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Complex traits
Original article
Intake levels of dietary polyunsaturated fatty acids modify the association between the genetic variation in PCSK5 and HDL cholesterol
  1. Han Byul Jang1,
  2. Joo-Yeon Hwang2,
  3. Ji Eun Park1,
  4. Ji Hee Oh2,
  5. YounJhin Ahn1,2,
  6. Jae-Heon Kang3,
  7. Kyung-Hee Park4,
  8. Bok-Ghee Han2,
  9. Bong Jo Kim2,
  10. Sang Ick Park1,
  11. Hye-Ja Lee1
  1. 1Center for Biomedical Science, Korea National Institute of Health, Cheongwon-gun, Chungcheongbuk-do, South Korea
  2. 2Center for Genome Science, Korea National Institute of Health, Cheongwon-gun, Chungcheongbuk-do, South Korea
  3. 3Department of Family Medicine, Obesity Research Institute, Seoul-Paik Hospital, Inje University, Seoul, South Korea
  4. 4Department of Family Medicine, Hallym University Sacred Heart Hospital, Hallym University, Anyang, Gyeonggi-do, South Korea
  1. Correspondence to Sang Ick Park and Hye-Ja Lee, Center for Biomedical Science, Korea National Institute of Health, Choengwon-gun, Chungcheongbuk-do 363-951, South Korea; parksi61{at}hotmail.com and hyejalee{at}yahoo.co.kr

Abstract

Background A low serum level of high-density lipoprotein cholesterol (HDL-C) is a risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 5 (PCSK5) modulates HDL-C metabolism through the inactivation of endothelial lipase activity.

Methods Therefore, we analysed the effects of PCSK5 on HDL-C and investigated the association between genetic variation in PCSK5 and dietary polyunsaturated fatty acids (PUFAs) intakes in Korean adults and children. This population-based study which was conducted in South Korea included 4205 adults (43% male) aged 40–69 years and 1548 children (48.6% boys) aged 8–13 years. Dietary intake was assessed using a semiquantitative food frequency questionnaire in adults and modified 3-day food records in children.

Results After adjustments for age and body mass index, we identified a significant association between SNP rs1029035 of the PCSK5 gene and HDL-C concentrations specifically for men in both populations (adults, p=0.004; children, p=0.003; meta, p=7×10−4). Additionally, the interaction between the PCSK5 rs1029035 genotype and dietary polyunsaturated fatty acids intake influenced serum HDL-C concentrations in men (adults, p=0.001; children, p=0.008). The deleterious effect of the C allele on serum HDL-C was present only when dietary PUFA intake was less than the dichotomised median level (adults, p=0.011; children, p=0.001). Serum HDL-C concentrations were decreased in men with the C allele genotype and low consumption of dietary PUFA including n-3 and n-6.

Conclusion According to these results, men carrying of the C allele were associated with low HDL-C concentrations and might exert beneficial effects on HDL-C concentrations following consumption of a high-PUFA diet.

  • Genetic epidemiology
  • Nutrition and Metabolism
  • Complex traits

https://doi.org/10.1136/jmedgenet-2014-102670

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    Introduction

    Blood lipid concentrations play a role in the development of cardiovascular disease (CVD), which is the leading cause of death worldwide.1 A low serum level of high-density lipoprotein cholesterol (HDL-C) is an important independent risk factor for CVD. A meta-analysis of four prospective studies showed that each 1 mg/dL decrease in HDL-C concentrations is associated with a 2–3% increased risk of CVD.2 Thus, it is crucial to manage HDL-C concentrations at an early stage to prevent CVD and its complications.3

    HDL-C metabolism is complex and involves the biosynthesis and secretion of its major protein components, such as remodelling of HDL particles. HDL particles are continuously remodelled by a variety of enzymes, especially lipases.4 Endothelial lipase (EL), a phospholipase present in vascular endothelial cells, decreases the size and cholesterol content of HDL particles. It is inhibited by angiopoietin-like protein 3 (ANGPTL3) or by proprotein convertases of the subtilisin/kexin type, including furin, PC5/6, and PACE4.5 ,6 The proprotein convertase subtilisin/kexin (PCSK) represent a family of nine subtilisin-like serine proteinases, comprising seven basic amino acid-specific proteinases encoded by the PCSK 1–7 genes and two other subtilases (SKI-1/S1P and PCSK9) that cleave at non-basic residues. Of these, several studies showed that PCSK5 and its encoded protein PC5/6 specifically inactivate EL and lipoprotein lipase in in vivo models.6 ,7 In addition, a family-based study reported that haplotypes of the PCSK5 gene locus influence low HDL-C concentrations.8

