Apolipoprotein (a) Isoforms and the Risk of Vascular Disease: A Systematic Review of 40 Studies Involving 58,000 Participants

Abstract

Conclusion: Smaller apolipoprotein (a) (apo[a]) isoforms confer an approximately twofold higher risk of ischemic stroke or coronary heart disease than larger isoforms of apo(a). Summary: Lipoprotein(a) (Lp[a]) is composed of a glycoprotein molecule, apo(a), and a low-density lipoprotein (LDL) particle. Apo(a) is responsible for the properties of Lp(a). (Marcovina SM et al [Am J Cardiol 1998:82:57U-66U]; McLean JW et al [Nature 1987;330:132-7]). Increased circulating Lp(a) concentration is associated with increased risk of coronary heart disease (CHD) and stroke and is independent of other conventional risk factors for vascular disease, including total cholesterol level. The overall additive risk of abnormalities of Lp(a) is only about one-quarter that seen with LDL cholesterol level (JAMA 2009;302:412-23). However, specific Lp(a) subtypes may confer higher cardiovascular risk. If that is the case, analysis for Lp(a) subtypes may be useful in the stratification of vascular risk. The authors postulated that Lp(a) particles associated with smaller rather than larger apo(a) isoforms may result in higher cardiovascular risk. They analyzed information from 40 studies published between January 1970 and June 2009 that reported an association between apo(a) isoforms and the risk of ischemic stroke or CHD. This involved 11,396 patients and 46,938 controls in 36 studies that used comparable phenotyping and analytic methods to assess apo(a) isoform size. These studies yielded a combined relative risk for CHD of 2.08 (95% confidence interval [CI], 1.67-2.58) for subjects with smaller vs larger apo(a) isoforms. There was substantial heterogeneity among the studies (I2 = 85%; 95% CI, 80%-89%). Heterogeneity was mainly explained by differences in analytical approaches and laboratory methods. Six studies of ischemic stroke used comparable phenotypic methods with a combined relative risk of 2.14 (95% CI, 1.85-2.97). Comment: Apo(a) size heterogeneity is a function of a copy number variation of one protein domain, kringle IV type 2, the gene for which exists in 5 to 50 identically repeated copies. Copy number variation of the gene confers marked heterogeneity in the molecular mass of the apo(a) isoform (Boffa MB [Clin Biochem 2004;37:333-43]). Apo(a) subtyping has been clinically limited because it adds a relatively modest incremental risk compared with other biomarkers for cardiovascular disease. However, this study indicates there are subtypes of apo(a) that may be worth looking for. It will need to be determined whether smaller apo(a) isoforms have sufficient relevance in determining vascular risk independent from Lp(a) concentration when compared to other more conventional risk factors for atherosclerosis.