Fish intake and LPA 93C>T polymorphism: Gene-environment interaction in modulating lipoprotein (a) concentrations

doi:10.1016/j.atherosclerosis.2007.05.020

Atherosclerosis

Volume 195, Issue 2, December 2007, Pages e147-e154

https://doi.org/10.1016/j.atherosclerosis.2007.05.020 Get rights and content

Abstract

High plasma lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for atherosclerotic diseases. To date, no effective intervention strategies on reducing Lp(a) concentrations have been reported. The aim of the study was to evaluate the possible modulation of two polymorphisms of LPA gene (LPA 93C>T and LPA 121G>A) and nutritional habits on Lp(a) concentrations. We studied 647 healthy Italian subjects (260 M; 387 F) with a median age of 48 years (range: 19–78) enrolled in an epidemiological study conducted in Florence, Italy. A linear regression analysis showed a significant negative influence of fish intake (β = −0.174 ± 0.084; p = 0.04) on Lp(a) concentrations, after adjustment for smoking habit, C-reactive protein serum concentrations, dietary habits and LDL-cholesterol concentrations. With regard to LPA polymorphisms, LPA 93C>T polymorphism resulted to significantly affect Lp(a) circulating concentrations in a dose-dependent manner, with lower concentrations shown by subjects carrying the T rare allele, whereas no significant influence of LPA 121G>A polymorphism on Lp(a) concentrations was observed. Moreover, by analyzing the possible interplay between LPA 93C>T and dietary fish intake, a significant interaction between these two determinants in lowering Lp(a) concentrations was reported. In addition, lower Lp(a) concentrations were observed in subjects carrying the T allele of the LPA 93C>T polymorphism and consuming a high intake of fish with respect to those being in the highest tertile of fish consumption but homozygotes for the common allele of the polymorphism. In conclusion, this study reported a significant interaction of daily fish intake and LPA 93C>T polymorphism in decreasing Lp(a) concentrations.

Introduction

Lipoprotein (a) [Lp(a)] is a plasma particle composed of a LDL particle and a highly glycosylated apolipoprotein, apo(a), disulfide linked to the apo B-100 of the LDL [1]. As a result of its structural similarity to LDL, Lp(a) has atherogenic properties [2]. In addition, Lp(a) has antifibrinolytic and thrombosis-promoting properties that arise from the structural similarity of apo(a) to plasminogen [3]. Over the last years, a large number of clinical studies reported evidence for an association between high Lp(a) concentrations and an increased risk for atherosclerotic diseases, including coronary heart disease, and stroke [4], [5], [6], [7], [8], [9]. However, despite much progress in the knowledge of the atherogenic role of Lp(a), no effective therapeutic strategies on lowering Lp(a) concentrations have been found [10]. Moreover, dietary habits seem not to significantly affect Lp(a) circulating concentrations [11]. Recently, some intervention studies based on the effect of fish oil rich in n-3 polyunsaturated fatty acids (PUFA) on Lp(a) concentrations have been conducted, but no clear indications have been obtained [12], [13], [14], [15]. Lp(a) concentrations are thought to be strongly under genetic control at the concentration of biosynthesis of the apo(a) protein, which is encoded by the LPA locus, so allelic differences at LPA are responsible for the variations in Lp(a) phenotype [16].

Data from in vitro and in vivo studies demonstrated that polymorphisms in the 5′-flanking region of the LPA gene affect the efficiency of its expression, so contributing to the regulation of Lp(a) concentrations, [17], [18] and influence the variation of the promoter transcription activity in HepG2 cells [19]. Suzuki et al. by exploring the mechanisms of the genetic control of Lp(a) concentrations, demonstrated a relationship between polymorphisms in the LPA 5′-flanking region and different Lp(a) concentrations [17]. In particular, the C→T transition at position +93 of the transcription start site creates a new translation start codon, leading to a negative regulation in the protein synthesis, while the change of G to A, at position +121, determine a positive regulation of gene expression [17].

Furthermore, a role for LPA 93C>T polymorphism in affecting both the promoter activity [19] and Lp(a) concentrations in Africans, but not in Caucasians, was demonstrated [18]. It has been recently demonstrated, indeed, that LPA 93C>T, but not LPA 121G>A polymorphism influences Lp(a) concentrations among a population from Czech Republic [20].

