Lack of Association Between Lipoprotein(a) and Coronary Artery Calcification in the Genetic Epidemiology Network of Arteriopathy (GENOA) Study

Division of Cardiovascular Diseases, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA.
Mayo Clinic Proceedings (Impact Factor: 6.26). 10/2004; 79(10):1258-63. DOI: 10.4065/79.10.1258
Source: PubMed


To investigate the relationship between lipoprotein(a) [Lp(a)] levels and the extent of coronary atherosclerosis in a cohort that consisted predominantly of hypertensive patients.
Patients were ascertained through sibships that contained at least 2 individuals with essential hypertension diagnosed before the age of 60 years. The 10-year coronary heart disease (CHD) risk was estimated on the basis of the Framingham risk equation. Serum Lp(a) was measured by an immunoturbidimetric assay. Coronary artery calcification (CAC) was measured noninvasively by electron beam computed tomography and CAC score calculated using the Agatston score.
Patients included 765 non-Hispanic, white individuals (59% women) participating in the Genetic Epidemiology Network of Arteriopathy study. The mean +/- SD age of the patients was 62 +/- 8 years, and 77% had hypertension. The prevalence of detectable CAC was 87% in men and 60% in women. The CAC scores did not differ significantly across quintiles of Lp(a) levels in either men or women. In a multiple regression model that included conventional risk factors, Lp(a) levels were not related to CAC quantity in either sex. No significant interactions were noted between Lp(a) levels and the conventional risk factors in the prediction of CAC quantity. When stratified on the basis of the 10-year CHD risk, 26.5% of the patients were low risk (< 6%), 60.5% were intermediate risk (6%-20%), and 12.9% were high risk (> 20%). Lipoprotein(a) was not associated with CAC quantity within subgroups based on 10-year CHD risk.
In this cohort enriched with hypertensive patients, the estimated 10-year CHD risk did not appear to modify the lack of an association between Lp(a) levels and CAC.