    The serum HDL-C level is influenced by genetic and environmental factors, including dietary polyunsaturated fatty acids (PUFAs), and the interactions between these factors.9 ,10 Dietary PUFAs, such as n-6 and n-3, are essential fatty acids that regulate lipid and lipoprotein metabolism and are not synthesised de novo in mammals. There is growing evidence regarding the beneficial effects of PUFAs on lipid profiles and CVD prevention.9 ,11–15 Well-controlled clinical trials and population studies have demonstrated that dietary PUFA intake is inversely related to total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) concentrations and positively related to HDL-C and/or HDL2-C concentrations,12–15 which are associated with a reduced risk of CVD.11

    Since dietary fatty acids, mainly PUFAs, can modulate gene expression, lipid concentrations may be regulated by gene-dietary fatty acid interactions,16 which have been associated with blood lipid concentrations in several studies. In the Framingham study, the APOA1 G/A polymorphism influenced the effect of PUFA intake on HDL-C concentrations. High PUFA intake (>8% of energy) was associated with higher HDL-C concentrations in the presence of the A allele, whereas the opposite effect was observed in the presence of the GG genotype.17 In another study, among individuals consuming high PUFA concentrations, the A227 allele of ABCG1 was associated with lower HDL-C,18 and the AA genotype with higher LDL-C concentrations.19

    There have been no previous studies on the effects of the PCSK5 genetic variant and dietary fatty acid interactions on lipid and lipoprotein profiles. Moreover, only one previous study exists on the effects of rare alleles of PCSK5 genetic variants on decreased HDL-C concentrations, conducted in a Western family.8 Therefore, we analysed the effects of PCSK5 on lipid concentrations and the potential modifying effects by dietary fatty acids such as PUFAs in Korean adults and children.

    Participants and methods

    Study population

    For this study, data were obtained from the Korean Genome Epidemiology Study (KoGES) and the Korean Children-Adolescents Study (KoCAS) conducted by the Korean National Institute of Health. The adult participants comprised 4205 individuals from the KoGES in 2001, living in Ansung and 40–69 years of age. Forty three per cent (n=1809) of the adults were male (57% female, n=2396). Detailed information on the sampling plan and genotype accuracies has been published previously.20 Written informed consent was obtained from the participants, and the study protocol was approved by the regional ethics committees. The 1548 student participants, aged 8–13 years, were recruited from Seoul and Kyunggi province between 2006 and 2012 as part of the KoCAS, which has monitored a cohort annually since they entered elementary school at age 7 years in 2005. Of the children 48.6% (n=750) were boys, 51.4% girls (n=798). The study was approved by the Institutional Review Board of Seoul-Paik Hospital, Inje University, and the Korea Centers for Disease Control and Prevention. Informed consent was obtained from the children's parents.

    Anthropometric and biochemical measurements

    Professionally trained personnel performed the anthropometric examinations and blood collections in each cohort study using a standardised protocol. The concentrations of TC, TGs and HDL-C were measured using the Advia 1650 analyser (Siemens, Tarrytown, New York, USA) for the Ansung study and the Hitachi 7180 analyser (Hitachi, Tokyo, Japan) for the KoCAS.

    Definition of low HDL-cholesterol concentration

    Low HDL-C concentration was defined as less than 40 mg/dL for participants of the Ansung study in accordance with the standards of the Korean Society of Lipidology and Atherosclerosis (KSLA, 2009). The low HDL-C in KoCAS was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III for adolescents (≤40 mg/dL).21

    Genotyping

    Genotype data from the KoGES, accessible to the research community through the Korean Associated Resource project, were used to evaluate SNPs located in the PCSK5 locus. The samples from the Ansung study were genotyped using the Affymetrix Genome-Wide Human SNP Array V.5.0 (Affymetrix, Santa Clara, California, USA) and processed using the Bayesian Robust Linear Model with Mahalanobis distance genotype calling algorithm.22 The KoCAS samples were genotyped for rs1029035 located in the seventh intron of PCSK5 using TaqMan assays. The 1542 student participants passed genotype procedure and no deviation from the Hardy-Weinberg equilibrium was observed for genotype distribution (p>0.05). The Primer Express software (Applied Biosystems, Foster City, California, USA) was used to design the PCR primers and the Taq-Man minor-groove-binding probes. Primer information is available at the following website: http://www.lifetechnologies.com/kr/ko/home/life-science/pcr/real-time-pcr/real-time-pcr-assays.html

