A novel molecular diagnostic marker for familial and early-onset coronary artery disease and myocardial infarction in the LRP8 gene

Abstract

Background: Many single-nucleotide polymorphisms have been associated with coronary artery disease (CAD)/myocardial infarction (MI) by genome-wide association studies, but the diagnostic value of these variants is limited. Functional single-nucleotide polymorphism R952Q in LRP8 is associated with familial and early-onset CAD/MI. The objective of this study is to test whether fine mapping and haplotype analysis for single-nucleotide polymorphisms flanking R952Q may identify a haplotype that may serve as a molecular diagnostic marker for familial and early-onset CAD/MI.

Methods and results: Five single-nucleotide polymorphisms (rs7546246, rs2297660, rs3737983, R952Q, and rs5177) were genotyped and analyzed in GeneQuest (381 patients with familial, early-onset CAD and 183 patients with MI versus 560 controls) and the Italian population (248 patients with familial MI versus 308 controls). One novel risk haplotype, TACGC, was found only in patients with CAD and MI but not in controls. It was significantly associated with CAD (P=7.4×10(-7)) and MI (P=2.2×10(-9)) in GeneQuest. The finding was replicated in the Italian cohort (P=0.041). Sib-transmission disequilibrium test analysis showed a significant association between haplotype TACGC and CAD in GeneQuest II (P=0.039). Haplotype TACGC was not present in a South Korean population of 611 patients with CAD and 294 normal controls. TACGC/TACGC homozygotes tended to develop CAD/MI earlier and showed higher low-density lipoprotein cholesterol levels than heterozygotes (P<0.05).

Conclusions: The rare haplotype TACGC in LRP8 confers a significant risk of familial, early-onset CAD/MI. Because the risk haplotype exists only in patients with familial and early-onset CAD/MI, we propose that it may be a molecular diagnostic marker for diagnosis of familial, early-onset CAD/MI in some white populations.

Keywords: cardiovascular diseases; myocardial infarction; polymorphism, single nucleotide.

Figure 1

Fine mapping to define the boundaries of the TACGC haplotype. Nineteen CAD/MI patients (#1 to #19) carrying the TACGC risk haplotype of LRP8 were genotyped with SNPs upstream and downstream of the haplotype. The results define SNP rs1288516 as the upstream flanking SNP for the risk haplotype as individuals 3, 7, and 17 did not show recombination. SNP rs6677126 is the downstream flanking SNP as multiple individuals, #6, #13, #15, and #19 showed recombination at this position.