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FOCUS ISSUE: BIOMARKERS IN CARDIOVASCULAR DISEASE: CLINICAL RESEARCH: BIOMARKERS IN VASCULAR DISEASE AND HYPERTENSION

Apolipoprotein(a) Isoforms and the Risk of Vascular Disease

Systematic Review of 40 Studies Involving 58,000 Participants

Sebhat Erqou, MD, PhD^_*, Alexander Thompson, PhD^_*, Emanuele Di Angelantonio, MD, PhD^_*, Danish Saleheen, MBBS, MPhil^_*, Stephen Kaptoge, MSc, PhD^_*, Santica Marcovina, PhD, DSc and John Danesh, DPhil^_*,_*

^_* Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, Washington

Manuscript received September 15, 2009; revised manuscript received October 26, 2009, accepted October 26, 2009.

^_* Reprint requests and correspondence: Dr. John Danesh, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratories, Cambridge CB1 8RN, United Kingdom (Email: john.danesh{at}phpc.cam.ac.uk).

Objectives: The purpose of this study was to assess the association of apolipoprotein(a) (apo[a]) isoforms with cardiovascular disease risk.

Background: Although circulating lipoprotein(a) (Lp[a]) is likely to be a causal risk factor in coronary heart disease (CHD), the magnitude of this association is modest. Lipoprotein(a) particles with smaller, rather than larger, apo(a) isoforms may be stronger risk factors.

Methods: Information was collated from 40 studies published between January 1970 and June 2009 that reported on associations between apo(a) isoforms and risk of CHD or ischemic stroke (involving a total of 11,396 patients and 46,938 controls).

Results: Thirty-six studies used broadly 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 intervals [CI]: 1.67 to 2.58) for individuals with smaller versus larger apo(a) isoforms (corresponding approximately to 22 or fewer kringle IV type 2 repeats vs. >22 repeats or analogously an apo[a] molecular weight of <640 kDa vs. 640 kDa). There was substantial heterogeneity among these studies (I² = 85%, 80% to 89%), which was mainly explained by differences in the laboratory methods and analytic approaches used. In the 6 studies of ischemic stroke that used comparable phenotypic methods, the combined relative risk was 2.14 (1.85 to 2.97). Overall, however, only 3 studies made allowances for Lp(a) concentration.

Conclusions: People with smaller apo(a) isoforms have an approximately 2-fold higher risk of CHD or ischemic stroke than those with larger proteins. Further studies are needed to determine whether the impact of smaller apo(a) isoforms is independent from Lp(a) concentration and other risk factors.

Key Words: lipoprotein(a) • apolipoprotein(a) isoforms • cardiovascular disease • meta-analysis • epidemiology

Abbreviations and Acronyms   apo(a) = apolipoprotein(a)   CHD = coronary heart disease   KIV2 = kringle IV type 2   LDL = low-density lipoprotein   Lp(a) = lipoprotein(a)   MI = myocardial infarction   RR = relative risk

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