A Novel Molecular Diagnostic Marker for Familial and Early-Onset CAD and MI in the LRP8 Gene
Background—Many SNPs have been associated with CAD/MI by GWAS, but the diagnostic value of these variants is limited. Functional SNP 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 SNPs flanking R952Q may identify a haplotype which may serve as a molecular diagnostic marker for familial and early-onset CAD/MI.
Methods and Results—Five SNPs (rs7546246, rs2297660, rs3737983, R952Q and rs5177) were genotyped and analyzed in GeneQuest (381 familial, early-onset CAD and 183 MI patients vs. 560 controls) and the Italian population (248 familial MI patients vs. 308 controls). One novel risk haplotype, TACGC, was found only in CAD and MI patients, 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-TDT 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 CAD patients and 294 normal controls. TACGC/TACGC homozygotes tended to develop CAD/MI earlier and showed higher LDL 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 the familial and early-onset CAD/MI patients, we propose that it may be a molecular diagnostic marker for diagnosis of familial, early-onset CAD/MI in some Caucasian populations.
- LRP8 gene
- cardiovascular disease
- myocardial infarction
- haplotype analysis
- single nucleotide polymorphism
- association study
- Received August 7, 2013.
- Revision received April 7, 2014.
- Accepted April 23, 2014.