Roberts R

References (4)

Title : Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies - Grallert_2012_Eur.Heart.J_33_238
Author(s) : Grallert H , Dupuis J , Bis JC , Dehghan A , Barbalic M , Baumert J , Lu C , Smith NL , Uitterlinden AG , Roberts R , Khuseyinova N , Schnabel RB , Rice KM , Rivadeneira F , Hoogeveen RC , Fontes JD , Meisinger C , Keaney JF, Jr. , Lemaitre R , Aulchenko YS , Vasan RS , Ellis S , Hazen SL , van Duijn CM , Nelson JJ , Marz W , Schunkert H , McPherson RM , Stirnadel-Farrant HA , Psaty BM , Gieger C , Siscovick D , Hofman A , Illig T , Cushman M , Yamamoto JF , Rotter JI , Larson MG , Stewart AF , Boerwinkle E , Witteman JC , Tracy RP , Koenig W , Benjamin EJ , Ballantyne CM
Ref : Eur Heart J , 33 :238 , 2012
Abstract : AIMS: Lipoprotein-associated phospholipase A2 (Lp-PLA2) generates proinflammatory and proatherogenic compounds in the arterial vascular wall and is a potential therapeutic target in coronary heart disease (CHD). We searched for genetic loci related to Lp-PLA2 mass or activity by a genome-wide association study as part of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. METHODS AND RESULTS: In meta-analyses of findings from five population-based studies, comprising 13 664 subjects, variants at two loci (PLA2G7, CETP) were associated with Lp-PLA2 mass. The strongest signal was at rs1805017 in PLA2G7 [P = 2.4 x 10(-23), log Lp-PLA2 difference per allele (beta): 0.043]. Variants at six loci were associated with Lp-PLA2 activity (PLA2G7, APOC1, CELSR2, LDL, ZNF259, SCARB1), among which the strongest signals were at rs4420638, near the APOE-APOC1-APOC4-APOC2 cluster [P = 4.9 x 10(-30); log Lp-PLA2 difference per allele (beta): -0.054]. There were no significant gene-environment interactions between these eight polymorphisms associated with Lp-PLA2 mass or activity and age, sex, body mass index, or smoking status. Four of the polymorphisms (in APOC1, CELSR2, SCARB1, ZNF259), but not PLA2G7, were significantly associated with CHD in a second study. CONCLUSION: Levels of Lp-PLA2 mass and activity were associated with PLA2G7, the gene coding for this protein. Lipoprotein-associated phospholipase A2 activity was also strongly associated with genetic variants related to low-density lipoprotein cholesterol levels.
ESTHER : Grallert_2012_Eur.Heart.J_33_238
PubMedSearch : Grallert_2012_Eur.Heart.J_33_238
PubMedID: 22003152
Gene_locus related to this paper: human-PLA2G7

Title : Clinical and genetic association of serum paraoxonase and arylesterase activities with cardiovascular risk - Tang_2012_Arterioscler.Thromb.Vasc.Biol_32_2803
Author(s) : Tang WH , Hartiala J , Fan Y , Wu Y , Stewart AF , Erdmann J , Kathiresan S , Roberts R , McPherson R , Allayee H , Hazen SL
Ref : Arterioscler Thromb Vasc Biol , 32 :2803 , 2012
Abstract : OBJECTIVE: Diminished serum paraoxonase and arylesterase activities (measures of paraoxonase-1 [PON-1] function) in humans have been linked to heightened systemic oxidative stress and atherosclerosis risk. The clinical prognostic use of measuring distinct PON-1 activities has not been established, and the genetic determinants of PON-1 activities are not known. METHODS AND
RESULTS: We established analytically robust high-throughput assays for serum paraoxonase and arylesterase activities and measured these in 3668 stable subjects undergoing elective coronary angiography without acute coronary syndrome and were prospectively followed for major adverse cardiovascular events (MACE= death, myocardial infarction, stroke) over 3 years. Low serum arylesterase and paraoxonase activities were both associated with increased risk for MACE, with arylesterase activity showing greatest prognostic value (quartile 4 versus quartile 1; hazard ratio 2.63; 95% CI, 1.97-3.50; P<0.01). Arylesterase remained significant after adjusting for traditional risk factors, C-reactive protein, and creatinine clearance (hazard ratio, 2.20; 95% CI, 1.60-3.02; P<0.01), predicted future development of MACE in both primary and secondary prevention populations, and reclassified risk categories incrementally to traditional clinical variables. A genome-wide association study identified distinct single nucleotide polymorphisms within the PON-1 gene that were highly significantly associated with serum paraoxonase (1.18x10(-303)) or arylesterase (4.99x10(-116)) activity but these variants were not associated with either 3-year MACE risk in an angiographic cohort (n=2136) or history of either coronary artery disease or myocardial infarction in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis consortium (n approximately 80 000 subjects).
CONCLUSIONS: Diminished serum arylesterase activity, but not the genetic determinants of PON-1 functional measures, provides incremental prognostic value and clinical reclassification of stable subjects at risk of developing MACE.
ESTHER : Tang_2012_Arterioscler.Thromb.Vasc.Biol_32_2803
PubMedSearch : Tang_2012_Arterioscler.Thromb.Vasc.Biol_32_2803
PubMedID: 22982463

