Lipoprotein(a) Concentration and Risks of Cardiovascular Disease and Diabetes

• Published in: Journal of the American College of Cardiology Vol. 74; no. 24; pp. 2982 - 2994
• Main Authors: Gudbjartsson, Daniel F., Thorgeirsson, Gudmundur, Sulem, Patrick, Helgadottir, Anna, Gylfason, Arnaldur, Saemundsdottir, Jona, Bjornsson, Eythor, Norddahl, Gudmundur L., Jonasdottir, Aslaug, Jonasdottir, Adalbjorg, Eggertsson, Hannes P., Gretarsdottir, Solveig, Thorleifsson, Gudmar, Indridason, Olafur S., Palsson, Runolfur, Jonasson, Fridbert, Jonsdottir, Ingileif, Eyjolfsson, Gudmundur I., Sigurdardottir, Olof, Olafsson, Isleifur, Danielsen, Ragnar, Matthiasson, Stefan E., Kristmundsdottir, Snaedis, Halldorsson, Bjarni V., Hreidarsson, Astradur B., Valdimarsson, Einar M., Gudnason, Thorarinn, Benediktsson, Rafn, Steinthorsdottir, Valgerdur, Thorsteinsdottir, Unnur, Holm, Hilma, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.12.2019; Elsevier Limited
• Subjects: Alternative splicing; Aortic valve; Apolipoproteins; Cardiology; Cardiovascular disease; Cardiovascular diseases; Case-Control Studies; Cholesterol; Congestive heart failure; Coronary artery; Coronary artery disease; Coronary Artery Disease - blood; Coronary Artery Disease - genetics; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; DNA Copy Number Variations; genetics; Genomes; Haplotypes; Health risks; Heart attacks; Homozygotes; Humans; Iceland; Kringles; Levels; Life span; Lipoprotein(a) - blood; Lipoprotein(a) - genetics; Lipoproteins; Lp(a); Mendelian randomization; Mendelian Randomization Analysis; Methods; Molecular Weight; Mutation; Protein Isoforms - blood; Rheumatic heart disease; Risk analysis; Risk Factors; Stenosis; Stroke; Thromboembolism; type 2 diabetes; Vascular diseases; Iceland; coronary artery disease; OR; CI; CAD; T2D; Mendelian randomization; Lp(a); HDL; genetics; type 2 diabetes; apo(a); SNP; LDL; HbA1c; KIV-2
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2019.10.019

Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular diseases that has no established therapy. The attribute of Lp(a) that affects cardiovascular risk is not established. Low levels of Lp(a) have been associated with type 2 diabetes (T2D). This study investigated whether cardiovascular risk is conferred by Lp(a) molar concentration or apolipoprotein(a) [apo(a)] size, and whether the relationship between Lp(a) and T2D risk is causal. This was a case-control study of 143,087 Icelanders with genetic information, including 17,715 with coronary artery disease (CAD) and 8,734 with T2D. This study used measured and genetically imputed Lp(a) molar concentration, kringle IV type 2 (KIV-2) repeats (which determine apo(a) size), and a splice variant in LPA associated with small apo(a) but low Lp(a) molar concentration to disentangle the relationship between Lp(a) and cardiovascular risk. Loss-of-function homozygotes and other subjects genetically predicted to have low Lp(a) levels were evaluated to assess the relationship between Lp(a) and T2D. Lp(a) molar concentration was associated dose-dependently with CAD risk, peripheral artery disease, aortic valve stenosis, heart failure, and lifespan. Lp(a) molar concentration fully explained the Lp(a) association with CAD, and there was no residual association with apo(a) size. Homozygous carriers of loss-of-function mutations had little or no Lp(a) and increased the risk of T2D. Molar concentration is the attribute of Lp(a) that affects risk of cardiovascular diseases. Low Lp(a) concentration (bottom 10%) increases T2D risk. Pharmacologic reduction of Lp(a) concentration in the 20% of individuals with the greatest concentration down to the population median is predicted to decrease CAD risk without increasing T2D risk. [Display omitted]