title: The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis--novel genomic variants and functional consequences.
abstract: The LDL receptor-related protein/alpha 2-macroglobulin receptor (LRP1/A2MR) is a multifunctional cell-surface glycoprotein that endocytoses several structurally and functionally distinct ligands. In clinical studies different genomic variants of the LRP1/A2MR and its role in the development of degenerative diseases like atherosclerosis or Alzheimer's disease were studied. We screened for novel genomic variants of LRP1/A2MR and investigated the importance of these variants in 214 coronary patients suffering from myocardial infarction as well as in 224 healthy controls. We detected a novel C>G polymorphism at position -25 in the functionally important promoter region of LRP1/A2MR. This polymorphism (c.1-25C>G) leads to the creation of a new GC-box, recognized by the constitutively expressed SP 1 transcription factor. Investigating the LRP1/A2MR gene expression with respect to this polymorphism, carriers of the mutant G-allele were found to have a higher mRNA expression level. A novel polymorphism in exon 22 (c.4012C>T), and two novel polymorphisms in intron 24 (IVS24+123C>A and IVS24+690G>A) associated with a previously described polymorphism in exon 61 (c.10249G>A), were related to the development of myocardial infarction. Two novel rare genetic variants of exon 88 (c.13933C>T) and intron 88 (IVS88+15G>A) were identified in four patients with severe coronary symptoms. However, the LRP1/A2MR gene expression was found to be independent of all identified novel genomic variants as well as other previously described changes (A217V, A775P, D2080N, D2632E, G4379S) except the promoter polymorphism.
authors.affiliation: Institute of Human Genetics and Medical Biology, University of Halle, Halle, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Schulz
authors.forename: Undraga
authors.initials: U
authors.lastname: Schagdarsurengin
authors.forename: Petra
authors.initials: P
authors.lastname: Greiser
authors.forename: Gerd
authors.initials: G
authors.lastname: Birkenmeier
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Werdan
authors.forename: Monika
authors.initials: M
authors.lastname: Hagemann
authors.forename: Dagmar
authors.initials: D
authors.lastname: Riemann
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.forename: Christiane
authors.initials: C
authors.lastname: Gläser
mesh_terms: D000328:Adult; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D008297:Male; D009000:Monocytes / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D026503:Low Density Lipoprotein Receptor-Related Protein-1; D012333:RNA, Messenger