Decrease of Lp(a) during weight reduction in obese children is modified by the apo(a) kringle-IV copy number variation

Abstract

Background:

Lipoprotein(a) [Lp(a)] is considered an independent risk factor for cardiovascular disease. Its concentration is mainly determined by the kringle-IV repeat copy number variation (CNV) at the apolipoprotein(a) [apo(a)] locus.

Objective:

We aimed to investigate the immediate effect of weight reduction on plasma Lp(a) levels and its dependency on the apo(a) CNV in obese children.

Design:

We performed a prospective longitudinal intervention study of a low-fat hypocaloric diet conducted in a 3-week dietary camp for obese children. In all, 140 obese participants (54 boys and 86 girls) with a mean age of 12.5±1.6 years and a mean relative body mass index (BMI) before treatment of 165.6±24.7% were included. Body weight and plasma levels of Lp(a), lipids, apolipoproteins A–I and B, insulin, and C-reactive protein were determined before the onset and after the end of the intervention. In addition, the number of apo(a) kringle-IV repeats were determined using sodium dodecyl sulfate agarose gel electrophoresis.

Results:

The mean loss of body weight was 5.0±1.3 kg (−6.6%), resulting in a mean decrease of the relative BMI of 6.6%. Blood chemistry revealed significant changes in all parameters, especially in Lp(a), with a decrease from 24.4±30.6 to 17.9±22.6 mg per 100 ml or −19% (P<0.001). The decrease of Lp(a) levels was higher in the group with low compared with high molecular weight apo(a) phenotypes (−23.9 vs −16.6%).

Conclusions:

Weight reduction in obese children is associated with significant changes in Lp(a) levels, especially in subjects with high pre-treatment Lp(a) concentrations. This effect is markedly influenced by the molecular phenotype at the copy-number variable apo(a) locus.

Introduction

During the last decades, obesity in children and adolescents has reached epidemic proportions.1, 2 It is the basis for the development of serious comorbidities including metabolic syndrome, type 2 diabetes mellitus, hyperlipidemia, and hypertension in adulthood.3, 4 The long-term consequences of the increasing prevalence of obesity at this early age will therefore lead to a pronounced burden for the health care systems. In view of this trend, treatment and prevention of childhood obesity have gained considerable interest and become one of the top priorities in the United States5 as well as in Europe.6 For example, the HOPE-project (Health Promotion through Obesity Prevention across Europe) aims at advancing the implementation of systematic, evidence-based European policies effective for the prevention of obesity and its negative consequences on health and health inequalities (http://www.hopeproject.eu/).

A low-fat and low-calorie diet in obese individuals improves total cholesterol, high-density lipoprotein cholesterol (HDL-C) or low-density lipoprotein cholesterol (LDL-C) levels.7, 8 Besides these traditional lipid measures, lipoprotein(a) [Lp(a)] was shown to be an independent risk factor for atherosclerosis.9, 10, 11 LPA, the gene coding for apolipoprotein(a) [apo(a)], is the major determinant of Lp(a) plasma levels, and associated with atherosclerotic vascular diseases (for review see12). One type of variation related to Lp(a) levels is the number of kringle-IV (K-IV) repeats in LPA, which range from 11 to >40 per allele.13 In fact, LPA was one of the first loci at which the existence of copy number variations (CNVs) was recognized. Each K-IV repeat involves 5.5 kb of DNA. About 75% of the variation of Lp(a) concentrations are determined by the LPA locus, of which 45% are explained by the K-IV repeat polymorphism.14 About 25% of the Lp(a) variance was suggested to be explained by non-genetic factors such as lifestyle factors like diet and physical exercise.

