common + snp)
Selected AbstractsSystematic evaluation of the effect of common SNPs on pre-mRNA splicing,HUMAN MUTATION, Issue 4 2009Abdou ElSharawy Abstract The evolutionary and biomedical importance of differential mRNA splicing is well established. Numerous studies have assessed patterns of differential splicing in different genes and correlated these patterns to the genotypes for adjacent single-nucleotide polymorphisms (SNPs). Here, we have chosen a reverse approach and screened dbSNP for common SNPs at either canonical splice sites or exonic splice enhancers (ESEs) that would be classified as putatively splicing-relevant by bioinformatic tools. The 223 candidate SNPs retrieved from dbSNP were experimentally tested using a previously established panel of 92 matching DNAs and cDNAs. For each SNP, 16 cDNAs providing a balanced representation of the genotypes at the respective SNP were investigated by nested RT-PCR and subsequent sequencing. Putative allele-dependent splicing was verified by the cloning of PCR products. The positive predictive value of the bioinformatics tools turned out to be low, ranging from 0% for ESEfinder to 9% (in the case of acceptor-site SNPs) for a recently reported neural network. The results highlight the need for a better understanding of the sequence characteristics of functional splice-sites to improve our ability to predict in silico the splicing relevance of empirically observed DNA sequence variants. Hum Mutat 0, 1,9, 2009. © 2009 Wiley-Liss, Inc. [source] Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer riskINTERNATIONAL JOURNAL OF CANCER, Issue 11 2008Victoria L. Stevens Abstract Toll-like receptors (TLRs) are key players in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. The proposed role of chronic inflammation in prostate carcinogenesis has prompted investigation into the association of common genetic variation in TLRs with the risk of this cancer. We investigated the role of common SNPs in a gene cluster encoding the TLR10, TLR6 and TLR1 proteins in prostate cancer etiology among 1,414 cancer cases and 1,414 matched controls from the Cancer Prevention Study II Nutrition Cohort. Twenty-eight SNPs, which included the majority of the common nonsynonymous SNPs in the 54-kb gene region and haplotype-tagging SNPs that defined 5 specific haplotype blocks, were genotyped and their association with prostate cancer risk determined. Two SNPs in TLR10 [I369L (rs11096955) and N241H (rs11096957)] and 4 SNPs in TLR1 [N248S (rs4833095), S26L (rs5743596), rs5743595 and rs5743551] were associated with a statistically significant reduced risk of prostate cancer of 29,38% (for the homozygous variant genotype). The association of these SNPs was similar when the analysis was limited to cases with advanced prostate cancer. Haplotype analysis and linkage disequilibrium findings revealed that the 6 associated SNPs were not independent and represent a single association with reduced prostate cancer risk (OR = 0.55, 95% CI: 0.33, 0.90). Our study suggest that a common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations. © 2008 Wiley-Liss, Inc. [source] UCHL-1 gene in multiple system atrophy: A haplotype tagging approachMOVEMENT DISORDERS, Issue 10 2005Daniel G. Healy MD Abstract To date, the etiology of multiple system atrophy (MSA) has proved impenetrable. We investigated the role of genetic variation in the UCHL-1 gene in MSA and looked for the presence of disease susceptibility alleles. We determined the linkage disequilibrium structure of the gene and employed a haplotype tagging strategy with power to represent 95% of the haplotype diversity. This approach was performed using a set of tagging single nucleotide polymorphisms (SNPs) that can infer the allelic state of all the common SNPs in UCHL-1 with a high coefficient of determination. This strategy enabled us to scan across the gene and maintain the power to detect signal(s) from any potential functional variant(s). In 257 Gilman-probable or -definite MSA subjects and 1,536 controls, we did not detect a case,control frequency difference for either the tagged haplotypes or for individual tagging SNPs. This search included the S18Y variant of UCHL-1, which has been reported to be protective in Parkinson's disease. © 2005 Movement Disorder Society [source] Unraveling the genetics of exfoliation glaucomaACTA OPHTHALMOLOGICA, Issue 2008F JONASSON Purpose To give an account of our recent discovery (2007) of the association of lysyl oxidase like 1 (LOXL1) sequence variants and exfoliation glaucoma (XFG) as well as later replications in other populations. Methods We did a genome-wide association study on open angle glaucoma cases and controls using the Illumina 300 chip. This chip includes probes for 317.000 single , nucleotide polymorphisms (SNPs), that tag, as highly correlated surrogates about 80% of the 2.1 million known common SNPs in the Caucasian genome. For diagnosis of exfoliation syndrome a peripheral band or central shield of exfoliative material on the anterior lens capsule was required. Results When we had done 195 open angle glaucoma cases high genome wide significance was achieved on chromosome 15q24.1 an association later found to be confined to XFG only. This SNP (rs2165241T) was located in the first intron of the LOXL1 gene. We then added 11 correlated SNPs that are not on the Illumina chip and found that two non-synonymous variants in the first exon of LOXL1 can jointly account for all the observed association (R141L, OR 2.5; G153D, OR 20.1). Combined the variants explained 99% of the population attributable risk for exfoliation glaucoma. Conclusion These findings have now largely been confirmed in numerous American, Asian, Australian and European studies, and in all instances do these polymorphisms in the LOXL1 gene confer risk to XFG. LOXL1 is cross linking enzyme responsible for elastin polymer deposition in ocular tissue. The LOXL1 discovery is the first big hit in the search for genetic background for exfoliation glaucoma. These findings may soon influence monitoring of glaucoma suspects in the clinic targeting persons with the high risk haplotypes. [source] ,2 -Adrenergic Receptor Promoter Haplotype Influences Spirometric Response During an Acute Asthma ExacerbationCLINICAL AND TRANSLATIONAL SCIENCE, Issue 2 2008Paul E. Moore M.D. Abstract Genetic variants in the ,2 -adrenergic receptor (ADRB2) coding block have been associated with different parameters of asthma severity, but there is no consensus on which variants are most important. Our objective was to determine whether the genetic variants in the 5,- or 3,-flanking regions of ADRB2 impact the response to therapy. DNA was obtained initially from 72 adults hospitalized for an asthma exacerbation. We sequenced a 5,000 bp region of the ADRB2 gene that spanned the flanking regions and identified 31 single nucleotide polymorphisms (SNPs). Nonresponders to asthma therapy were defined as patients whose forced expiratory volume in 1 second (FEV1) worsened by >10% at 24 hours after admission. We then evaluated the relationship between the 19 common SNPs and response to asthma-specific therapy during acute disease exacerbations. Our results showed a significant association between nonresponders and a haplotype of five promoter SNPs in a nearly complete linkage disequilibrium. An analysis of the promoter and coding block polymorphisms in an extended cohort of 99 patients confirmed that promoter haplotype was the genetic component most strongly associated with asthmatic nonresponders, which was statistically significant among whites (p < 0.05). An identification of this promoter haplotype may provide an alternate explanation for the variation in the asthma responses observed with ADRB2 coding block polymorphisms. [source] | ||||||||||