An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction.
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.
Shen
Gong-Qing
GQ
Department of Molecular Cardiology, Lerner Research Institute, Center for Cardiovascular Genetics, Cleveland, OH 44195, USA.
Li
Lin
L
Girelli
Domenico
D
Seidelmann
Sara B
SB
Rao
Shaoqi
S
Fan
Chun
C
Park
Jeong Euy
JE
Xi
Quansheng
Q
Li
Jing
J
Hu
Ying
Y
Olivieri
Oliviero
O
Marchant
Kandice
K
Barnard
John
J
Corrocher
Roberto
R
Elston
Robert
R
Cassano
June
J
Henderson
Susan
S
Hazen
Stanley L
SL
Plow
Edward F
EF
Topol
Eric J
EJ
Wang
Qing K
QK
D000328:Adult; D017668:Age of Onset; D000368:Aged; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007558:Italy; D026502:LDL-Receptor Related Proteins; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D009820:Ohio; D020641:Polymorphism, Single Nucleotide; D018110:Receptors, Lipoprotein / Q000235:genetics*
D026502:LDL-Receptor Related Proteins; D018110:Receptors, Lipoprotein; C098773:low density lipoprotein receptor-related protein 8