Showing papers by "Michael S. Phillips published in 2014"

CKM and LILRB5 are associated with serum levels of creatine kinase.

Abstract: Background—Statins (HMG-CoA reductase inhibitors) are the most prescribed class of lipid-lowering drugs for the treatment and prevention of cardiovascular disease. Creatine kinase (CK) is a commonly used biomarker to assist in the diagnosis of statin-induced myotoxicity but the normal range of CK concentrations is wide, which limits its use as a diagnostic biomarker. Methods and Results—We conducted a genome-wide association study of serum CK levels in 3412 statin users. Patients were recruited in Quebec, Canada, and genotyped on Illumina Human610-Quad and an iSelect panel enriched for lipid homeostasis, hypertension, and drug metabolism genes. We found a strong association signal between serum levels of CK and the muscle CK (CKM) gene (rs11559024: P=3.69×10 −16 ; R 2 =0.02) and with the leukocyte immunoglobulin-like receptor subfamily B member 5 (LILRB5) gene (rs2361797: P=1.96×10 −10 ; R 2 =0.01). Genetic variants in those 2 genes were independently associated with CK levels in statin users. Results were successfully replicated in 5330 participants from the Montreal Heart Institute Biobank in statin users for CKM (rs11559024: P=4.32×10 −16 ; R 2 =0.02) and LILRB5 (rs12975366 P=4.45×10 −10 ; R 2 =0.01) and statin nonusers (P=4.08×10 −7 , R 2 =0.01; P=3.17×10 −9 , R 2 =0.02, respectively). Conclusions—This is the first genome-wide study to report on the underlying genetic determinants of CK variation in a population of statin users. We found statistically significant association for variants in the CKM and LILRB5 genes. ( Circ Cardiovasc Genet. 2014;7:880-886.)

SNP arrays: comparing diagnostic yields for four platforms in children with developmental delay

Abstract: Molecular karyotyping is now the first-tier genetic test for patients affected with unexplained intellectual disability (ID) and/or multiple congenital anomalies (MCA), since it identifies a pathogenic copy number variation (CNV) in 10-14% of them. High-resolution microarrays combining molecular karyotyping and single nucleotide polymorphism (SNP) genotyping were recently introduced to the market. In addition to identifying CNVs, these platforms detect loss of heterozygosity (LOH), which can indicate the presence of a homozygous mutation or uniparental disomy. Since these abnormalities can be associated with ID and/or MCA, their detection is of particular interest for patients whose phenotype remains unexplained. However, the diagnostic yield obtained with these platforms is not confirmed, and the real clinical value of LOH detection has not been established. We selected 21 children affected with ID, with or without congenital malformations, for whom standard genetic analyses failed to provide a diagnosis. We performed high-resolution SNP array analysis with four platforms (Affymetrix Genome-Wide Human SNP Array 6.0, Affymetrix Cytogenetics Whole-Genome 2.7 M array, Illumina HumanOmni1-Quad BeadChip, and Illumina HumanCytoSNP-12 DNA Analysis BeadChip) on whole-blood samples obtained from children and their parents to detect pathogenic CNVs and LOHs, and compared the results with those obtained on a moderate resolution array-based comparative genomic hybridization platform (NimbleGen CGX-12 Cytogenetics Array), already used in the clinical setting. We identified a total of four pathogenic CNVs in three patients, and all arrays successfully detected them. With the SNP arrays, we also identified a LOH containing a gene associated with a recessive disorder consistent with the patient’s phenotype (i.e., an informative LOH) in four children (including two siblings). A homozygous mutation within the informative LOH was found in three of these patients. Therefore, we were able to increase the diagnostic yield from 14.3% to 28.6% as a result of the information provided by LOHs. This study shows the clinical usefulness of SNP arrays in children with ID, since they successfully detect pathogenic CNVs, identify informative LOHs that can lead to the diagnosis of a recessive disorder. It also highlights some challenges associated with the use of SNP arrays in a clinical laboratory.

Communication of historical and real-time information about devices in a building

Abstract: Electrical usage of devices in a building may be monitored to provide information about the operation of the devices to a user. The information communicated to a user may include historical information that is retrieved from a server and real-time information that is received from a power monitoring device. The historical information may be transmitted to the user device over a first network connection where the historical information is retrieved using an identifier received from the user device. The real-time information may be received from a power monitoring device and transmitted to the user device over a second network connection.

Development of a broad-based ADME panel for use in pharmacogenomic studies

Abstract: Aim: To optimally address the interindividual variability observed in pharmacokinetic drug response, we have created a custom genotyping panel that interrogates most of the key genetic variations present in a set of 181 prioritized genes responsible for the absorption, distribution, metabolism and excretion (ADME) of many therapeutic agents. This consensus list of genes and variants was based on the ADME core and extended gene lists compiled by a group of pharmaceutical companies as having relevance. Although these pharmacokinetic genes and pathways are well known, tools that can interrogate a large number of these genes simultaneously within a single experiment are not currently available. Methods: Using novel design strategies, we have developed an optimized and validated ADME genotyping panel, encompassing approximately 3000 variants, that has broad applicability to any study or clinical trial that would benefit from the evaluation of an extensive list of ADME genes. Results & conclusion: Over the cour...