To the best of our knowledge, no study which investigated both genetic and nutritional determinants of Lp(a) concentrations among a clinically healthy population was performed.

Therefore, aims of the study were: (1) to investigate the role of nutritional habits on modulating Lp(a) concentrations, (2) to evaluate the weight of the LPA locus in influencing Lp(a) concentrations by analysing the 93C>T and 121G>A polymorphisms at LPA locus, (3) to establish the possible interplay existing between LPA locus and dietary habits in modulating Lp(a) concentrations.

Section snippets

Subjects

The study population includes subjects enrolled in an epidemiologic study “Alimentazione per la Salute e la Prevenzione di Malattia”, which was conducted in Florence, Italy with the aim of evaluating dietary and lifestyle habits of a middle-aged clinically healthy population. Details of the study are described in details elsewhere [21]. Briefly, from January 2002 to January 2004, 932 healthy subjects randomly drawn from the population registers of Florence, Italy, which are updated regularly,

Statistical analysis

Statistical analyses were performed using the SPSS software (Chicago, IL, USA) for Windows (Version 11.5). Variables were reported as mean and S.D. or median and range, as appropriate. To evaluate the influence of nutritional as well as demographic and anthropometric biomarkers on Lp(a) concentrations we divided our study population into tertiles of age (first tertile: <40 years; second tertile: 40–54 years; third tertile: >55 years) and of Lp(a) distribution (first tertile: <104.8 mg/L; second

Nutritional determinants of Lp(a) concentrations

Median value of Lp(a) in our study population was 107 with a range of 3–1670 mg/L. Females showed significantly higher Lp(a) concentrations with respect to males [111 (3–1670) mg/L versus 105 (6–1500) mg/L; p = 0.02]. In particular, the subgroup of 137 menopausal women reported significantly (p = 0.006) higher Lp(a) concentrations than nonmenopausal women [129 (6–1390) mg/L versus 105 (3–1670) mg/L, respectively].

Demographic, anthropometric, laboratory, and nutritional parameters according to different

Discussion

This study observed a significant interaction between a dietary component, namely fish intake and a genetic determinant, the LPA 93C>T polymorphism, in modulating circulating Lp(a) concentrations. Indeed, significantly lower Lp(a) concentrations in subjects carrying the LPA 93T allele of the LPA 93C>T polymorphism and who were in the highest tertile of fish intake, as compared to subjects who consume a high intake of fish from diet but who carry the LPA 93C wild-type allele, were observed. To

Acknowledgements

Minister of health, Italy – “Progetto Alimentazione per la salute e la prevenzione di malattia” 2001–2003; Ente Cassa di Risparmio di Firenze, Florence, Italy

References (33)

M. Hartmann et al.
Relation between lipoprotein (a) and fibrinogen and serial intravascular ultrasound plaque progression in left main coronary arteries
J Am Coll Cardiol
(2006)
O. Haglund et al.
Effects of fish oil on some parameters of fibrinolysis and lipoprotein(a) in healthy subjects
Am J Cardiol
(1994)
F.U. Beil et al.
Dietary fish oil lowers lipoprotein(a) in primary hypertriglyceridemia
Atherosclerosis
(1991)
G.L. Colussi et al.
ω-3 polyunsaturated fatty acids decrease plasma lipoprotein(a) concentrations in hypertensive subjects
Clin Nutr
(2004)
J.H. Wu et al.
Studies of apolipoprotein (a) promoter from subjects with different plasma lipoprotein (a) concentrations
Clin Biochem
(2003)
K. Zidkova et al.
Detection of variability in apo(a) gene transcription regulatory sequences using the DGGE method
Clin Chim Acta
(2007)
F. Sofi et al.
Low adherence of a clinically healthy Italian population to nutritional recommendations for primary prevention of chronic diseases
Nutr Metab Cardiovas Dis
(2006)
E. Sticchi et al.
LPA +93C>T and +121G>A polymorphisms detection by electronic microchip technology
Mol Genet Metab
(2007)
K. Berg
A new serum system in man: the Lp system
Acta Pathol Microbiol Scand
(1963)
L. Berglund et al.
Lipoprotein (a). An elusive cardiovascular risk factor
Arterioscler Thromb Vasc Biol
(2004)

J.W. McLean et al.

cDNA sequence of human apolipoprotein(a) is homologous to plasminogen

Nature

(1987)

G.G. Rhoads et al.

