There was a dose-dependent association between the molar concentration of lipoprotein (a), Lp(a), and the risk of developing a number of cardiovascular diseases, including coronary artery disease (CAD), according to study results published in the Journal of the American College of Cardiology.
In this case-control study conducted in Iceland, a total of 143,087 Icelanders with available genetic data were included (n=17,715 with CAD; n=8734 with type 2 diabetes).
Polymorphism in the LPA gene that encodes the apolipoprotein (a) glycoprotein, which leads to variations in the copy number of the kringle IV type 2 (KIV-2) domain of this protein, is known to affect its size and, as a result, Lp(a) concentration. Fewer KIV-2 repeats have been associated with smaller apo(a) isoforms. In addition, the presence of a splice variant of the LPA gene, G4925A, was found to be associated with lower Lp(a) molar concentration in people with few KIV-2 repeats.
The molar concentration of Lp(a) was measured in serum samples, and the number of KIV-2 repeats as well as the presence of the G4925A splice variant were assessed. A very low concentration of Lp(a) and a high number of KIV-2 repeats have been associated with an increased risk for type 2 diabetes.
In 2930 cases and 8913 control individuals with directly measured Lp(a), there was an association between Lp(a) molar concentration and the risk for CAD (odds ratio [OR], 1.15 per 50 nM; P <.0001). A similar association was found in 14,785 cases and 116,826 controls with genetically imputed Lp(a) concentrations (OR, 1.16 per 50 nM; 95% CI, 1.14-1.18; P <.0001). In addition, an association between a loss-of-function mutation of the LPA gene and a reduced risk for CAD was established.
Participants with very low Lp(a) molar concentration (ie, <3.5 nM; 10% of participants) had the greatest risk for type 2 diabetes (OR, 1.44; 95% CI, 1.21–1.71; P <.0001). Other factors associated with an increased risk for type 2 diabetes included loss-of-function homozygosity (OR, 1.45; 95% CI, 1.05-1.99; P =.022) and very low genetically imputed Lp(a) molar concentrations (OR, 1.16; 95% CI, 1.06-1.27; P =.0012).
Study limitations include the sole enrollment of Icelanders.
“Lowering the Lp(a) levels of subjects with concentration above the 79th percentile (50 nM) to the population median of 14 nM could substantially reduce risk of cardiovascular disease and is not predicted to increase risk [for] type 2 diabetes,” concluded the study authors.
Gudbjartsson DF, Thorgeirsson G, Sulem P, et al. Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes. J Am Coll Cardiol. 2019;74:2982–2994.