Showing papers by "Myriad Genetics published in 2008"

Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene

Abstract: Psoriasis is an immune-mediated skin disorder that is inherited as a multifactorial trait. Linkage studies have clearly identified a primary disease susceptibility locus lying within the major histocompatibility complex (MHC), but have generated conflicting results for other genomic regions. To overcome this difficulty, we have carried out a genome-wide association scan, where we analyzed more than 408,000 SNPs in an initial sample of 318 cases and 288 controls. Outside of the MHC, we observed a single cluster of disease-associated markers, spanning 47 kb on chromosome 20q13. The analysis of two replication data sets confirmed this association, with SNP rs495337 yielding a combined P-value of 1.4 x 10(-8) in an overall sample of 2679 cases and 2215 controls. Rs495337 maps to the SPATA2 transcript and is in absolute linkage disequilibrium with five SNPs lying in the adjacent ZNF313 gene (also known as RNF114). Real-time PCR experiments showed that, unlike SPATA2, ZNF313 is abundantly expressed in skin, T-lymphocytes and dendritic cells. Furthermore, an analysis of the expression data available from the Genevar database indicated that rs495337 is associated with increased ZNF313 transcripts levels (P = 0.003), suggesting that the disease susceptibility allele may be a ZNF313 regulatory variant tagged by rs495337. Homology searches indicated that ZNF313 is a paralogue of TRAC-1, an ubiquitin ligase regulating T-cell activation. We performed cell-free assays and confirmed that like TRAC-1, ZNF313 binds ubiquitin via an ubiquitin-interaction motif (UIM). These findings collectively identify a novel psoriasis susceptibility gene, with a putative role in the regulation of immune responses.

Association of the FTO gene with BMI.

Abstract: Variants in the FTO gene have been strongly associated with obesity in a very large sample (38,759) of diabetic and control subjects. To replicate these findings, the previously reported SNP in the FTO gene (rs9939609, T/A) was genotyped in 5,607 subjects from five different Utah studies. The studies included a random sample of the Utah population, families selected for aggregation of extreme thinness, families selected for severe obesity, a series of unrelated severe obesity subjects, and families participating in a 25-year longitudinal study of cardiovascular disease and aging. Results show a strong significant increase in the rs9939609 A allele frequency with increasing BMI (P < 0.0001). In the longitudinal study, FTO genotypes were significantly associated with BMI at a baseline exam, a 2½-year follow-up exam and a 25-year follow-up exam using an additive genetic model. The mean genotype difference in BMI ranged from 1.3 to 2.1 kg/m2 across exams. The genotype difference in BMI means was established in youth, and at-risk subjects under age 20 at baseline had a significantly larger 25-year BMI increase (10.0 for A/A; 9.7 for A/T, and 8.5 kg/m2 for T/T, P = 0.05). We conclude that the BMI increases associated with FTO genotypes begin in youth and are maintained throughout adulthood.

Genome-wide Association Scan Identifies a Prostaglandin-Endoperoxide Synthase 2 Variant Involved in Risk of Knee Osteoarthritis

Abstract: Osteoarthritis (OA), the most prevalent form of arthritis in the elderly, is characterized by the degradation of articular cartilage and has a strong genetic component. Our aim was to identify genetic variants involved in risk of knee OA in women. A pooled genome-wide association scan with the Illumina550 Duo array was performed in 255 controls and 387 cases. Twenty-eight variants with p < 1 x 10(-5) were estimated to have probabilities of being false positives

A reference integrated map for cultivated grapevine (Vitis vinifera L.) from three crosses, based on 283 SSR and 501 SNP-based markers

Abstract: We have developed an integrated map from five elite cultivars of Vitis vinifera L.; Syrah, Pinot Noir, Grenache, Cabernet Sauvignon and Riesling which are parents of three segregating populations. A new source of markers, SNPs, identified in ESTs and unique BAC-end sequences was added to the available IGGP reference set of SSRs. The complete integrated map comprises 1,134 markers (350 AFLP®, 332 BESs, 169 ESTs, 283 SSRs) spanning 1,443 cM over 19 linkage groups and shows a mean distance between neighbouring loci of 1.27 cM. Marker order was mainly conserved between the integrated map and the highly dense Syrah × Pinot Noir consensus map except for few inversions. Moreover, the marker order has been validated through the assembled genome sequence of Pinot Noir. We have also assessed the transferability of SNP-based markers among five V. vinifera varieties, enabling marker validation across different genotypes. This integrated map can serve as a fundamental tool for molecular breeding in V. vinifera and related species and provide a basis for studies of genome organization and evolution in grapevines.