Title : Human nocturnal frontal lobe epilepsy: pharmocogenomic profiles of pathogenic nicotinic acetylcholine receptor beta-subunit mutations outside the ion channel pore - Hoda_2008_Mol.Pharmacol_74_379
Author(s) : Hoda JC , Gu W , Friedli M , Phillips HA , Bertrand S , Antonarakis SE , Goudie D , Roberts R , Scheffer IE , Marini C , Patel J , Berkovic SF , Mulley JC , Steinlein OK , Bertrand D
Ref : Molecular Pharmacology , 74 :379 , 2008
Abstract : Certain mutations in specific parts of the neuronal nicotinic acetylcholine receptor (nAChR) subunit genes CHRNA4, CHRNB2, and probably CHRNA2, can cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). All but one of the known causative mutations are located in the second transmembrane region (TM2), which serves as the major ion poreforming domain of the receptor. Functional characterization of these ADNFLE mutations has shown that although each mutant exhibits specific properties, they all confer a gain of function with increased sensitivity to acetylcholine. In this work, we characterize the second and third ADNFLE-associated mutations that are external to TM2 but affect different amino acid residues within the third transmembrane region (TM3). The two new CHRNB2 mutations were identified in three families of Turkish Cypriot, Scottish, and English origin. These TM3 mutations elicit the same gain of function pathomechanism as observed for the TM2 mutations with enhanced acetylcholine sensitivity, despite their unusual localization within the gene. Electrophysiological experiments, including single channel measurements, revealed that incorporation of these new mutant subunits does not affect the conductance of the ionic pore but increases the probability of opening. Determination of the sensitivity to nicotine for nAChRs carrying mutations in TM2 and TM3 showed clear differences in the direction and the extent to which the window current for nicotine sensitivity was shifted for individual mutations, indicating differences in pharmacogenomic properties that are not readily correlated with increased ACh affinity.
ESTHER : Hoda_2008_Mol.Pharmacol_74_379
PubMedSearch : Hoda_2008_Mol.Pharmacol_74_379
PubMedID: 18456869

Title : Reduced receptor aggregation and altered cytoskeleton in cultured myocytes after space-flight - Gruener_1994_Biol.Sci.Space_8_79
Author(s) : Gruener R , Roberts R , Reitstetter R
Ref : Biol Sci Space , 8 :79 , 1994
Abstract : We carried out parallel experiments first on the slow clinostat and then in space-flight to examine the effects of altered gravity on the aggregation of the nicotinic acetylcholine receptors and the structure of the cytoskeleton in cultured Xenopus embryonic muscle cells. By examining the concordance between results from space flight and the clinostat, we tested whether the slow clinostat is a relevant simulation paradigm. Space-flown cells showed marked changes in the distribution and organization of actin filaments and had a reduced incidence of acetylcholine receptor aggregates at the site of contact with polystyrene beads. Similar effects were found after clinostat rotation. The sensitivity of synaptic receptor aggregation and cytoskeletal morphology suggests that in the microgravity of space cell behavior may be importantly altered.
ESTHER : Gruener_1994_Biol.Sci.Space_8_79
PubMedSearch : Gruener_1994_Biol.Sci.Space_8_79
PubMedID: 11542735