The LDL receptor-related protein (LRP1/A2MR) and coronary atherosclerosis--novel genomic variants and functional consequences.

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. Copyright 2002 Wiley-Liss, Inc.