SNP high-throughput screening in grapevine using the SNPlex™ genotyping system

Abstract: Until recently, only a small number of low- and mid-throughput methods have been used for single nucleotide polymorphism (SNP) discovery and genotyping in grapevine (Vitis vinifera L.). However, following completion of the sequence of the highly heterozygous genome of Pinot Noir, it has been possible to identify millions of electronic SNPs (eSNPs) thus providing a valuable source for high-throughput genotyping methods. Herein we report the first application of the SNPlex™ genotyping system in grapevine aiming at the anchoring of an eukaryotic genome. This approach combines robust SNP detection with automated assay readout and data analysis. 813 candidate eSNPs were developed from non-repetitive contigs of the assembled genome of Pinot Noir and tested in 90 progeny of Syrah × Pinot Noir cross. 563 new SNP-based markers were obtained and mapped. The efficiency rate of 69% was enhanced to 80% when multiple displacement amplification (MDA) methods were used for preparation of genomic DNA for the SNPlex assay. Unlike other SNP genotyping methods used to investigate thousands of SNPs in a few genotypes, or a few SNPs in around a thousand genotypes, the SNPlex genotyping system represents a good compromise to investigate several hundred SNPs in a hundred or more samples simultaneously. Therefore, the use of the SNPlex assay, coupled with whole genome amplification (WGA), is a good solution for future applications in well-equipped laboratories.

Next-day cognition, psychomotor function, and driving-related skills following nighttime administration of eszopiclone

Abstract: OBJECTIVE: To evaluate next-day driving ability, as assessed by brake reaction time (BRT), and cognitive/psychomotor function following nighttime administration of 3 mg eszopiclone. METHODS: Two randomized, double-blind, placebo-controlled, cross-over studies were performed in healthy volunteers (n = 32) and patients with primary insomnia (n = 32). Study participants received nighttime dosing of 3 mg eszopiclone or placebo. BRT and a psychometric test battery were used to assess the next-day effects of eszopiclone treatment. RESULTS: In both studies, driving ability and measures of cognitive and psychomotor function were not impaired the morning after eszopiclone, as compared to placebo. All eszopiclone subjects reported improved ease in getting to sleep and quality of sleep with no significant changes in behavior upon awakening. A significant increase in next-day feelings of sedation was reported in healthy volunteers, but not in patients with primary insomnia, following eszopiclone treatment relative to placebo. Sleep induction, maintenance, duration, and efficiency, as assessed by PSG, were significantly improved following eszopiclone treatment in patients with insomnia. CONCLUSIONS: Nighttime administration of 3 mg eszopiclone improved objective and subjective sleep measures in patients with insomnia (and subjective sleep measures in healthy patients) and did not impair next-day driving-related skills or measures of cognition in either study population relative to placebo. Language: en

Construction and characterization of a normalized yeast two-hybrid library derived from a human protein-coding clone collection

Abstract: The nuclear yeast two-hybrid (Y2H) system is the most widely used technology for detecting interactions between proteins. A common approach is to screen specific test proteins (baits) against large compilations of randomly cloned proteins (prey libraries). For eukaryotic organisms, libraries have traditionally been generated using messenger RNA (mRNA) extracted from various tissues and cells. Here we present a library construction strategy made possible by ongoing public efforts to establish collections of full-length protein encoding clones. Our approach generates libraries that are essentially normalized and contain both randomly fragmented as well as full-length inserts. We refer to this type of protein-coding clone-derived library as random and full-length (RAFL) Y2H library. The library described here is based on clones from the Mammalian Gene Collection, but our strategy is compatible with the use of any protein-coding clone collection from any organism in any vector and does not require inserts to be devoid of untranslated regions. We tested our prototype human RAFL library against a set of baits that had previously been searched against multiple cDNA libraries. These Y2H searches yielded a combination of novel as well as expected interactions, indicating that the RAFL library constitutes a valuable complement to Y2H cDNA libraries.

Enzyme assay and use thereof

Abstract: An assay and kit for determining the activity of an enzyme such as kinase, ATPase and GTPase is disclosed The assay and kit are useful in drug screening to select modulators of such an enzyme

Method and composition for reducing the expression of rock-ii

Abstract: Methods and compositions for reducing the expression of Rho-associated, coiled-coil containing protein kinase 2 (ROCK-II) are provided.