An LRP8 Variant Is Associated with Familial and Premature Coronary Artery Disease and Myocardial Infarction

Abstract

Our previous genomewide linkage scan of 428 nuclear families (GeneQuest) identified a significant genetic susceptibility locus for premature myocardial infarction (MI) on chromosome 1p34-36. We analyzed candidate genes in the locus with a population-based association study involving probands with premature coronary artery disease (CAD) and/or MI from the GeneQuest families (381 cases) and 560 controls without stenosis detectable by coronary angiography. A nonconservative substitution, R952Q, in LRP8 was significantly associated with susceptibility to premature CAD and/or MI by use of both population-based and family-based designs. Three additional white populations were used for follow-up replication studies: another independent cohort of CAD- and/or MI-affected families (GeneQuest II: 441 individuals from 22 pedigrees), an Italian cohort with familial MI (248 cases) and 308 Italian controls, and a separate Cleveland GeneBank cohort with sporadic MI (1,231 cases) and 560 controls. The association was significantly replicated in two independent populations with a family history of CAD and/or MI, the GeneQuest II family-based replication cohort and the Italian cohort, but not in the population with sporadic disease. The R952Q variant of LRP8 increased activation of p38 mitogen-activated protein kinase by oxidized low-density lipoprotein. This extensive study, involving multiple independent populations, provides the first evidence that genetic variants in LRP8 may contribute to the development of premature and familial CAD and MI.

Genetic variants of ApoE and ApoER2 differentially modulate endothelial function

“…There is greater cardiovascular disease risk associated with the apoE4 allele vs. apoE3, and also with the ApoER2 variant ApoER2-R952Q, and there is evidence that the increased disease predisposition may be related to mechanisms other than changes in lipid status (3)(4)(5)(6)(7)(8)(9). How ApoER2 and its interactive actions with apoE potentially influence the behavior of endothelial cells, which are critically involved in vascular health and disease, has been unknown.…”

“…The LRP8 gene, which encodes ApoER2, is a major gene locus for premature atherosclerosis and acute myocardial infarction identified in four independent human populations. In particular, homozygous carriers of the ApoER2-R952Q variant have a twofold increased risk of these conditions (3)(4)(5). ApoER2-R952Q also has an additive effect with apoE4, with the combined genotype QQ/E4 showing a 3.9-fold greater susceptibility to cardiovascular disease (5).…”

“…ApoER2-R952Q also has an additive effect with apoE4, with the combined genotype QQ/E4 showing a 3.9-fold greater susceptibility to cardiovascular disease (5). ApoER2 polymorphism-associated risk is independent of cholesterol levels (3)(4)(5), and although apoE4 may impact LDL abundance (2), there is also evidence that apoE4-associated risk goes well beyond changes in lipoprotein status (6)(7)(8)(9). Whereas there is considerable understanding of the biology of the apoE-ApoER2 tandem in the central nervous system and in Alzheimer's disease (10), the basis for the cardiovascular impact of the receptor and apoE variants remains unclear.…”

Up-regulation of ATP Binding Cassette Transporter A1 Expression by Very Low Density Lipoprotein Receptor and Apolipoprotein E Receptor 2

“…Furthermore, a VLDLR deficiency increased intimal thickening after vascular injury and increased necrosis in atherosclerotic lesions (32). In addition, an apoER2 variant has been shown to increase the risk of atherosclerotic coronary artery disease (33). These observations imply that the pro-atherogenic effect of VLDLR (possibly apoER2) arising from the lipoprotein uptake function of macrophages may be counterbalanced by their anti-atherogenic effects, such as conversion of macrophages from a proinflammatory to an anti-inflammatory phenotype (31) and the inhibition of macrophage death in atherosclerotic lesions (32).…”

Four SNPS on Chromosome 9p21 Confer Risk to Premature, Familial CAD and MI in an American Caucasian Population (GeneQuest)

“…Our GeneQuest cohort with premature and familial CAD and MI has been previously described (Shen et al 2007c;Wang et al 2004). Briefly, over a five year span, patients were recruited by cardiologists and data coordinators in the Department of Cardiovascular Medicine at Cleveland Clinic and 10 other collaborating institutions.…”