Lp(a) lipoprotein as a risk factor for myocardial infarction

JAMA

(1986)

A.A. Ariyo et al.

Cardiovascular health study investigators. Lp(a), lipoprotein, vascular disease, and mortality in the elderly

N Engl J Med

(2003)

G. Zenker et al.

Lipoprotein (a) as a strong indicator for cerebrovascular disease

Stroke

(1986)

T. Ohira et al.

Lipoprotein (a) and incident ischemic stroke, the atherosclerosis risk in communities (ARIC) study

Stroke

(2006)

J. Suk Danik et al.

Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women

JAMA

(2006)

Cited by (17)

Searching for a common mechanism for placenta-mediated pregnancy complications and cardiovascular disease: Role of lipoprotein(a)
2016, Fertility and Sterility
Citation Excerpt :
A limitation of our study is the lack of information concerning KIV repeat number, which better determines Lp(a) concentrations. Also, we are aware that the two polymorphisms investigated in the present study have a relatively small influence on Lp(a) levels; nevertheless we selected these two functional polymorphisms based on others and our previous study (28, 29). Our is a follow-up referral center, at which the most severely affected women as well as healthy women referred for other CVD risk factors would attend, thus representing a further limitation.
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.
Retrospective observational study.
University hospital.
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.
Not applicable.
Lp(a) levels measurement and LPA +93C >T and +121G>A polymorphisms genotyping.
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.
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.
Significant associations between lipoprotein(a) and corrected apolipoprotein B-100 levels in African-Americans
2014, Atherosclerosis
Citation Excerpt :
We have previously demonstrated a concept of allele-specific apo(a) level which determines the amount of Lp(a) associated with a defined apo(a) allele/isoform size, and reported that these levels were important in assessing the Lp(a)-associated cardiovascular risk across ethnicity [12]. Environmental and lifestyle-related factors and currently available lipid-lowering medications have no or minimal effects on Lp(a) levels [13–18] with exception of niacin [19] and hormone replacement therapy [20]. New evidence on the interactions between Lp(a) and inflammation [21–23] or chronic immune activation [24] has emerged, as studies have suggested an impact of these factors on Lp(a) with a variable effect across ethnicity.
Lipoprotein(a), Lp(a), represents an apolipoprotein (apo) B-carrying lipoprotein, yet the relationship between Lp(a) and apoB levels has not been fully explored.
We addressed the relationship between Lp(a) and apoB-containing lipoprotein levels in 336 Caucasians and 224 African–Americans. Our approach takes unique molecular properties of Lp(a) as well as contribution of Lp(a) to the levels of these lipoproteins into account.
Levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apoB and apoB/apoA-1 did not differ across ethnicity. African–Americans had higher levels of Lp(a) and high-density lipoprotein cholesterol and lower triglyceride levels compared to Caucasians. Lp(a) levels were correlated with levels of TC (p < 0.005), LDL-C (p < 0.001), apoB (p < 0.05) or apoB/apoA-1 (p < 0.05) in both ethnic groups. These associations remained significant only in African–Americans after adjustments for the contribution of Lp(a)-cholesterol or Lp(a)-apoB. Furthermore, taking Lp(a)-apoB into account, allele-specific apo(a) levels were significantly associated with apoB levels and the apoB/apoA-1 ratio in African–Americans. The latter associations in African–Americans remained significant for allele-specific apo(a) levels for smaller apo(a) sizes (<26 K4 repeats), after controlling for the effects of age, sex, and BMI.
Although TC, LDL-C, and apoB levels were comparable between African–Americans and Caucasians, the associations of these parameters with Lp(a) and allele specific apo(a) levels differed between these two ethnic groups. In African–Americans, apoB and apoB/apoA-1 remained consistently and positively associated with both Lp(a) and allele-specific apo(a) levels after adjustments for the contribution of Lp(a)-apoB. The findings suggest an interethnic difference with a closer relationship between Lp(a) and apoB among African–Americans.
High lipoprotein (a) levels are associated with an increased risk of retinal vein occlusion
2010, Atherosclerosis
Citation Excerpt :
