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The impact of newly identified loci on coronary heart disease, stroke and total mortality in the MORGAM prospective cohorts

Authors
Publication Date
Keywords
  • Recently
  • Genome Wide Association Studies (Gwas) Have Identified A Number Of Single Nucleotide Polymorphisms (
  • We Estimated The Effect Of These Snps On Incident Chd
  • Stroke And Total Mortality In The Prospective Cohorts Of The Morgam Project
  • We Studied Cohorts From Finland
  • Sweden
  • France And Northern Ireland (Total N=33
  • 282
  • Including 1
  • 436 Incident Chd Events And 571 Incident Stroke Events)
  • The Lead Snps At Seven Loci Identified Thus Far And Additional Snps (In Total 42) Were Genotyped Usi
  • We Estimated The Effect Of The Snps On Disease History At Baseline
  • Disease Events During Follow-Up And Classic Risk Factors
  • Multiple Testing Was Taken Into Account Using False Discovery Rate (Fdr) Analysis
  • Snp Rs1333049 On Chromosome 9P21
  • 3 Was Associated With Both Chd And Stroke (Hr5=
  • 20
  • 95% Ci 1
  • 08-1
  • 34 For Incident Chd Events And 1
  • 15
  • 0
  • 99-1
  • 34 For Incident Stroke)
  • Snp Rs11670734 (19Q12) Was Associated With Total Mortality And Stroke
  • Snp Rs2146807 (10Q11
  • 21) Showed Some Association With The Fatality Of Acute Coronary Event
  • Snp Rs2943634 (2Q36
  • 3) Was Associated With High Density Lipoprotein (Hdl) Cholesterol And Snps Rs599839
  • Rs4970834 (1P13
  • 3) And Rs17228212 (15Q22
  • 23) Were Associated With Non-Hdl Cholesterol
  • Snps Rs2943634 (2Q36
  • 3) And Rs12525353 (6Q25
  • 1) Were Associated With Blood Pressure
  • These Findings Underline The Need For Replication Studies In Prospective Settings And Confirm The Ca
Disciplines
  • Biology
  • Design
  • Engineering

Abstract

31 From: Methods in Molecular Biology, vol. 435: Chromosomal Mutagenesis Edited by: G. Davis and K. J. Kayser © Humana Press Inc., Totowa, NJ 3 Robust Cell Line Development Using Meganucleases Jean-Pierre Cabaniols and Frédéric Pâques Summary Cell line development for protein production or for the screening of drug targets requires the reproducible and stable expression of transgenes. Such cell lines can be engineered with meganu- cleases, sequence-specific endonucleases that recognize large DNA target sites. These proteins are powerful tools for genome engineering because they can increase homologous gene targeting by several orders of magnitude in the vicinity of their cleavage site. Here, we describe in details the use of meganucleases for gene targeting in Chinese hamster ovary-K1 cells, with a special emphasis on a gene insertion procedure using a promoter-less marker gene for selection. We have also monitored the expression of genes inserted by meganucleases-induced recombination, and show that expres- sion is reproducible among different targeted clones, and stable over a 4 mo period. These experi- ments were conducted with the natural yeast I-SceI meganuclease, but the general design and process can also be applied to engineered meganucleases. Key Words: Cell line development; double-strand break; gene targeting; homologous recombi- nation; I-SceI; meganucleases; protein production. 1. Introduction Homologous recombination is a powerful tool for genome engineering. Since the first gene targeting experiments in yeast more than 25 yr ago (1,2), homologous recombination (HR) has been used to insert, replace, or delete genomic sequences in a variety of cells (3–5). However, targeted events occur at a very low frequency in mammalian cells. The frequency of HR can be significantly increased by a specific DNA double-strand break (DSB) in the targeted locus (6,7). Such DSBs can be delivered with meganucleases, sequence-specific endonucleases that recog- nize large DNA target si

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