An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction.

Authors: Shen, GQ  Li, L  Girelli, D  Seidelmann, SB  Rao, S  Fan, C  Park, JE  Xi, Q  Li, J  Hu, Y  Olivieri, O  Marchant, K  Barnard, J  Corrocher, R  Elston, R  Cassano, J  Henderson, S  Hazen, SL  Plow, EF  Topol, EJ  Wang, QK 
Citation: Shen GQ, etal., Am J Hum Genet. 2007 Oct;81(4):780-91. Epub 2007 Aug 31.
Pubmed: (View Article at PubMed) PMID:17847002
DOI: Full-text: DOI:10.1086/521581

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.

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CRRD Object Information
CRRD ID: 2306124
Created: 2009-03-20
Species: All species
Last Modified: 2009-03-20
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.