Recently published research studies have provided the strongest evidence so far that Lipoprotein (a) causes coronary disease.

Research by Dr Robert Clarke and colleagues at the University of Oxford, supported by the British Heart foundation claims to support a causal role for Lp (a) lipoprotein in coronary disease¹. They identified two common single nucleotide polymorphisms (SNPs) in the LPA locus on chromosome 6q26-27 encoding Lp(a) lipoprotein. These SNPs account for a third of the variation in Lp (a) lipoprotein levels and were found to have strong association with coronary artery disease (CAD).

 Lp(a) lipoprotein, discovered in 1963 has been implicated in the development of CAD. Lp(a) consists of Apo(a), a very large protein molecule wrapped around and covalently bound to an LDL like particle. Even though a clear association has been demonstrated between Lp(a) lipoprotein and CAD, the causal role has never been conclusively proven before. 

This well designed study called the Precocious Coronary Artery Disease study (PROCARDIS) tested the association between coronary artery disease and 48,742 common SNPs in more than 2000 candidate genes. Case subjects had a diagnosis of CAD before the age of 66 years and also had a sibling in whom CAD was diagnosed prior to that age. This group with 3145 subjects was compared with 3352 strong control group. Three chromosomal regions (6q26-27, 9p21 and 1p13) had strong association with risk of CAD. Of these, 9p21 and 1p13 are already known to be associated with coronary atherosclerosis. The LPA locus on chromosome 6q26-27 had the strongest association among all the candidate genes. This gene encodes apo(a) the main constituent of Lp(a) lipoprotein. Two variants at the LPA locus were identified, which were strongly associated with elevated levels of plasma Lp(a), a reduced copy number in LPA and small Lp(a) lipoprotein size. The investigators tested replication of association in 3 independent populations consisting of 4846 case subjects and 4594 controls and confirmed the association between Lp(a) lipoprotein and coronary artery disease. Adjustment for the plasma Lp(a) levels abolished this association between the genotypes and CAD.

Mechanisms by which Lp(a) lipoprotein increase the risks of CAD remains speculative. Due to the structural homology between plasminogen and apo(a), it competitively inhibits conversion of plasminogen to plasmin and could be prothrombotic. Authors also suggest other mechanisms including the inhibition of expression of tissue factor and carriage of pro-inflammatory oxidised phospholipids.

These findings have implications in the direction of research in future. Further studies are required to determine the clinical utility of Lp(a) levels in risk stratification. The mechanisms by which elevated Lp(a) lipoprotein levels increase the risk of CAD also need to be confirmed.  This study  was conducted in European countries and  additional studies are required to confirm the relation between CAD and Lp(a) in other population groups.   Sawabe et al. recently published the results of their study in which a path analysis was conducted on the association of Lp(a) levels with coronary atherosclerosis and MI using 1062 autopsy cases². This paper suggests that high Lp(a) levels are associated with CAD and myocardial infarction in a population sample from Tokyo. These results also suggest that the increased risk conferred by Lp(a) is very important in non-Caucasian population as well.  South Asians are known to have high Lp(a) levels³ and this may account , at least in part for the higher prevalence of CAD  among this population group. Further studies are needed to explore this.

The most important area of further  research is  how this “new” risk factor can be modified to reduce the risk of future coronary events. In an editorial accompanying the NEJM paper, Dr Kathiresan points out that niacin is the only approved medication which lowers the Lp(a) levels.  Research in future is likely to be aimed towards developing a therapeutic intervention which selectively reduces plasma Lp(a) levels.

 

 

1.       Clarke R, Peden JF, Hopewell JC, et al. PROCARDIS Consortium. Genetic variants associated with

Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009 Dec

24;361(26):2518-28.