Lipoprotein(a): Are we ready for large-scale clinical trials?

Cardiovascular diseases (CVD) are currently the most important disease threatening human health, which may be due to the high incidence of risk factors including hyperlipidemia. With the deepening of research on lipoprotein, lipoprotein (a) [Lp(a)] has been shown to be an independent risk factor for atherosclerotic cardiovascular diseases and calcified aortic valve stenosis and is now an unaddressed "residual risk" in current CVD management. Accurate measurement of Lp(a) concentration is the basis for diagnosis and treatment of high Lp(a). This review summarized the Lp(a) structure, discussed the current problems in clinical measurement of plasma Lp(a) concentration and the effects of existing lipid-lowering therapies on Lp(a).

Assessment of Apolipoprotein(a) Isoform Size Using Phenotypic and Genotypic Methods.

Apolipoprotein(a) (apo(a)) is the protein component that defines lipoprotein(a) (Lp(a)) particles and is encoded by the LPA gene. The apo(a) is extremely heterogeneous in size due to the copy number variations in the kringle-IV type 2 (KIV2) domains. In this review, we aim to discuss the role of genetics in establishing Lp(a) as a risk factor for coronary heart disease (CHD) by examining a series of molecular biology techniques aimed at identifying the best strategy for a possible application in clinical research and practice, according to the current gold standard.

CORONARY ARTERY CALCIUM IS ASSOCIATED WITH LPA GENE VARIANT RS7765803-C IN MEXICAN MESTIZO POPULATION. THE GEA PROJECT.

BACKGROUND: Lipoprotein(a) [Lp(a)] levels are genetically determined; high levels are a risk factor for coronary disease, although their association with coronary artery calcium (CAC) is controversial. Objective: The objective of the study was to assess the association of LPA gene polymorphisms with CAC in a Mexican Mestizo population. METHODS: We included 1594 subjects 35-70 years old. Six polymorphisms of the LPA gene were analyzed. CAC score was determined by tomography and Lp(a) serum levels by immunonephelometry. The association of LPA polymorphism with CAC and Lp(a) was evaluated by logistic regression. RESULTS: The prevalence of Lp(a) ≥30 mg/dL was 10%, and of CAC >0 was 26.9%. Three polymorphisms were associated with high Lp(a) levels: rs10455872-G (p = 0.013), rs6907156-T (p = 0.021), and rs7765803-C (p = 0.001). Homozygotes (CC) for the rs7765803 variant compared with the G allele (CG + GG) carriers had higher Lp(a) levels (8.9 [3.3-23.9] vs. 4.9 [2.3-11.2] mg/dL; p = 0.015) and higher prevalence of CAC >0 (36.5% vs. 26.3%, p = 0.045) and were associated with CAC > 0 (odds ratio = 1.7, 95% confidence interval: 1.06-2.7; p < 0.026). The other polymorphisms were not associated with CAC. CONCLUSIONS: This is the first study to demonstrate in a Mexican Mestizo population that carriers of the rs7765803-C allele of LPA gene have 2.6 times greater risk for high Lp(a) values and 1.7 times higher risk for coronary artery disease.

Coronary artery calcium is associated with lpa gene variant RS7765803-C in Mexican mestizo population The GEA Project

ABSTRACT Background: Lipoprotein(a) [Lp(a)] levels are genetically determined; high levels are a risk factor for coronary disease, although their association with coronary artery calcium (CAC) is controversial. Objective: The objective of the study was to assess the association of LPA gene polymorphisms with CAC in a Mexican Mestizo population. Methods: We included 1594 subjects 35-70 years old. Six polymorphisms of the LPA gene were analyzed. CAC score was determined by tomography and Lp(a) serum levels by immunonephelometry. The association of LPA polymorphism with CAC and Lp(a) was evaluated by logistic regression. Results: The prevalence of Lp(a) ≥30 mg/dL was 10%, and of CAC >0 was 26.9%. Three polymorphisms were associated with high Lp(a) levels: rs10455872-G (p = 0.013), rs6907156-T (p = 0.021), and rs7765803-C (p = 0.001). Homozygotes (CC) for the rs7765803 variant compared with the G allele (CG + GG) carriers had higher Lp(a) levels (8.9 [3.3-23.9] vs. 4.9 [2.3-11.2] mg/dL; p = 0.015) and higher prevalence of CAC >0 (36.5% vs. 26.3%, p = 0.045) and were associated with CAC > 0 (odds ratio = 1.7, 95% confidence interval: 1.06-2.7; p < 0.026). The other polymorphisms were not associated with CAC. Conclusions: This is the first study to demonstrate in a Mexican Mestizo population that carriers of the rs7765803-C allele of LPA gene have 2.6 times greater risk for high Lp(a) values and 1.7 times higher risk for coronary artery disease.