The Mercodia assay's isoform independent detection of apo(a) is reported in the study by Dembisnki et al. [20]. The results are expressed in mg/dL, where 1 U of apo(a) is approximately equal to 0.7 mg of Lp(a) (Mercodia Manual) [21–23]. The lipid profile was assessed by conventional methods.
Retinal vein occlusion (RVO) is one of the most common retinal vascular disorders affecting ocular vessels. Few studies, with conflicting results and conducted in limited study populations, have hypothesised the role of high levels of lipoprotein (a) [Lp(a)] in the occurrence of RVO. The aim of this study was to investigate, in a large group of RVO patients, the role of such an emerging thrombophilic parameter on the pathogenesis of RVO.
We compared 262 patients [median age: 66 years (15–88); 122 M, 140 F] with 262 age- and sex-comparable healthy subjects.
Circulating concentrations of Lp(a) were found to be significantly different in patients when compared to healthy subjects [189 (60–1898) mg/L vs. 119.5 (6–1216) mg/L; p < 0.0001, respectively]. No significant differences were observed relating to the different types of occlusion (central or branch occlusion). In order to investigate the possible association between high Lp(a) levels and the disease we performed a logistic regression analysis. In the univariate analysis, Lp(a) levels > 300 mg/L were found to be associated with an increased risk of RVO (OR: 2.39, 95%CI 1.39–3.59; p < 0.0001). Following this, three models of multivariate analysis were performed, firstly by adjusting for age, gender, and traditional cardiovascular risk factors, secondly for triglycerides and thirdly for homocysteine levels. In all the models, Lp(a) levels > 300 mg/L confirmed their role as a risk factor for RVO [first model, OR: 2.15 (95%CI 1.39–3.32), p = 0.0001; second model, OR: 3.11 (95%CI 1.77–5.62), p < 0.00001; third model, OR: 3.48 (95%CI 1.88–6.43), p < 0.00001].
This study reports that, in a large population of RVO patients, high Lp(a) concentrations are significantly related to RVO, independent from other traditional and emerging risk factors, suggesting that they may play a role in its pathogenesis.
Gene-Environment Interactions: Where are we and where Should we be Going?
2009, Nutrition and Genomics
This chapter examines the reasons for studying gene–environment interactions and evaluates recent reports of interactions between genes and environmental modulators in relation to cardiovascular disease and its common risk factors. The chapter provides recent studies, which are focusing on cardiovascular risk factors, such as alcohol, smoking, physical activities, and on coffee that are observational and include relatively large sample sizes. Studies examining gene–diet interactions include both observational and interventional designs and are of smaller scale, especially those including dietary interventions. The chapter raises some of the issues that are required to be addressed to advance the field of research and to develop applications for the public. The number of publications addressing gene–environment interactions reflects a robust interest toward gaining much needed knowledge in the area of metabolic traits and cardiovascular diseases. The concept of gene–environment interactions modulating common disease risk factors can provide future scientific knowledge to address major health problems using molecular and more individually targeted approaches to disease prevention and therapy.
Gene–Environment Interactions: Where are we and where should we be Going?
2009, Nutrition and Genomics: Issues of Ethics, Law, Regulation and Communication
This chapter examines the reasons for studying gene–environment interactions and evaluates recent reports of interactions between genes and environmental modulators in relation to cardiovascular disease and its common risk factors. The chapter provides recent studies, which are focusing on cardiovascular risk factors, such as alcohol, smoking, physical activities, and on coffee that are observational and include relatively large sample sizes. Studies examining gene–diet interactions include both observational and interventional designs and are of smaller scale, especially those including dietary interventions. The chapter raises some of the issues that are required to be addressed to advance the field of research and to develop applications for the public. The number of publications addressing gene–environment interactions reflects a robust interest toward gaining much needed knowledge in the area of metabolic traits and cardiovascular diseases. The concept of gene–environment interactions modulating common disease risk factors can provide future scientific knowledge to address major health problems using molecular and more individually targeted approaches to disease prevention and therapy.
