Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study.
Zewinger S., Kleber ME., Tragante V., McCubrey RO., Schmidt AF., Direk K., Laufs U., Werner C., Koenig W., Rothenbacher D., Mons U., Breitling LP., Brenner H., Jennings RT., Petrakis I., Triem S., Klug M., Filips A., Blankenberg S., Waldeyer C., Sinning C., Schnabel RB., Lackner KJ., Vlachopoulou E., Nygård O., Svingen GFT., Pedersen ER., Tell GS., Sinisalo J., Nieminen MS., Laaksonen R., Trompet S., Smit RAJ., Sattar N., Jukema JW., Groesdonk HV., Delgado G., Stojakovic T., Pilbrow AP., Cameron VA., Richards AM., Doughty RN., Gong Y., Cooper-DeHoff R., Johnson J., Scholz M., Beutner F., Thiery J., Smith JG., Vilmundarson RO., McPherson R., Stewart AFR., Cresci S., Lenzini PA., Spertus JA., Olivieri O., Girelli D., Martinelli NI., Leiherer A., Saely CH., Drexel H., Mündlein A., Braund PS., Nelson CP., Samani NJ., Kofink D., Hoefer IE., Pasterkamp G., Quyyumi AA., Ko YA., Hartiala JA., Allayee H., Tang WHW., Hazen SL., Eriksson N., Held C., Hagström E., Wallentin L., Åkerblom A., Siegbahn A., Karp I., Labos C., Pilote L., Engert JC., Brophy JM., Thanassoulis G., Bogaty P., Szczeklik W., Kaczor M., Sanak M., Virani SS., Ballantyne CM., Lee VV., Boerwinkle E., Holmes MV., Horne BD., Hingorani A., Asselbergs FW., Patel RS., GENIUS-CHD consortium None., Krämer BK., Scharnagl H., Fliser D., März W., Speer T.
BACKGROUND: Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. METHODS: We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. FINDINGS: The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14-1·83) and the presence of either LPA SNP (1·88, 1·40-2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81-1·11 and either LPA SNP 1·10, 0·92-1·31) or cardiovascular mortality (0·99, 0·81-1·2 and 1·13, 0·90-1·40, respectively) or in the validation studies. INTERPRETATION: In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. FUNDING: Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.