Genetic and nutritional factors determining circulating levels of lipoprotein(a): results of the "Montignoso Study".

Increasing evidence shows an association between high lipoprotein(a) [Lp(a)] levels and atherothrombotic diseases. Lp(a) trait is largely controlled by kringle-IV type 2 (KIV-2) size polymorphism in LPA gene, encoding for apo(a). Environmental factors are considered to determinate minor phenotypic variability in Lp(a) levels. In the present study, we investigated the possible gene-environment interaction between KIV-2 polymorphism and Mediterranean diet adherence or fish weekly intake in determining Lp(a) levels. We evaluated Lp(a), KIV-2 polymorphism, fish intake and Mediterranean diet adherence in 452 subjects [median age (range) 66 (46-80)years] from Montignoso Heart and Lung Project (MEHLP) population. In subjects with high KIV-2 repeats number, influence of Mediterranean diet adherence in reducing Lp(a) levels was observed (p = 0.049). No significant difference in subjects with low KIV-2 repeats according to diet was found. Moreover, in high-KIV-2-repeat subjects, we observed a trend towards influence of fish intake on reducing Lp(a) levels (p = 0.186). At multivariate linear regression analysis, high adherence to Mediterranean diet remains a significant and independent determinant of lower Lp(a) levels (ß = - 64.97, standard error = 26.55, p = 0.015). In conclusion, this study showed that only subjects with high KIV-2 repeats can take advantage to lower Lp(a) levels from correct nutritional habits and, in particular, from Mediterranean diet.

The Association of SNPs Located in the CDKN2B-AS1 and LPA Genes With Carotid Artery Stenosis and Atherogenic Stroke.

Introduction: The aim of this project was to assess the prevalence of four selected SNPs rs4977574 and rs7857345 (CDKN2B-AS1 gene) and rs3798220 and rs10455872 polymorphisms (the LPA gene) in the subpopulation of patients with symptomatic and asymptomatic carotid stenosis. Material and Methods: This study included 623 individuals (244 patients with symptomatic carotid artery stenosis, 176 patients with asymptomatic carotid artery stenosis and 203 healthy people. All the participants underwent neurological examination, duplex Doppler ultrasound examination and molecular procedures. Results: In the first part of the analysis the assiociation of SNPs with stroke/TIA was investigated. The association was seen in symptomatic vs. control group for two SNPs: rs4977574 and rs7857345 (CDKN2B-AS1 gene); genotype distributions for rs4977574 and rs7857345 showed the statistically significant differences between patients and controls (p = 0.043 and 0.017, respectively). No association was observed for rs3798220 and rs10455872 located in the LPA gene. There were statistically significant differences between asymptomatic patients vs. control group in genotype distribution for the SNPs located in CDKN2B-AS1: rs4977574 and rs7857345 (p = 0.031 and 0.0099, respectively); and for the rs3798220 (LPA gene; p = 0.003); however, statistically significant differences did not occur for the rs10455872 polymorphism located in the LPA gene. In the next part of the evaluation, a comparison between symptomatic and asymptomatic patients was performed. Significant differences in genotype distribution were seen only for the rs3798220 polymorphism located in the LPA gene (p = 0.0015). The analysis of the prevalence of the polymorphisms in the total group (symptomatic and asymptomatic) patients in comparison with the control group showed significant differences for three polymorphisms: rs4977574 and rs7857345 (CDKN2B-AS1 gene; p = 0.015 and 0.0046, respectively) and rs3798220 (LPA gene, p = 0.044). Conclusions: The present research on the carotid artery stenosis patient cohort suggests the significant association between the rs4977574, rs7857345 and rs3798220 polymorphisms and carotid artery stenosis as well as between the rs4977574 and rs7857345 polymorphisms and atherogenic stroke. The rs4977574 and rs7857345 polymorphisms in patients with carotid artery stenosis appear to affect a person's susceptibility to atherogenic brain ischemia. Our results need to be replicated in future studies.