Gene-Environment Interactions and Cardiovascular Risk Factors
2009, Revista Espanola de Cardiologia Suplementos
En esta revisión se discuten las razones para analizar las interacciones entre genes y entorno, y los estudios recientes que examinan las interacciones entre genes y moduladores ambientales en relación con la enfermedad cardiovascular y sus factores de riesgo comunes.
Los estudios que se han centrado en el tabaquismo, el alcohol, la actividad física y el café son todos ellos de tipo observacional y tienen unos tamaños muestrales relativamente grandes. Sin embargo, tienden a examinar un único gen y no abordan las interacciones con otros genes y con otros factores ambientales relacionados. El diseño de los estudios que han examinado las interacciones entre genes y dieta ha sido observacional o de intervención, éstos de tamaño mucho menor. Entre las interacciones descritas de los genes y la dieta, es importante resaltar la confirmación de que APOA5 es un gen importante que interviene en el metabolismo de los triglicéridos, que se armoniza por factores de la dieta, así como la identificación del APOA2 como modulador de la ingesta alimentaria y del riesgo de obesidad.
El estudio de las interacciones entre genes y entorno es un campo activo en el que hay una gran necesidad de investigación. Los obstáculos técnicos para la realización de los estudios genéticos están siendo superados con rapidez. La inclusión de una información detallada y fiable sobre los factores ambientales constituye una dificultad importante para estas investigaciones. Los avances en este campo deberán incluir el uso de poblaciones más amplias y zonas geográficas múltiples, pero también el empleo de enfoques más precisos, estandarizados y exhaustivos, que permitan capturar la información sobre los factores ambientales.
The aims of this review were to examine the rationale for investigating the interaction between genes and the environment and to discuss recent studies into the interactions of genes and environmental modulators that are relevant to cardiovascular disease and its principle risk factors.
Studies that have focused on smoking, alcohol and coffee consumption, and physical activity have all been observational studies and have involved relatively large samples. However, they tended to examine single genes and failed to take into account interactions with other genes or associated environmental factors. Both observational and interventional studies have been used to explore the interaction between genes and diet, with interventional studies being much smaller. Of the gene– diet interactions reported, two important highlights are, firstly, the confirmation that the apolipoprotein A-V gene (APOA5) is involved in triglyceride metabolism and is modulated by dietary factors and, secondly, the discovery that apolipoprotein A-II (APOA2) modulates food intake and the risk of obesity.
The study of gene-environment interactions is an active and vital area of research. While the technical barriers to carrying out genetic studies are rapidly being overcome, studies are still hampered by the substantial difficulty of including comprehensive and reliable data on environmental factors. Progress in this area depends on involving large study populations across a range of geographical regions, as well as on employing a more comprehensive, standardized and precise approach to acquiring information about environmental factors.

View all citing articles on Scopus

View full text

Fish intake and LPA 93C>T polymorphism: Gene-environment interaction in modulating lipoprotein (a) concentrations

Abstract

Introduction

Section snippets

Subjects

Statistical analysis

Nutritional determinants of Lp(a) concentrations

Discussion

Acknowledgements

J Am Coll Cardiol

Am J Cardiol

Atherosclerosis

Clin Nutr

Clin Biochem

Clin Chim Acta

Nutr Metab Cardiovas Dis

Mol Genet Metab

A new serum system in man: the Lp system

Acta Pathol Microbiol Scand

Lipoprotein (a). An elusive cardiovascular risk factor

Arterioscler Thromb Vasc Biol

cDNA sequence of human apolipoprotein(a) is homologous to plasminogen

Nature

Lp(a) lipoprotein as a risk factor for myocardial infarction

JAMA

Cardiovascular health study investigators. Lp(a), lipoprotein, vascular disease, and mortality in the elderly

N Engl J Med

Lipoprotein (a) as a strong indicator for cerebrovascular disease

Stroke

Lipoprotein (a) and incident ischemic stroke, the atherosclerosis risk in communities (ARIC) study

Stroke

Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women

JAMA