A Causal Factor for Heart Disease

• Although more than 300 risk factors for atherosclerosis and CVD (cardiovascular disease) have been identified, only elevated LDL cholesterol (low-density lipoprotein cholesterol) was recognized as a causative factor until the European Consensus statement recognized elevated lipoprotein(a) as the second causative factor.¹

• Mechanistic studies, epidemiological studies, as well as recent genetic findings, suggest Lp(a) is a causal risk factor for premature CAD (coronary artery disease) and CVD demonstrating atherogenic and thrombogenic properties, including enhanced uptake by macrophages, interference with fibrinolysis, and increased expression of adhesion molecules.^2-4 The association is continuous without a threshold, but further increased in those with high LDL- or non-HDL-cholesterol levels. ^{5, 6}

• Scientific and clinical evidence favoring an interpretation of causality between elevated levels of a lipoprotein and increased CVD risk constitutes a prerequisite for selection of desirable levels. For an interpretation of causality, five types of evidence should each favor causality and all three types of human evidence (epidemiology, genetics, and intervention trials) must concur.¹ For elevated LDL-cholesterol levels, all five criteria are well documented and the consensus is causality. Based on the same criteria, elevated Lp(a) levels probably are also causally related to increased CVD risk.¹

• Preliminary genome-wide association studies support a causal role of Lp(a). In the Procardis Consortium Mendelian Randomization study, subjects carrying variants on chromosome 6Q26-27 in the region encoding Lp(a) exhibited both elevated circulating Lp(a) levels and a greater risk of CAD. Among the single nucleotide polymorphisms (SNPs) identified, those in the coding region of Lp(a) demonstrated the strongest association with CAD with an odds ratio of 1.51.⁴

• Recently, genetic association studies with Mendelian randomization approaches have clearly demonstrated that Lp(a) is a strong, causal, genetic risk factor in heart attack and CAD.³ In fact, its association with CAD  was the strongest in a study evaluating 48,742 SNPs in 2,100 candidate genes, including a higher odds ratio than the previously reported 9p21 SNP.⁴

• Clarke et al ⁴ have found the effects of Lp(a) variants on the risk of CAD correlated with the Lp(a) level. The linear dose-response relationship of the LPA variants with both level and the risk of CAD   provides compelling support for the causal role of elevated blood level of Lp(a) in the risk of CAD.⁴

• One in six whites carries a variant of LPA allele and has 50% increased risk of CAD. Those carrying both alleles have an even greater risk (4-fold) and Lp(a) levels exceeding 100 mg/dl.⁴ The frequency of these Lp(a) variants have not been reported in other populations.

Sources

1. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. Oct 21 2010.

2. Boffa MB, Marcovina SM, Koschinsky ML. Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models. Clinical biochemistry. May 2004;37(5):333-343.

3. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. Jun 10 2009;301(22):2331-2339.

4. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. Dec 24 2009;361(26):2518-2528.

5. Erqou S., Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. Jul 22 2009;302(4):412-423.

6. Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Extreme Lipoprotein(a) Levels and Risk of Myocardial Infarction in the General Population. The Copenhagen City Heart Study. Circulation. Dec 17 2007:176-184.