Dataset Information

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.

ABSTRACT:

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.

SUBMITTER: Zewinger S

PROVIDER: S-EPMC5651679 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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 Stephen S Kleber Marcus E ME Tragante Vinicius V McCubrey Raymond O RO Schmidt Amand F AF Direk Kenan K Laufs Ulrich U Werner Christian C Koenig Wolfgang W Rothenbacher Dietrich D Mons Ute U Breitling Lutz P LP Brenner Herrmann H Jennings Richard T RT Petrakis Ioannis I Triem Sarah S Klug Mira M Filips Alexandra A Blankenberg Stefan S Waldeyer Christoph C Sinning Christoph C Schnabel Renate B RB Lackner Karl J KJ Vlachopoulou Efthymia E Nygård Ottar O Svingen Gard Frodahl Tveitevåg GFT Pedersen Eva Ringdal ER Tell Grethe S GS Sinisalo Juha J Nieminen Markku S MS Laaksonen Reijo R Trompet Stella S Smit Roelof A J RAJ Sattar Naveed N Jukema J Wouter JW Groesdonk Heinrich V HV Delgado Graciela G Stojakovic Tatjana T Pilbrow Anna P AP Cameron Vicky A VA Richards A Mark AM Doughty Robert N RN Gong Yan Y Cooper-DeHoff Rhonda R Johnson Julie J Scholz Markus M Beutner Frank F Thiery Joachim J Smith J Gustav JG Vilmundarson Ragnar O RO McPherson Ruth R Stewart Alexandre F R AFR Cresci Sharon S Lenzini Petra A PA Spertus John A JA Olivieri Oliviero O Girelli Domenico D Martinelli Nicola I NI Leiherer Andreas A Saely Christoph H CH Drexel Heinz H Mündlein Axel A Braund Peter S PS Nelson Christopher P CP Samani Nilesh J NJ Kofink Daniel D Hoefer Imo E IE Pasterkamp Gerard G Quyyumi Arshed A AA Ko Yi-An YA Hartiala Jaana A JA Allayee Hooman H Tang W H Wilson WHW Hazen Stanley L SL Eriksson Niclas N Held Claes C Hagström Emil E Wallentin Lars L Åkerblom Axel A Siegbahn Agneta A Karp Igor I Labos Christopher C Pilote Louise L Engert James C JC Brophy James M JM Thanassoulis George G Bogaty Peter P Szczeklik Wojciech W Kaczor Marcin M Sanak Marek M Virani Salim S SS Ballantyne Christie M CM Lee Vei-Vei VV Boerwinkle Eric E Holmes Michael V MV Horne Benjamin D BD Hingorani Aroon A Asselbergs Folkert W FW Patel Riyaz S RS Krämer Bernhard K BK Scharnagl Hubert H Fliser Danilo D März Winfried W Speer Thimoteus T

The lancet. Diabetes & endocrinology 20170526 7

<h4>Background</h4>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.<h4>Methods</h4>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) co ...[more]

PMID: 28566218

Similar Datasets

Project description:ImportanceHuman genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.ObjectiveTo estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD.Design, setting, and participantsA mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.ExposuresGenetic LPA score and plasma Lp(a) mass concentration.Main outcomes and measuresCoronary heart disease.ResultsOf the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10-37), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10-12). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk.Conclusions and relevanceThe clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).

Project description:ContextCirculating concentration of lipoprotein(a) (Lp[a]), a large glycoprotein attached to a low-density lipoprotein-like particle, may be associated with risk of coronary heart disease (CHD) and stroke.ObjectiveTo assess the relationship of Lp(a) concentration with risk of major vascular and nonvascular outcomes.Study selectionLong-term prospective studies that recorded Lp(a) concentration and subsequent major vascular morbidity and/or cause-specific mortality published between January 1970 and March 2009 were identified through electronic searches of MEDLINE and other databases, manual searches of reference lists, and discussion with collaborators.Data extractionIndividual records were provided for each of 126,634 participants in 36 prospective studies. During 1.3 million person-years of follow-up, 22,076 first-ever fatal or nonfatal vascular disease outcomes or nonvascular deaths were recorded, including 9336 CHD outcomes, 1903 ischemic strokes, 338 hemorrhagic strokes, 751 unclassified strokes, 1091 other vascular deaths, 8114 nonvascular deaths, and 242 deaths of unknown cause. Within-study regression analyses were adjusted for within-person variation and combined using meta-analysis. Analyses excluded participants with known preexisting CHD or stroke at baseline.Data synthesisLipoprotein(a) concentration was weakly correlated with several conventional vascular risk factors and it was highly consistent within individuals over several years. Associations of Lp(a) with CHD risk were broadly continuous in shape. In the 24 cohort studies, the rates of CHD in the top and bottom thirds of baseline Lp(a) distributions, respectively, were 5.6 (95% confidence interval [CI], 5.4-5.9) per 1000 person-years and 4.4 (95% CI, 4.2-4.6) per 1000 person-years. The risk ratio for CHD, adjusted for age and sex only, was 1.16 (95% CI, 1.11-1.22) per 3.5-fold higher usual Lp(a) concentration (ie, per 1 SD), and it was 1.13 (95% CI, 1.09-1.18) following further adjustment for lipids and other conventional risk factors. The corresponding adjusted risk ratios were 1.10 (95% CI, 1.02-1.18) for ischemic stroke, 1.01 (95% CI, 0.98-1.05) for the aggregate of nonvascular mortality, 1.00 (95% CI, 0.97-1.04) for cancer deaths, and 1.00 (95% CI, 0.95-1.06) for nonvascular deaths other than cancer.ConclusionUnder a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke that appear exclusive to vascular outcomes.

Dataset Information

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.

Background

Methods

Findings

Interpretation

Funding

Publications

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.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets