title: A low-frequency variant in MAPK14 provides mechanistic evidence of a link with myeloperoxidase: a prognostic cardiovascular risk marker.
abstract: BACKGROUND
  Genetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen-activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in MAPK11/14 genes by exome sequencing and follow-up genotyping or imputation in participants well-phenotyped for cardiovascular and metabolic traits.
  
  
  RESULTS
  Investigation of genetic variation in MAPK11 and MAPK14 genes using additive genetic models in linear or logistic regression with cardiovascular, metabolic, and biomarker phenotypes highlighted an association of RS2859144 in MAPK14 with myeloperoxidase in a dyslipidemic population (Genetic Epidemiology of Metabolic Syndrome Study), P=2.3×10(-6)). This variant (or proxy) was consistently associated with myeloperoxidase in the Framingham Heart Study and Cardiovascular Health Study studies (replication meta-P=0.003), leading to a meta-P value of 9.96×10(-7) in the 3 dyslipidemic groups. The variant or its proxy was then profiled in additional population-based cohorts (up to a total of 58 930 subjects) including Cohorte Lausannoise, Ely, Fenland, European Prospective Investigation of Cancer, London Life Sciences Prospective Population Study, and the Genetics of Obesity Associations study obesity case-control for up to 40 cardiovascular and metabolic traits. Overall analysis identified the same single nucleotide polymorphisms to be nominally associated consistently with glomerular filtration rate (P=0.002) and risk of obesity (body mass index ≥30 kg/m(2), P=0.004).
  
  
  CONCLUSIONS
  As myeloperoxidase is a prognostic marker of coronary events, the MAPK14 variant may provide a mechanistic link between p38 map kinase and these events, providing information consistent with current indication of Losmapimod for acute coronary syndrome. If replicated, the association with glomerular filtration rate, along with previous biological findings, also provides support for kidney diseases as alternative indications.
authors.affiliation: GlaxoSmithKline, Philadelphia, PA (D.M.W., L.S.B., D.S.).
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Waterworth
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK (R.S., C.G., N.W.).
authors.forename: Robert
authors.initials: R
authors.lastname: Scott
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
authors.forename: Liling
authors.initials: L
authors.lastname: Warren
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK (R.S., C.G., N.W.).
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillson
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Aponte
authors.affiliation: GlaxoSmithKline, Philadelphia, PA (D.M.W., L.S.B., D.S.).
authors.forename: Lea
authors.initials: L
authors.lastname: Sarov-Blat
authors.affiliation: GlaxoSmithKline, Philadelphia, PA (D.M.W., L.S.B., D.S.).
authors.forename: Dennis
authors.initials: D
authors.lastname: Sprecher
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA (J.D.) Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA (J.D.).
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.affiliation: Group Health Research Institute, Group Health Cooperative, Seattle, WA (A.R.).
authors.forename: Alex
authors.initials: A
authors.lastname: Reiner
authors.affiliation: University of Vermont, Burlington, VT (B.M.P.).
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Psaty
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA (R.P.T., H.L.).
authors.forename: Russell P
authors.initials: RP
authors.lastname: Tracy
authors.affiliation: Boston University and National Heart, Lung and Blood Institute's Framingham Heart Study, Framingham, MA (H.L.) Department of Medicine, Boston University School of Medicine, Boston, MA (R.P.T., H.L.).
authors.forename: Honghuang
authors.initials: H
authors.lastname: Lin
authors.affiliation: Division of Cardiology and Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada (R.M.P.).
authors.forename: Ruth
authors.initials: R
authors.lastname: McPherson
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chissoe
authors.affiliation: MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK (R.S., C.G., N.W.).
authors.forename: Nick
authors.initials: N
authors.lastname: Wareham
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC (L.L., L.W., J.A., S.C., M.G.E.).
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Ehm
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D050171:Dyslipidemias / Q000097:blood / Q000235:genetics; D059472:Exome; D005260:Female; D005838:Genotype; D006801:Humans; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D048290:Mitogen-Activated Protein Kinase 11 / Q000235:genetics*; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics*; D009765:Obesity / Q000097:blood / Q000235:genetics; D009195:Peroxidase / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012307:Risk Factors; D017422:Sequence Analysis, DNA
chemical_list: D009195:Peroxidase; D048290:Mitogen-Activated Protein Kinase 11; D048308:Mitogen-Activated Protein Kinase 14
keywords: acute coronary syndrome; drug target gene; exome sequencing; myeloperoxidase; rare variation