title: 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.
  
  
  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.
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Gong-Qing
authors.initials: GQ
authors.lastname: Shen
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Domenico
authors.initials: D
authors.lastname: Girelli
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Shaoqi
authors.initials: S
authors.lastname: Rao
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Stephen
authors.initials: S
authors.lastname: Archacki
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Oliviero
authors.initials: O
authors.lastname: Olivieri
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Nicola
authors.initials: N
authors.lastname: Martinelli
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Jeong Euy
authors.initials: JE
authors.lastname: Park
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Qiuyun
authors.initials: Q
authors.lastname: Chen
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.).
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Topol
authors.affiliation: From the Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, OH (G.-Q.S., L.L., S.R., S.A., Q.C., Q.K.W.); Department of Medicine, University of Verona, Verona, Italy (D.G., O.O., N.M.); Samsung Medical Center, Sungkyunkwan University, Seoul, South Korea (J.E.P.); The Scripps Research Institute, Scripps Clinic, La Jolla, CA (E.J.T.); and Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, China (Q.K.W.). wangq2@ccf.org qkwang@mail.hust.edu.cn.
authors.forename: Qing K
authors.initials: QK
authors.lastname: Wang
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D044466:Asian People / Q000235:genetics; D001483:Base Sequence; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood; D015331:Cohort Studies; D003324:Coronary Artery Disease / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007558:Italy; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis* / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D056910:Republic of Korea; D012306:Risk; D044465:White People / Q000235:genetics
chemical_list: D008078:Cholesterol, LDL; D026502:LDL-Receptor Related Proteins; C098773:low density lipoprotein receptor-related protein 8
keywords: cardiovascular diseases; myocardial infarction; polymorphism, single nucleotide