Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.
Helgadottir A., Gretarsdottir S., Thorleifsson G., Holm H., Patel RS., Gudnason T., Jones GT., van Rij AM., Eapen DJ., Baas AF., Tregouet DA., Morange PE., Emmerich J., Lindblad B., Gottsäter A., Kiemeny LA., Lindholt JS., Sakalihasan N., Ferrell RE., Carey DJ., Elmore JR., Tsao PS., Grarup N., Jørgensen T., Witte DR., Hansen T., Pedersen O., Pola R., Gaetani E., Magnadottir HB., Wijmenga C., Tromp G., Ronkainen A., Ruigrok YM., Blankensteijn JD., Mueller T., Wells PS., Corral J., Soria JM., Souto JC., Peden JF., Jalilzadeh S., Mayosi BM., Keavney B., Strawbridge RJ., Sabater-Lleal M., Gertow K., Baldassarre D., Nyyssönen K., Rauramaa R., Smit AJ., Mannarino E., Giral P., Tremoli E., de Faire U., Humphries SE., Hamsten A., Haraldsdottir V., Olafsson I., Magnusson MK., Samani NJ., Levey AI., Markus HS., Kostulas K., Dichgans M., Berger K., Kuhlenbäumer G., Ringelstein EB., Stoll M., Seedorf U., Rothwell PM., Powell JT., Kuivaniemi H., Onundarson PT., Valdimarsson E., Matthiasson SE., Gudbjartsson DF., Thorgeirsson G., Quyyumi AA., Watkins H., Farrall M., Thorsteinsdottir U., Stefansson K.
OBJECTIVES: The purpose of this study is investigate the effects of variants in the apolipoprotein(a) gene (LPA) on vascular diseases with different atherosclerotic and thrombotic components. BACKGROUND: It is unclear whether the LPA variants rs10455872 and rs3798220, which correlate with lipoprotein(a) levels and coronary artery disease (CAD), confer susceptibility predominantly via atherosclerosis or thrombosis. METHODS: The 2 LPA variants were combined and examined as LPA scores for the association with ischemic stroke (and TOAST [Trial of Org 10172 in Acute Stroke Treatment] subtypes) (effective sample size [n(e)] = 9,396); peripheral arterial disease (n(e) = 5,215); abdominal aortic aneurysm (n(e) = 4,572); venous thromboembolism (n(e) = 4,607); intracranial aneurysm (n(e) = 1,328); CAD (n(e) = 12,716), carotid intima-media thickness (n = 3,714), and angiographic CAD severity (n = 5,588). RESULTS: LPA score was associated with ischemic stroke subtype large artery atherosclerosis (odds ratio [OR]: 1.27; p = 6.7 × 10(-4)), peripheral artery disease (OR: 1.47; p = 2.9 × 10(-14)), and abdominal aortic aneurysm (OR: 1.23; p = 6.0 × 10(-5)), but not with the ischemic stroke subtypes cardioembolism (OR: 1.03; p = 0.69) or small vessel disease (OR: 1.06; p = 0.52). Although the LPA variants were not associated with carotid intima-media thickness, they were associated with the number of obstructed coronary vessels (p = 4.8 × 10(-12)). Furthermore, CAD cases carrying LPA risk variants had increased susceptibility to atherosclerotic manifestations outside of the coronary tree (OR: 1.26; p = 0.0010) and had earlier onset of CAD (-1.58 years/allele; p = 8.2 × 10(-8)) than CAD cases not carrying the risk variants. There was no association of LPA score with venous thromboembolism (OR: 0.97; p = 0.63) or intracranial aneurysm (OR: 0.85; p = 0.15). CONCLUSIONS: LPA sequence variants were associated with atherosclerotic burden, but not with primarily thrombotic phenotypes.