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

BACKGROUND AND AIMS: We 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. METHODS: The 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. RESULTS: Plasma 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. CONCLUSIONS: Statins 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.

Lipoprotein(a) Removal Still a Mystery.

See Article by Shapiro et al.

Searching for a common mechanism for placenta-mediated pregnancy complications and cardiovascular disease: role of lipoprotein(a).

OBJECTIVE: To investigate lipoprotein(a) [Lp(a)], a well known cardiovascular risk factor, in women with history of placenta-mediated pregnancy complications (PMPC) compared with healthy uneventful-pregnancy women (HW), and the role of LPA gene functional polymorphisms in modulating both Lp(a) levels and PMPC risk. DESIGN: Retrospective observational study. SETTING: University hospital. PATIENT(S): A total of 360 women with history of PMPC (154 preeclampsia [PE], 121 stillbirth [SB], and 85 small for gestational age [SGA]) and 270 HW. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Lp(a) levels measurement and LPA +93C >T and +121G>A polymorphisms genotyping. RESULT(S): In PMPCs we observed higher Lp(a) levels than those found in HW and an association with PMPC risk, also after adjustment for age, familial history of cardiovascular disease, and traditional risk factors. By analyzing Lp(a) concentrations according to each pregnancy complication, we observed significantly higher Lp(a) levels in women with history of SB and PE, conferring 2.5-fold and 2-fold increased risks, respectively; no association with SGA was observed. Lp(a) concentrations progressively and significantly increased as LPA unfavorable allelic burden increased; unfavorable allelic burden influenced SB and PE risk. CONCLUSION(S): We evidenced, for the first time, an association between high Lp(a) concentrations and history of SB, and we confirmed the role of Lp(a) in PE risk; this well known atherothrombotic marker might represent one of the possible mechanisms shared by PMPC and cardiovascular disease.

[Clinical significance of and treatment options for increased lipoprotein(a)]. / Az emelkedett lipoprotein(a)-szint klinikai jelentosége és kezelési lehetoségei.

Lipoprotein(a) has been shown to be associated with an increased incidence of cardiovascular diseases for decades. However, only recent research revealed more about its physiological function and its role in the development of cardiovascular diseases. The authors summarize the physiological role of lipoprotein(a), causes and treatment of elevated lipoprotein(a) level, and the association between lipoprotein(a) and cardiovascular diseases.

Association study of lipoprotein(a) genetic markers, traditional risk factors, and coronary heart disease in HIV-1-infected patients.

OBJECTIVES: General population studies have shown associations between copy number variation (CNV) of the LPA gene Kringle-IV type-2 (KIV-2) coding region, single-nucleotide polymorphism (SNP) rs6415084 in LPA and coronary heart disease (CHD). Because risk factors for HIV-infected patients may differ from the general population, we aimed to assess whether these potential associations also occur in HIV-infected patients. METHODS: A unicenter, retrospective, case-control (1:3) study. Eighteen HIV-patients with confirmed diagnosis of acute myocardial infarction (AMI) were adjusted for age, gender, and time since HIV diagnosis to 54 HIV-patients without CHD. After gDNA extraction from frozen blood, both CNV and SNP genotyping were performed using real-time quantitative PCR. All genetic and non-genetic variables for AMI were assessed in a logistic regression analysis. RESULTS: Our results did not confirm any association in terms of lipoprotein(a) LPA structural genetic variants when comparing KIV-2 CNV (p = 0.67) and SNP genotypes (p = 0.44) between AMI cases and controls. However, traditional risk factors such as diabetes mellitus, hypertension, and CD4(+) T cell count showed association (p < 0.05) with CHD. CONCLUSION: Although significant associations of AMI with diabetes, hypertension and CD4(+) T cell count in HIV-patients were found, this study could not confirm the feasibility neither of KIV-2 CNV nor rs6415084 in LPA as genetic markers of CHD in HIV-infected patients. HIGHLIGHTS: ● Individuals with HIV infection are at higher risk of coronary heart disease (CHD) than the non-infected population.● Our results showed no evidence of LPA structural genetic variants associated with CHD in HIV-1-infected patients.● Associations were found between diabetes mellitus, arterial hypertension, CD4(+) T cell count, and CHD.● The clinical usefulness of these biomarkers to predict CHD in HIV-1-infected population remains unproven.● Further studies are needed to assess the contribution of common genetic variations to CHD in HIV-infected individuals.