Genetic variant R952Q in LRP8 is associated with increased plasma triglyceride levels in patients with early-onset CAD and MI.

We previously identified a novel locus for plasma triglyceride (TG) levels on chromosome 1p31-32 by genome-wide linkage analysis in the GeneQuest population with familial and premature coronary artery disease (CAD). Here we tested a hypothesis that variants in LRP8, a gene that is under the 1p31-32 linkage peak and associated with risk of familial and premature CAD and increased platelet activation, are associated with TG levels. Seven tagSNPs that cover the entire LRP8 gene were characterized in 358 GeneQuest Caucasian probands. Only SNP R952Q (rs5174) was associated with TG levels (P-adj = 0.0016), and this finding was replicated in one other independent population of 134 patients with early-onset myocardial infarction (males <45; females <55; P-adj = 0.0098). TG levels were higher in the group with higher body mass index (BMI ≥ 25) than in the group with lower BMI (BMI < 25). The association was significant in the overweight group (P-adj = 0.0029) or in the smoking group (P-adj = 0.0004), but not in the group with normal BMI or without smoking history. These results suggest that genetic variant R952Q of LRP8 is associated with increased plasma TG levels in patients who are overweight and have premature CAD/MI and history of smoking.