LPA Single Nucleotide Polymorphisms Research Articles

Elevated lipoprotein(a) and genetic polymorphisms in the LPA gene may predict cardiovascular events

Elevated lipoprotein(a) [Lp(a)] is a risk factor for coronary heart disease (CHD), but there are few studies on the prediction of future cardiovascular events by Lp(a) and its LPA single nucleotide polymorphisms (SNPs). The aim of this study was to investigate whether elevated Lp(a) and its SNPs can predict cardiovascular events. We evaluated whether Lp(a) and LPA SNPs rs6415084 and rs12194138 were associated with the incidence rate and severity of CHD. All participants were followed up for 5 years. Elevated Lp(a) is an independent risk factor for the risk and severity of CHD (CHD group vs. control group: OR = 1.793, 95% CI: 1.053–2.882, p = 0.043; multiple-vessel disease group vs. single-vessel disease group: OR = 1.941, 95% CI: 1.113–3.242, p = 0.027; high GS group vs. low GS group: OR = 2.641, 95% CI: 1.102–7.436, p = 0.040). Both LPA SNPs were risk factors for CHD, and were positively associated with the severity of CHD (LPA SNPs rs6415084: CHD group vs. control group: OR = 1.577, 95% CI: 1.105–1.989, p = 0.004; multiple-vessel disease group vs. single-vessel disease group: OR = 1.613, 95% CI: 1.076–2.641, p = 0.030; high GS group vs. low GS group: OR = 1.580, 95% CI: 1.088–2.429, p = 0.024; LPA SNPs rs12194138: CHD group vs. control group: OR = 1.475, 95% CI: 1.040–3.002, p = 0.035; multiple-vessel disease group vs. single-vessel disease group: OR = 2.274, 95% CI: 1.060–5.148, p = 0.038; high GS group vs. low GS group: OR = 2.067, 95% CI: 1.101–4.647, p = 0.021). After 5 years of follow-up, elevated Lp(a) and LPA SNPs rs6415084 and rs12194138 can independently predict cardiovascular events. The increase of serum Lp(a) and LPA SNPs rs6415084 and rs12194138 are associated with increased prevalence and severity of CHD, and can independently predict cardiovascular events.

Coronary artery disease and the risk-associated LPA variants, rs3798220 and rs10455872, in patients with suspected familial hypercholesterolaemia

BackgroundThe rs3798220 and rs10455872 single nucleotide polymorphisms (SNPs) in LPA are associated with increased plasma concentrations of lipoprotein(a) [Lp(a)] and coronary artery disease (CAD). MethodsWe investigated the association between rs3798220 and rs10455872 and prevalent CAD in 763 patients with suspected familial hypercholesterolaemia (FH). The rs3798220 and rs10455872 SNPs in LPA were detected using a SEQUENOM platform. ResultsBoth LPA SNPs were significantly associated with CAD, but only rs3798220 after adjustment for other risk factors (odds ratio [OR] 2.05; 95% confidence interval [CI] 1.02–4.12; p = 0.045), and neither after adjustment for Lp(a) concentrations. Both SNPs were positively and independently associated with increased Lp(a) (rs3798220: OR 1.27; 95% CI 0.96–1.57; p < 0.001. rs10455872: OR 1.41; 95% CI 1.24–1.58; p < 0.001). Plasma concentrations of Lp(a) were independently associated with prevalent CAD (OR 1.28; 95% CI 1.08–1.52, p = 0.005) after adjustment for LPA SNPs and other cardiovascular risk factors. While both the rs3798220 and rs10455872 SNPs were associated with Lp(a) concentrations and prevalent CAD in patients with suspected FH, this was not independent of Lp(a) concentration. ConclusionsQuantification of Lp(a) is more likely to be useful than assessment of these Lp(a)-associated SNPs to augment CAD risk prediction.

Association between lipoprotein(a) (Lp(a)) levels and Lp(a) genetic variants with coronary artery calcification