Very controversial data exist on the effect of obesity and weight reduction on Lp(a) levels.15, 16, 17 Some of these studies suggested that Lp(a) decreases after weight loss only in individuals with high Lp(a) levels.18, 19 Similarly, the effect of physical exercise on Lp(a) levels is not fully understood, with several contradicting reports.20, 21, 22, 23, 24, 25, 26, 27, 28, 29 Only few studies were performed in children.27, 28 In this study, we therefore tested the possibility of lowering Lp(a) levels by a weight reduction program during a 3-week dietary camp for obese children. This program included a low-fat hypocaloric diet and a controlled exercise program. We also examined the influence of the apo(a) K-IV repeat polymorphism on the effect of the intervention on Lp(a) levels.

Patients and methods

Study group

The study population consisted of 140 obese children (54 males, 86 females) aged between 8 and 17 years (12.3±1.7 years), who participated in a 3-week dietary camp in July and August of 2000, 2001, and 2004. Fifteen of these 140 children attended the camp twice. For comparative data analysis, only the first attendance was taken into account. The changes of Lp(a) in the 15 children who participated twice were only used to exclude a regression to the mean effect. According to the recommendations of the European Childhood Obesity Group, we used the relative body mass index (RBMI), which considers the age- and sex-dependent physiological fluctuations of BMI.30 The RBMI is calculated as follows: RBMI (%)=(measured BMI/age- and sex-specific 50th percentile of BMI) × 100. The age- and sex-specific 50th percentile of BMI is derived from nomograms.31 By this method, the BMI can be expressed independently from age and sex and, therefore, physiological developmental stage. The average RBMI was 165.6±24.7% before treatment. Baseline characteristics at the start of the summer camps are summarized in Table 1.

Table 1 Baseline characteristics of the participants at the start of the dietary camps

Dietary camp program

The participants received a low-fat hypocaloric mixed diet.8 Mean daily energy intake during the 3-week period was 1600 kcal at the start of the camp and decreased to 1200 kcal by the end of the camp. No electrolyte or vitamin supplementation was provided. The exercise program consisted of a 1-hour standardized exercise program that was supervised by a physiotherapist and another hour of walking or playing games outside. The exercise program included warm up, gym training, different training stations, sit-ups, push-ups, pull-ups, and running. After the intense phase of the exercise program, which was heart rate controlled, easy run-out games were performed.

The set-up of this dietary camp was approved by the ethics committee of the Medical Faculty of the University of Vienna.

Laboratory measurements

EDTA plasma samples were obtained in the morning after an overnight fasting period of 12 h. Blood samples were drawn at the beginning and end of the weight reduction program. Plasma total cholesterol and triglycerides were measured by enzymatic methods. HDL-C was determined using polyanion precipitation. LDL-C was calculated using the Friedewald formula. Lp(a) plasma concentrations were measured in duplicate by a double-antibody enzyme-linked immunosorbant assay.32 To account for possible changes in hemodilution over time, we also calculated whole blood Lp(a) concentrations using the formula described in Ref.33

Lp(a) is an LDL-like particle and consists of 45% cholesterol. The usual methods to determine total and LDL-C do not distinguish between cholesterol derived from LDL and Lp(a) and are thus the net result of cholesterol levels from both lipoproteins. High Lp(a) concentrations, therefore, significantly contribute to the measured total cholesterol and to the calculated LDL-C levels. We, therefore, also provide Lp(a)-corrected cholesterol levels, which were calculated by subtracting 45% of the measured Lp(a) levels.34

Apo(a) isoforms were determined by sodium dodecyl sulfate agarose gel electrophoresis under reducing conditions followed by immunodetection.9 Apo(a) phenotypes were stratified into two subgroups according to the molecular weight of the smaller apo(a) isoform.9 The low molecular weight (LMW) apo(a) phenotype group included all subjects with at least one apo(a) isoform with 11–22 K-IV repeats; the high molecular weight (HMW) group comprised all subjects having only isoforms with >22 K-IV repeats. If two apo(a) isoforms were detectable, we used only the smaller apo(a) isoform for categorization, which we discussed in detail earlier.9

