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.

Figure 1.

Relationship between LRP8 SNP R952Q and the chromosome 1p34-36 premature MI susceptibility locus. The X-axis shows the position of markers, and the Y-axis is −log(P).

Figure 2.

Pairwise LD analysis. LD between SNPs in LRP8, including R952Q (rs5174), and SNPs in two nearby genes (rs6673692 and rs10788949 in MAGOH and rs1134688 and rs1056425 in FLJ20580) was derived from genotyping data from the GeneQuest control (top) and MI (bottom) populations. LD for the CAD population was nearly identical to the MI population (data not shown). The pairwise correlation between SNPs was measured as D′ and is shown (×100) in each diamond. The red-to-white color gradient indicates the magnitude of pairwise LD, ranging from higher to lower values of LD.

Figure 3.

Effects of the LRP8 R952Q SNP on phosphorylation of p38 MAPK induced by oxidized LDL (ox-LDL). Meg-01 cells were transfected with pEGFP-hLRP8 wild type (WT) or pEGFP-hLRP8 mutant (R952Q) by use of Nucleofector. After 48 h, cells were incubated with ox-LDL (2 μg/ml) for different times and were lysed. An equal amount of total cellular proteins (30 μg) was analyzed for phosphorylated (p-p38) and total p38 MAPK by western-blot analysis. A representative image of the blot is shown (A). The images were scanned and quantified. The experiments were replicated six times, and the graph (B) represents the data from six independent experiments. Data are shown as mean ± SD densitometric units.

Figure 4.

Effects of LRP8 SNP R952Q on platelet aggregation