BackgroundTo examine the association between lipoprotein(a) (Lp(a)) levels, LPA (rs10455872 and rs3798220) and IL1F9 (rs13415097) single nucleotide polymorphisms (SNPs) with coronary artery calcification (CAC), an important predictor for coronary artery disease (CAD).MethodsWe used data from 3799 (mean age ± SD: 59.0 ± 7.7 years, 47.1% men) Heinz Nixdorf Recall study participants. We applied linear regression models to explore the relation between the log-transformed Lp(a) levels and LPA and IL1F9 SNPs with loge (CAC + 1). The association between the SNPs and log-transformed Lp(a) levels was further assessed using linear regression. The models were adjusted for age and sex (Model 1) and additionally for Lp(a) levels (Model 2).ResultsWe observed a statistically significant association between log-transformed Lp(a) levels and CAC (Model 1: beta per log-unit increase in Lp(a) levels = 0.11; 95% confidence interval [95% CI] [0.04; 0.18], p = 0.002). Furthermore, the LPA SNP rs10455872 showed a statistically significant association with CAC (Model 1: beta per allele = 0.37 [0.14; 0.61], p = 0.002). The association between rs10455872 and CAC was attenuated after adjustment for Lp(a) levels (Model 2: beta per allele = 0.26 [− 0.01; 0.53], p = 0.06). Both LPA SNPs also showed a statistically significant association with Lp(a) levels (Model 1: betars10455872 per allele: 1.56 [1.46; 1.65], p < 0.0001 and betars3798220 per allele: 1.51 [1.33; 1.69], p < 0.0001)). The Mendelian randomization analysis showed that Lp(a) is a causal risk factor for CAC (estimate per log-unit increase in Lp(a) levels (95% CI), p: 0.27 [0.11; 0.44], p = 0.001). The IL1F9 SNP did not show any statistically significant association with Lp(a) levels or with CAC.ConclusionsWe provide evidence for the association of LPA rs10455872 with higher levels of Lp(a) and CAC in our study. The results of our study suggest that rs10455872, mediated by Lp(a) levels, might play a role in promoting the development of atherosclerosis leading to cardiovascular disease events.

Statin treatment increases lipoprotein(a) levels in subjects with low molecular weight apolipoprotein(a) phenotype

Background and aimsWe aimed to evaluate the effect of statin treatment initiation on lipoprotein(a) [Lp(a)] levels in patients with dyslipidemia, and the interactions with the apolipoprotein(a) [apo(a)] phenotype, LPA single nucleotide polymorphisms (SNPs) and change in LDL cholesterol. MethodsThe study population consisted of patients with dyslipidemia, predominantly familial hypercholesterolemia, who first initiated statin treatment (initiation group; n = 39) or were already on stable statin treatment for at least 4 months (control group; n = 42). Plasma Lp(a) levels were determined with a particle-enhanced immunoturbidimetric assay before and at least 2 months after start of statin treatment in individuals of the initiation group, and at two time points with an interval of at least 2 months in the control group. High and low molecular weight (HMW and LMW, respectively) apo(a) phenotype was determined by immunoblotting, and the common LPA SNPs rs10455872, rs3798220 and rs41272110 by Taqman assay. ResultsPlasma Lp(a) levels did not increase significantly in the initiation group (median 20.5 (IQR 10.9–80.7) to 23.3 (10.8–71.8) mg/dL; p = 0.09) nor in the control group (30.9 (IQR 9.2–147.0) to 31.7 (IQR 10.9–164.0) mg/dL; p = 0.61). In patients with the LMW apo(a) phenotype, Lp(a) levels increased significantly from 66.4 (IQR 23.5–148.3) to 97.4 (IQR 24.9–160.4) mg/dL (p = 0.026) in the initiation group, but not in the control group and not in patients characterized by the HMW apo(a) phenotype. Interactions with common LPA SNPs and change in LDL cholesterol were not significant. ConclusionsStatins affect Lp(a) levels differently in patients with dyslipidemia depending on the apo(a) phenotype. Statins increase Lp(a) levels exclusively in patients with the LMW apo(a) phenotype.

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

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. 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. 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. 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. 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.

LPA Gene, Ethnicity, and Cardiovascular Events.

The relationship of LPA single nucleotide polymorphisms (SNPs), apolipoprotein(a) isoforms, and lipoprotein(a) [Lp(a)] levels with major adverse cardiovascular events (MACE) in different ethnic groups is not well known. LPA SNPs, apolipoprotein(a) isoforms, Lp(a), and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) levels were measured in 1792 black, 1030 white, and 597 Hispanic subjects enrolled in the Dallas Heart Study. Their interdependent relationships and prospective association with MACE after median 9.5-year follow-up were determined. LPA SNP rs3798220 was most prevalent in Hispanics (42.38%), rs10455872 in whites (14.27%), and rs9457951 in blacks (32.92%). The correlation of each of these SNPs with the major apolipoprotein(a) isoform size was highly variable and in different directions among ethnic groups. In the entire cohort, Cox regression analysis with multivariable adjustment revealed that quartiles 4 of Lp(a) and OxPL-apoB were associated with hazard ratios (95% confidence interval) for time to MACE of 2.35 (1.50-3.69, P<0.001) and 1.89 (1.26-2.84, P=0.003), respectively, versus quartile 1. Addition of the major apolipoprotein(a) isoform and the 3 LPA SNPs to these models attenuated the risk, but significance was maintained for both Lp(a) and OxPL-apoB. Evaluating time to MACE in specific ethnic groups, Lp(a) was a positive predictor and the size of the major apolipoprotein(a) isoform was an inverse predictor in blacks, the size of the major apolipoprotein(a) isoform was an inverse predictor in whites, and OxPL-apoB was a positive predictor in Hispanics. The prevalence and association of LPA SNPs with size of apolipoprotein(a) isoforms, Lp(a), and OxPL-apoB levels are highly variable and ethnicity-specific. The relationship to MACE is best explained by elevated plasma Lp(a) or OxPL-apoB levels, despite significant ethnic differences in LPA genetic markers.