Statistical analyses

Relative differences in blood parameters were calculated as the difference between the value at the end of the diet and the beginning of the diet divided by the value at the beginning of the diet. For comparison of independent metric variables, the t-test (for normally distributed variables) or the Mann–Whitney U-test was applied. The Kolmogorov–Smirnov test was applied to test for normality of distribution. The Wilcoxon signed-rank test was used to detect differences in the distributions of the parameters from paired samples (before diet–after diet). Spearman's rank correlation coefficient was used as a non-parametric measure of correlation. Linear regression was used to investigate the influence of age, pre-diet plasma Lp(a) concentrations and the number of K-IV repeats on the decrease of Lp(a) after dietary intervention. To evaluate the effects of the intervention in this uncontrolled longitudinal study and to rule out regression to the mean effects, we applied a new detection method for unknown population means.35 Statistical analyses were performed with SPSS 15.0 (SPSS Inc., Chicago, IL, USA) and SAS 9.1 (SAS Institute Inc., Cary, NC, USA). Statistical graphs were drawn with GraphPad Prism 4.0 (GraphPad Software, Santiago, CA, USA).

Results

Effects of weight reduction

The efficiency of the intervention program was demonstrated by a reduction of the relative BMI from 165.6% to 154.7%, which corresponds to a relative change of 6.6% and an average weight reduction of 5 kg (Table 2). During the 3 weeks of intervention, the mean plasma Lp(a) levels decreased from 24.4±30.6 to 17.9±22.6 mg per 100 ml (P<0.001) corresponding to an average relative decrease of 19%. The pronounced weight loss had its greatest impact on LDL-C levels, with a decrease of 33%. Further strong effects were observed for total cholesterol and triglycerides as well as apolipoproteins A-I and B (all average relative decreases above 20%). An interesting observation was the average decrease in HDL-C levels of 11%. Similar findings were reported after moderate intensity exercise in overweight hypertensives36 and from a dietary program without exercise in obese individuals.37

Table 2 Clinical and laboratory data of participants at the start and the end of the dietary camps

We had to rule out that the observed changes are an effect of a regression to the mean, which occurs in situations of repeated measurements when extreme values are followed by measurements in the same subjects that are closer to the mean of the basic population. We therefore performed two experiments: first, we measured Lp(a) levels in 15 children, who participated twice in the 3-week dietary camps in two independent years. Mean Lp(a) plasma levels decreased by 16±22% during the first intervention and after a re-increase during the following year, Lp(a) decreased once again by 31±16% during the second intervention. The relative decrease rates at the two times were statistically equivalent (P>0.05). Secondly, when we applied the method proposed by Ostermann et al.35 assuming a range of a typical population mean concentration of plasma Lp(a) between 7 and 67 mg per 100 ml, the treatment effect was classified as real effect (P<0.001). Only if the real population mean was outside of this range, could the effects observed in our study be classified as regression to the mean. As there in no population known with such mean concentrations outside of this range, regression to the mean can clearly be excluded.

Influence of CNV at the apo(a) locus on the effect of weight reduction on plasma Lp(a) levels

The variable number of K-IV repeats in the human apo(a) gene results in a size polymorphism of the protein and correlates inversely with the plasma levels of the atherogenic Lp(a).13 As expected, Lp(a) levels were significantly higher in the LMW apo(a) group (defined as having at least one apo(a) isoform with 11–22 KIV repeats) compared with the HMW group (samples with only isoforms of >22 KIV repeats) (P<0.001) (Table 3). The most interesting observation was that the average absolute decrease of Lp(a) during the camp intervention was significantly higher in the LMW group than in the HMW group (−13.9±13.5 vs −3.3±7.5 mg per 100 ml, P<0.001). The absolute Lp(a) changes were negatively correlated with the number of K-IV repeats of the smaller apo(a) allele (r=−0.43; P<0.001), and positively correlated with the Lp(a) plasma level before the dietary intervention (r=0.73; P<0.001) as well as age (r=0.16; P<0.05). Similarly, the number of K-IV repeats of the smaller allele also correlated strongly with the Lp(a) plasma levels before diet (r=−0.392; P<0.001) and after diet (r=−0.375; P<0.001). Linear regression revealed that the absolute decrease in Lp(a) levels was four times steeper in the LMW group than in the HMW group (Figure 1).

