Atherosclerosis 206 (2009) 17–30 Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis Review Apolipoprotein B levels, APOB alleles, and risk of ischemic cardiovascular disease in the general population, a review Marianne Benn ∗ Department of Clinical Biochemistry KB3011, Section for Molecular Genetics, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark article info Article history: Received 4 December 2008 Received in revised form 5 January 2009 Accepted 5 January 2009 Available online 15 January 2009 Keywords: Apolipoprotein B Low density lipoprotein cholesterol Atherosclerosis Ischemic heart disease Ischemic stroke Genetics Epidemiology abstract Apolipoprotein B is a key component in lipid metabolism. Subendothelial retention of apolipoprotein B containing lipoproteins is a necessary initiating event in atherogenesis, and high plasma levels of apolipoprotein B is a risk factor for atherosclerosis, whereas low levels may provide protection. The present review examines, with focus on general population studies, apolipoprotein B levels as a predictor of ischemic cardiovascular disease, as well as the association of mutations and polymorphisms in APOB with plasma apolipoprotein B levels, and risk of ischemic cardiovascular disease. The studies can be summarized as follows: (1) apolipoprotein B predicts ischemic cardiovascular events in both genders, and is better than LDL cholesterol in this respect; (2) linkage disequilibrium structure in APOB is more complex than expected from HapMap data, because a minimal set of tag single nucleotide polymorphisms capturing the entire variation in APOB cannot be identified, and thus most polymor- phisms must be evaluated separately in association studies; (3) APOB mutations and polymorphisms are associated with a range of apolipoprotein B and LDL cholesterol levels, although the magnitude of effect sizes of common polymorphisms are modest; (4) both mutations and polymorphisms are associated with LDL metabolism in vivo; (5) association of APOB mutations and polymorphisms with lipid and disease phenotype cannot be predicted in silico using evolutionary conservation or existing prediction programs; and finally, (6) except for the E4154K polymorphism that possibly predicts a reduction in risk of ischemic cerebrovascular disease and ischemic stroke, common APOB polymorphisms with modest effect sizes on lipid levels do not predict risk of ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, or ischemic stroke in the general population. © 2009 Elsevier Ireland Ltd. All rights reserved. Contents 1. Introduction .......................................................................................................................................... 18 2. Plasma apolipoprotein B levels and risk of ischemic cardiovascular disease ....................................................................... 18 3. APOB mutations and polymorphisms and linkage disequilibrium structure ........................................................................ 19 4. APOB mutations and polymorphisms and plasma apolipoprotein B levels ......................................................................... 20 5. APOB mutations and polymorphisms and LDL metabolism ......................................................................................... 21 6. Evolutionary conservation and predicted effects .................................................................................................... 26 7. APOB mutations and polymorphisms and risk of ischemic cardiovascular disease ................................................................. 26 8. Discussion and perspectives ......................................................................................................................... 26 Acknowledgements .................................................................................................................................. 28 Appendix A. Supplementary data ................................................................................................................... 28 References ........................................................................................................................................... 28 Abbreviations: APOB, apolipoprotein B gene; IDL, intermediate density lipoprotein; LDL, low density lipoprotein; LDLR, low density lipoprotein receptor gene; LIPC, hepatic lipase gene; LPL, lipoprotein lipase gene; MTP, microsomal triglyceride transfer protein gene; SNP, single nucleotide polymorphism; PCSK9, pro-protein convertase subtilisin/kexin 9 gene; UTR, un-translated region; VLDL, very low density lipoprotein. ∗ Tel.: +45 35456506; fax: +45 35456500. E-mail address: marianne@benn.dk. 0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2009.01.004