Abstract 11339: Relationship of LPA Single Nucleotide Polymorphisms With Apolipoprotein (a) Isoforms and Biomarkers of Oxidized Lipoproteins in African-Americans, Caucasians and Hispanics: Results From the DALLAS Heart Study

Background: Oxidized phospholipids (OxPL) measured on apolipoprotein B-100 particles (OxPL-apoB) are a measure of the pro-inflammatory activity of Lp(a). Lp(a) in plasma is genetically determined by variability in kringle IV (KIV) repeats and single nucleotide polymorphisms (SNPs) in the LPA gene, is causally related to cardiovascular disease (CVD) and has become a target of therapy. Methods and Results: OxPL-apoB IgG and IgM autoantibodies to oxidized LDL and apoB-immune complexes, KIV repeats of the major apolipoprotein (a) isoform, LPA snps rs3798220, rs10455872 and rs9457951 were measured in 3454 subjects (1798 African-Americans, 1032 Caucasian and 576 Hispanic) subjects enrolled in the Dallas Heart Study (Table). All 3 snps were highly correlated with the number of KIV repeats in African-Americans but only rs3798220 and rs10455872 were correlated with KIV repeats in Caucasians or Hispanics. rs3798220 and rs10455872 demonstrated strong correlations with Lp(a) and OxPL-apoB levels in subjects with low numbers of KIV repeats, whereas rs9457951 showed similar associations only in African-Americans. None of the LPA snps correlated with the other biomarkers of oxidation. Conclusion: Significant racial differences exist among LPA SNPs and their relationship to Lp(a), apolipoprotein (a) isoforms and OxPL-apoB. These findings may provide insights into the clinical variability of Lp(a)-mediated risk in different racial groups and suggests novel avenues of investigation and therapeutic potential in mitigating the CVD risk of Lp(a) and OxPL-apoB.

Elevated Lipoprotein(a) Does Not Cause Low-Grade Inflammation Despite Causal Association With Aortic Valve Stenosis and Myocardial Infarction: A Study of 100,578 Individuals from the General Population.

It is unknown whether elevated lipoprotein(a) is causally associated with low-grade inflammation. We tested the hypothesis that elevated lipoprotein(a) is observationally and causally associated with low-grade inflammation together with aortic valve stenosis and myocardial infarction. Using a multidirectional Mendelian randomization approach, we studied 100,578 individuals from the Danish general population with plasma levels of and/or genotypes known to affect levels of lipoprotein(a) and C-reactive protein (CRP), and using information regarding diagnosis of aortic valve stenosis and of myocardial infarction (MI) from registries. Observationally, CRP increased by 29% (95% confidence interval [CI], 23-34) per 50-mg/dL increase in lipoprotein(a). However, two LPA single nucleotide polymorphisms (SNPs) and the kringle IV type 2 (KIV-2) genotype that were associated with 98, 95, and 68 mg/dL higher lipoprotein(a) levels were not causally associated with increased CRP levels. For aortic valve stenosis, a 1-SD increase in lipoprotein(a) levels was associated observationally with a multifactorially adjusted hazard ratio of 1.23 (95% CI, 1.06-1.41), with corresponding causal risk ratios of 1.38 (1.23-1.55) based on LPA SNPs and of 1.21 (1.06-1.40) based on LPA KIV-2 genotype. For myocardial infarction, corresponding values were 1.20 (1.10;1.31) observationally, and 1.18 (1.11;1.26) and 1.31 (1.22;1.42) causally, respectively. Observational hazard ratios for aortic valve stenosis and MI were similar after further adjustment for CRP levels. Elevated levels of lipoprotein(a) were not causally associated with increased low-grade inflammation as measured through CRP despite a causal association with increased risk of aortic valve stenosis and MI.