Table 3 Clinical and laboratory data of participants at the start and the end of the dietary camps stratified for participants with high and low molecular weight apo(a) phenotypes
Figure 1
figure1

Effect of the apolipoprotein(a) K-IV repeat polymorphism on Lp(a) changes during a dietary camp intervention in 140 children.

Because of the pronounced absolute differences in the Lp(a) levels between children with LMW and HMW apo(a) phenotypes, we also calculated the relative changes of Lp(a) levels during the dietary camp, which were higher in LMW compared with HMW apo(a) phenotypes (−23.9±19.8% vs −16.6±36.3%). Given the strong determination of Lp(a) plasma concentrations by the apo(a) K-IV repeat polymorphism and the problem of multicolinearity of these two variables, we calculated the influence of pre-treatment Lp(a) plasma concentrations and number K-IV repeats on the relative decrease of Lp(a) levels by two age-adjusted linear regression models (Table 4). This analysis demonstrated that both the pre-intervention Lp(a) plasma concentrations and the number of K-IV repeats were significantly associated with the relative decrease of Lp(a) following the lifestyle intervention. Thus, the main factor influencing the decrease in Lp(a) levels seems to be the pre-intervention Lp(a) concentration, which itself is genetically determined by the number of K-IV repeats of the minor apo(a) allele. Interestingly, the differences in the absolute and relative decrease of Lp(a) between LMW and HMW apo(a) isoform groups was not influenced by the changes in insulin and CRP levels (Table 3).

Table 4 The association of variables with the relative decrease of Lp(a) concentrationsa after a 3-week lifestyle intervention by a dietary camp in 140 children determined by linear regression analysis

Discussion

The main findings of our study are that (i) the mean plasma Lp(a) levels decrease by a fifth of baseline levels after weight reduction on a short-term low-fat hypocaloric diet and (ii) the decrease in Lp(a) levels is modified by a CNV at the apo(a) locus, which supports a gene–environmental interaction. Several studies demonstrated effects of weight reduction on cardiovascular risk factors in children.8, 38 However, this is the first study to demonstrate a beneficial effect of short-term weight-reduction on Lp(a) levels in children, and to show that this effect depends on the CNV in the apo(a) gene.

CNVs represent the most prevalent type of structural variation in the human genome and significantly contribute to genetic heterogeneity. To date, 19% of the human genome have been annotated as copy-number variations.39 CNVs involve deletions, insertions, duplications, and complex rearrangements of genomic regions of 1 kb length or larger. Reports on disease associations and the impact of CNVs on gene expression phenotypes are steadily increasing39; thus, CNVs could explain variable penetrance of inherited diseases and variation in phenotypic expression and might represent a major factor in the etiology of complex, multifactorial traits. About 75% of the variation in Lp(a) levels is genetically determined and Lp(a) may be the protein with the most pronounced genetic determination of its plasma concentration.14 A large part of this genetic influence is caused by the apo(a) K-IV repeat polymorphism. Nevertheless, there is still room for environmental factors that influence Lp(a) levels. We observed a decrease as high as 19% following the lifestyle intervention in our study. The decrease occurred in each of the three yearly dietary camps that were studied. Furthermore, we accounted in a sensitivity analysis for possible hematocrit changes during the camp as discussed recently.33 This, however, did not influence our results (Tables 1, 2 and 3). As the decrease of Lp(a) was strongly dependent on the pre-intervention Lp(a) concentrations and as these levels are dependent on the apo(a) K-IV repeat polymorphism, it can be concluded that the decrease of Lp(a) caused by the lifestyle intervention is genetically influenced. Figure 1 clearly illustrates the interaction of the apo(a) K-IV repeat polymorphism and the lifestyle intervention on Lp(a) levels.

