Lipoprotein(a) and the risk of vascular disease

Background: 
Lipoprotein(a) [Lp(a)] is composed of a low density-lipoprotein (LDL) particle and a glycoprotein molecule known as apolipoprotein(a) [apo(a)]. Apo(a) exists in several differently-sized isoforms and is responsible for the unique properties of Lp(a). Although Lp(a) has been known for the past 40 years its relationship with coronary heart disease (CHD) has not been characterized in sufficient detail. Whether Lp(a) causes CHD is not clear. Furthermore, the role of apo(a) isoform variation and other sources of Lp(a) heterogeneity (e.g., level of oxidized phospholipids) in Lp(a)-disease association has not been determined. 

Objectives:
To characterize in detail the association of circulating Lp(a) levels with the risk CHD
To assess the nature of Lp(a)-CHD association using an integrative genetic study
To explore the role of Lp(a) heterogeneity in its association with CHD

Data sources:
1.	The Emerging Risk Factors Collaboration (ERFC) database (36 studies, 127,000 participants)
2.	The European Prospective Investigation of Cancer – Norfolk (EPIC-Norfolk) study (2200CHD cases, 2200 controls)
3.	The Pakistani Risk of Myocardial Infarction Study (PROMIS) (1800 MI cases and 1800 controls)
4.	Systematic quantitative reviews of published epidemiological studies

Results:
ERFC data - Analyses of cross-sectional data on up to 127,000 participants (predominantly of European descent) demonstrated that Lp(a) is generally not strongly correlated with known CHD risk factors. Weakly positive correlations were observed with LDL-cholesterol, apolipoprotein B100 and fibrinogen. Levels were over 2-fold higher in Blacks compared to Whites. Analyses of available data on repeat measurements in 6600 participants demonstrated that Lp(a) values have very high long-term within-person consistency (regression dilution ratio ~ 0.9). Outcome data involved 9300 incident CHD events, 1900 ischaemic strokes and 8100 nonvascular deaths. The risk ratio for CHD per 1SD higher Lp(a) concentration, adjusted for age, sex, lipids and other conventional vascular risk factors, was 1.13 (95% CI, 1.09-1.18). The corresponding risk ratios for ischaemic stroke and nonvascular death were 1.10 (1.02 – 1.18) and 1.01 (0.98-1.05), respectively. Data were too limited to assess association in nonwhites.

PROMIS data – the adjusted odds ratio for MI in South Asians was comparable to that of Europeans.

EPIC-Norfolk genetic data - The odds ratio for CHD per 1-SD higher Lp(a) concentration, after adjustment for cardiovascular risk factors, was 1.37 (1.20-1.56).  Tagging SNPs rs10455872 and rs11751605 (minor allele frequency: 8% and 18%, respectively) were associated with 207% (95% CI, 188 - 227%) and 38% (31 - 46%) higher Lp(a) concentrations per copy of minor allele, respectively. These SNPs accounted for 35% and 5% of the variation in circulating Lp(a) levels, respectively, and were associated with an odds ratio for CHD of 1.34 (1.14-1.58) and 1.17 (1.04-1.33), respectively. The observed SNP-CHD associations were consistent with expected odds ratios corresponding to the Lp(a) effect of the SNPs.

Systematic reviews – meta-analysis of published data from 40 studies (11,300 cases, 47,000 controls) demonstrated that people with smaller apo(a) isoforms have about a 2-fold higher risk of CHD or ischemic stroke than those with larger isoforms. Meta-analysis of published data from 10 studies (1500 cases, 10,200 controls) showed that people in the top third of baseline distribution of oxidized LDL levels have a 1.8-fold higher risk of CHD than those in bottom third.

EPIC-Norfolk biomarker data – Levels of oxidized phospholipids were strongly correlated with Lp(a) concentration (r = 0.7, p-value < 0.0001). One SD higher concentration of oxidized phospholipids was associated with an adjusted odds ratio for CHD of 1.31 (1.15-1.49). The risk ratio was no longer significant after adjustment for Lp(a) concentration (1.08; 95% CI, 0.91-1.29).

Conclusion:
Lp(a) concentration is specifically, continuously and independently associated with the risk of ischaemic vascular outcomes. Available evidence supports the causal role of the particle in CHD. Lp(a) appears to induce vascular damage through causal mechanisms that involve apo(a) isoforms and oxidized phospholipids. A comprehensive study of markers of Lp(a) heterogeneity should help to understand the full impact of Lp(a) on cardiovascular diseases. In addition, further study is needed in nonwhites to assess the relevance of the factor to vascular disease risk in these populations.Gates Cambridge Trust, Overseas Research Studentshi