Lack of association between lipoprotein(a) genetic variants and subsequent cardiovascular events in Chinese Han patients with coronary artery disease after percutaneous coronary intervention

BackgroundElevated lipoprotein(a) [Lp(a)] levels predict cardiovascular events incidence in patients with coronary artery disease (CAD). Genetic variants in the rs3798220, rs10455872 and rs6415084 single-nucleotide polymorphisms (SNPs) in the Lp(a) gene (LPA) correlate with elevated Lp(a) levels, but whether these SNPs have prognostic value for CAD patients is unknown. The present study evaluated the association of LPA SNPs with incidence of subsequent cardiovascular events in CAD patients after percutaneous coronary intervention (PCI).MethodsTaqMan SNP genotyping assays were performed to detect the rs6415084, rs3798220 and rs10455872 genotypes in 517 Chinese Han patients with CAD after PCI. We later assessed whether there was an association of these SNPs with incidence of major adverse cardiovascular events (MACE: cardiac death, nonfatal myocardial infarction, ischemic stroke and coronary revascularization). Serum lipid profiles were also determined using biochemical methods.ResultsOnly the rs6415084 variant allele was associated with higher Lp(a) levels [41.3 (20.8, 74.6) vs. 18.6 (10.3, 40.9) mg/dl, p < 0.001]. During a 2-year follow-up period, 102 patients suffered MACE, and Cox regression analysis demonstrated that elevated Lp(a) (≥30 mg/dl) levels correlated with increased MACE (adjusted HR, 1.69; 95% CI 1.13-2.53), but there was no association between LPA genetic variants (rs6415084 and rs3798220) and MACE incidence (p > 0.05).ConclusionsOur data did not support a relationship between genetic LPA variants (rs6415084 and rs3798220) and subsequent cardiovascular events after PCI in Chinese Han CAD patients.

Genome-wide association study of genetic determinants of LDL-c response to atorvastatin therapy: importance of Lp(a)

We carried out a genome-wide association study (GWAS) of LDL-c response to statin using data from participants in the Collaborative Atorvastatin Diabetes Study (CARDS; n = 1,156), the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT; n = 895), and the observational phase of ASCOT (n = 651), all of whom were prescribed atorvastatin 10 mg. Following genome-wide imputation, we combined data from the three studies in a meta-analysis. We found associations of LDL-c response to atorvastatin that reached genome-wide significance at rs10455872 (P = 6.13 × 10−9) within the LPA gene and at two single nucleotide polymorphisms (SNP) within the APOE region (rs445925; P = 2.22 × 10−16 and rs4420638; P = 1.01 × 10−11) that are proxies for the ϵ2 and ϵ4 variants, respectively, in APOE. The novel association with the LPA SNP was replicated in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial (P = 0.009). Using CARDS data, we further showed that atorvastatin therapy did not alter lipoprotein(a) [Lp(a)] and that Lp(a) levels accounted for all of the associations of SNPs in the LPA gene and the apparent LDL-c response levels. However, statin therapy had a similar effect in reducing cardiovascular disease (CVD) in patients in the top quartile for serum Lp(a) levels (HR = 0.60) compared with those in the lower three quartiles (HR = 0.66; P = 0.8 for interaction). The data emphasize that high Lp(a) levels affect the measurement of LDL-c and the clinical estimation of LDL-c response. Therefore, an apparently lower LDL-c response to statin therapy may indicate a need for measurement of Lp(a). However, statin therapy seems beneficial even in those with high Lp(a).

Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy

Lipoprotein(a) [Lp(a)] has enhanced atherothrombotic properties. The ability of Lp(a) levels to predict adverse cardiovascular outcomes in patients undergoing coronary angiography has not been examined. The relationship between serum Lp(a) levels and both the extent of angiographic disease and 3-year incidence of major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, and coronary revascularization) was investigated in 2,769 patients who underwent coronary angiography [median Lp(a) 16.4 mg/dl, elevated levels (≥30 mg/dl) in 38%]. An elevated Lp(a) was associated with a 2.3-fold [95% confidence interval (CI), 1.7-3.2, P < 0.001] greater likelihood of having a significant angiographic stenosis and 1.5-fold (95 CI, 1.3-1.7, P < 0.001) greater chance of three-vessel disease. Lp(a)≥30 mg/dl was associated with a greater rate of MACE (41.8 vs. 35.8%, P = 0.005), primarily due to a greater need for coronary revascularization (30.9 vs. 26.0%, P = 0.02). A relationship between Lp(a) levels and cardiovascular outcome was observed in patients with an LDL cholesterol (LDL-C) ≥70-100 mg/dl (P = 0.049) and >100 mg/dl (P = 0.02), but not <70 mg/dl (P = 0.77). Polymorphisms of Lp(a) were also associated with both plasma Lp(a) levels and coronary stenosis, but not a greater rate of MACE. Lp(a) levels correlate with the extent of obstructive disease and predict the need for coronary revascularization in subjects with suboptimal LDL-C control. This supports the need to intensify lipid management in patients with elevated Lp(a) levels.

Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease

An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.