Only few studies that investigated lifestyle influences on Lp(a) levels accounted for the special physiology of children: one study that included 24 obese girls reported an increase in Lp(a) with physical activity,27 whereas physical activity was associated with favorable Lp(a) levels in a cross-sectional study of about 2500 children and young adults, as high levels of Lp(a) (>25 mg per 100 ml) were less frequent in the physically most active subjects.28 Other studies were mainly done on adults. Although an early study reported a beneficial effect of weight loss on Lp(a) levels,15 a study of overweight women aged between 30 and 50 years, who lost 9% of body weight after a 16 weeks diet,16 and a study of moderately obese subjects of both genders, found no significant change in Lp(a) levels.17 However, other studies found that substantial weight loss resulted in a lowering of Lp(a) only in individuals with pre-treatment Lp(a) levels above 30 mg per 100 ml.18, 19 Apart from weight reduction by diet programs, lowered Lp(a) levels were correlated with substantial weight loss after intestinal bypass surgery for obesity.40 Contradicting reports also reflect the uncertainty of whether physical activity could modify Lp(a) levels. As regular exercise was associated with favorable changes in plasma lipoprotein profile,41 attention has focused on whether serum Lp(a) levels are also influenced by physical activity. Several population and cross-sectional studies showed a lack of association between serum Lp(a) levels and regular moderate physical activity or moderate exercise training.20, 21, 22, 23, 24, 29 The few studies that found a beneficial effect of exercise on Lp(a) were either confounded by ethnical issues25 or included only men.26 Therefore, it appears likely that the changes in Lp(a) levels observed in our study were caused by the dietary intervention rather than by the increased physical activity.

Strengths and limitations of our study

We consider the prospective design of our study as a major strength as cross-sectional studies require a very large sample size if the effect of lifestyle on a variable such as Lp(a) is to be investigated with reliability when this variable shows a genetic determination of about 75% as known for Lp(a).14 Furthermore, our study considered the effect of the apo(a) K-IV repeat polymorphism, which was not determined by other studies. The prospective design in a setting of a dietary camp allowed a strong control of the intervention with little room for measurement error, which is usually observed when diet is investigated by questionnaires on food frequencies and physical activity behavior.

Our study is limited by the lack of a control group of children observed for 3 weeks without any lifestyle changes. However, when we performed a stratified analysis for children above and below the median of the relative body weight change (6.5%) during the 3 weeks of observation, we observed a trend to a stronger decrease of Lp(a) in children above compared with those below the median of the relative weight change (23.0% vs 14.5%, P=0.12). This supports a dose-dependent effect of weight loss on Lp(a) changes. Furthermore, a false positive finding might be unlikely due to the fact that the relative decrease of Lp(a) was dependent on the apo(a) K-IV repeat polymorphism.

It may be considered as a limitation that the follow-up period lasted only 3 weeks and no data are available on long-term effects. However, the beneficial short-term changes in plasma Lp(a) levels and other cardiovascular risk factors are a strong supportive argument to encourage children and their families to continue the lifestyle improvements initiated during the intervention program.

Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

We appreciate the technical assistance of Nadja Baumgartner from the Division of Genetic Epidemiology, Innsbruck Medical University. The project was supported by the Medizinische Forschungsförderung Innsbruck (Grant 2007-402) and the Österreichische Nationalbank (Grant 13059) to A Brandstätter and by a grant from the Austrian GEN-AU-Programme ‘GOLD’ to F Kronenberg.

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Brandstätter, A., Lingenhel, A., Zwiauer, K. et al. Decrease of Lp(a) during weight reduction in obese children is modified by the apo(a) kringle-IV copy number variation. Int J Obes 33, 1136–1142 (2009). https://doi.org/10.1038/ijo.2009.144

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Keywords

  • lipoproteins
  • lipoprotein(a)
  • weight reduction
  • children
  • polymorphism

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