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Available from: Iftikhar Kullo, May 14, 2015
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    • "Lee et al. examined 1000 young (age 40–45, 19.4% black) healthy individuals and also observed a positive association [14]. However, in the GENOA study, 756 Caucasians with hypertension were enrolled (59% women, of whom 14% were diabetic), and no relationship was discovered between Lp(a) and CACs [15]. Similarly, in the multi-ethnic Dallas Heart Study, 761 blacks and 527 whites (8% diabetic, half women) were enrolled, and there was no clear relationship between Lp(a) and CACs [16]. "
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    ABSTRACT: Elevated plasma levels of lipoprotein(a) (Lp(a)) and a higher degree of coronary artery calcification (CAC) are both considered to be risk factors for atherosclerosis. However, previous studies have demonstrated that the relationship between Lp(a) levels and the degree of CAC indicates significant heterogeneity that may be due to varying ethnicities. The purpose of this study was to examine the predictive power of Lp(a) for CAC as measured by multidetector computed tomography (MDCT) in the Han ethnic group of China. A total of 1082 subjects were recruited in this study. The patients were divided into four groups: patients without hypertension or diabetes were group 1, patients with hypertension were group 2, patients with diabetes were group 3 and patients with both hypertension and diabetes were group 4. CAC score (CACs), lipid profiles (Lp(a), LDL, HDL, TG, TC), HbA1C, glucose, personal health history and body morphology were measured in all participants. The predictive power of Lp(a) for calcified atherosclerotic plaque was determined by correlations and ordinal logistic regression. There was no significant difference in the CACs between group 2 and group 3 (z = 1.790, p = 0.736), and there were significant differences among the other groups. However, there was no significant difference in the total Lp(a) among the 4 groups (χ(2) = 0.649, p = 0.885). Only In group 1, Lp(a) was a statistically significant predictor of the presence of calcified coronary plaque using ordinal logistic regression. Levels of Lp(a) positively correlate with CACs among Chinese Han people who are without diabetes and hypertension, suggesting that Lp(a) may be an important risk factor for the presence of calcified atheromas.
    Full-text · Article · Aug 2013 · PLoS ONE
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    • "Guerra et al. [19] investigated 1288 patients and did not find a relationship between Lp(a) and CAC. Kullo et al. [20] reported no association between Lp(a) and CAC burden. However, Qasim et al. [8] described Lp(a) as a strong predictor of CAC in type-2 diabetic women but not in men. "
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    ABSTRACT: Introduction: Lipoprotein a (Lp(a)) has been recognized as a risk factor for both coronary heart diseases and for cardiovascular events. Coronary artery calcification (CAC) is a well proven marker for coronary artery disease and risk factor for cardiovascular events. Still there are conflicting data regarding the relationship of Lp(a) and CAC. We therefore wanted to evaluate the influence of Lp(a) on CAC. Methods: 1560 European patients (1123 men, age 59.3 ± 20.8 years) with typical or atypical chest pain underwent CAC scoring by a multi-slice CT-scanner, using a standard protocol. Blood samples were evaluated the same day using an automated particle enhanced immunoturbidimetric assay to determine Lp(a) serum levels. Results: There was a positive correlation between CAC score, age, and common cardiovascular risk factors. Lp(a) serum levels were not associated with age but a positive correlation between Lp(a) serum levels and CAC was found. In the multivariate analysis age, diabetes, statin therapy, and Lp(a) could be identified as independent risk factors for CAC. (p<0.001). BMI, smoking, hypertension and LDL-C were not independently associated with CAC. Conclusion: Lp (a) could be identified as an independent predictor of CAC, a marker of coronary atherosclerosis. Further a positive correlation between increasing Lp (a) levels and CAC scores was found.
    Full-text · Article · Sep 2012 · European Journal of Internal Medicine
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    • "Fibrinogen was measured by the Clauss (clotting time based) method [17]. Lp(a) in serum was measured by an immunoturbidimetric assay using the SPQ™ Test System (Diasorin, Stillwater MN) as previously described [18]. Plasma homocysteine was measured by high-pressure liquid chromatography. "
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    ABSTRACT: Atherosclerotic peripheral arterial disease (PAD) affects 8-10 million people in the United States and is associated with a marked impairment in quality of life and an increased risk of cardiovascular events. Noninvasive assessment of PAD is performed by measuring the ankle-brachial index (ABI). Complex traits, such as ABI, are influenced by a large array of genetic and environmental factors and their interactions. We attempted to characterize the genetic architecture of ABI by examining the main and interactive effects of individual single nucleotide polymorphisms (SNPs) and conventional risk factors. We applied linear regression analysis to investigate the association of 435 SNPs in 112 positional and biological candidate genes with ABI and related physiological and biochemical traits in 1046 non-Hispanic white, hypertensive participants from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. The main effects of each SNP, as well as SNP-covariate and SNP-SNP interactions, were assessed to investigate how they contribute to the inter-individual variation in ABI. Multivariable linear regression models were then used to assess the joint contributions of the top SNP associations and interactions to ABI after adjustment for covariates. We reduced the chance of false positives by 1) correcting for multiple testing using the false discovery rate, 2) internal replication, and 3) four-fold cross-validation. When the results from these three procedures were combined, only two SNP main effects in NOS3, three SNP-covariate interactions (ADRB2 Gly 16 - lipoprotein(a) and SLC4A5 - diabetes interactions), and 25 SNP-SNP interactions (involving SNPs from 29 different genes) were significant, replicated, and cross-validated. Combining the top SNPs, risk factors, and their interactions into a model explained nearly 18% of variation in ABI in the sample. SNPs in six genes (ADD2, ATP6V1B1, PRKAR2B, SLC17A2, SLC22A3, and TGFB3) were also influencing triglycerides, C-reactive protein, homocysteine, and lipoprotein(a) levels. We found that candidate gene SNP main effects, SNP-covariate and SNP-SNP interactions contribute to the inter-individual variation in ABI, a marker of PAD. Our findings underscore the importance of conducting systematic investigations that consider context-dependent frameworks for developing a deeper understanding of the multidimensional genetic and environmental factors that contribute to complex diseases.
    Full-text · Article · Feb 2008 · BMC Medical Genomics
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