    Assessment of dietary intake

    Among the Ansung study participants, dietary intake was assessed using a semiquantitative food frequency questionnaire developed and validated in the KoGES.23 This questionnaire was completed by 3845 participants and included questions about standard serving size intakes of 103 food items divided into three categories: small (0.5 serving), medium (1 serving) and large (1.5 servings). Average daily nutrient intake was calculated by multiplying the consumption frequency per serving by the portion size for each food item. We estimated dietary fatty acid intake, including saturated fatty acid (SFA), monounsaturated fatty acid, PUFA, n-3 and n-6, using the food composition table published by the Rural Development Administration of Korea.24 Typical dietary intake for the KoCAS participants was estimated based on 3-day food diary records documented over 3 consecutive days (2 week days, 1 weekend day) and completed by 1376 students. Parents helped their children to complete the dietary records, and trained researchers checked whether the records contained sufficient information. Nutrient intakes were determined from food intakes using the Computer-Aided Nutritional Analysis for Professionals, V.3.0, software (CAN-pro 3.0, Korean Nutrition Society, Seoul, Korea). To investigate the interaction effects between rs1029035 at the PCSK5 locus and dietary PUFA intake, we divided the participants according to the distribution median for PUFA intake, which was determined as a percentage of the total energy intake.

    Statistical analysis

    Statistical analysis was performed using the SAS software package (V.9.2; SAS Institute, Cary, North Carolina, USA), and values are presented as means±SDs. Variables with non-normal distributions were log-transformed before analysis. Allele frequencies and Hardy-Weinberg equilibrium were evaluated using Haploview 4.2 (Broad Institute, Cambridge, Massachusetts, USA). Comparison among male and female groups was performed by the Student's t test. Linear regression analyses of the associations between genotypes and lipid-related phenotypes were performed using an additive (minor allele homozygotes vs heterozygotes vs major allele homozygotes) after adjusting for age and body mass index (BMI). Linear meta-analysis was conducted with the random effects method. The logistic regression model to estimate the ORs and 95% CIs after adjusting for age and BMI was used for the analysis of genotype distributions of participants with and without low HDL-C concentrations in the additive model for Ansung and the dominant (minor allele homozygotes plus heterozygotes vs major allele homozygotes) model for small KoCAS. The combined ORs were assessed by weighing to the study-specific estimates in additive models. The PCSK5 genotype and dietary PUFA intake interaction effect on serum HDL-C concentrations was evaluated using the general linear model with interaction terms and controlled confounding factors, age and BMI. p Values <0.05 were considered to indicate statistical significance.

    Results

    General characteristics and genotype distribution of the study population

    The general characteristics of the study participants classified by gender are shown in table 1. The allele frequencies were 0.671 for the C allele and 0.329 for the A allele in the Ansung study participants and 0.647 for the C allele and 0.353 for the A allele in the KoCAS participants. There were differences in anthropometric measurements and blood lipid concentrations between men and women in both studies, with the exceptions of age and genotype distribution. Dietary fatty acid intake did not differ between the genders in the KoCAS participants, but male participants had a higher fatty acid intake than female participants in the Ansung study.

    View this table:
    Table 1

    General characteristics of study participants

    Serum HDL-C concentrations according to PCSK5 genotype

    Table 2 shows the serum HDL-C concentrations of the study population according to the PCSK5 genotype. In both studies, rs1029035 was associated with a genotype-related difference in HDL-C concentrations, after adjustment for age and BMI, in men only. The meta-analysis in male participants of two independent samples showed that HDL-C concentrations were also significantly lower in carriers of the C allele (p=0.0005). No differences in TG, TC and LDL-C concentrations were detected across the PCSK5 genotypes (data not shown).

    View this table:
    Table 2

    Serum HDL-C concentrations according to PCSK5 polymorphisms

    Risk of low HDL-C concentrations according to the PCSK5 genotype

    We next evaluated the association between PCSK5 polymorphisms and low HDL-C concentrations using multivariate-adjusted ORs (table 3). In the Ansung study, an increased risk of low HDL-C concentrations was found in male carriers of the CA or CC genotype (AA used as the reference, p=0.020 and p=0.025, respectively). In the KoCAS, because of the small sample number of AA carriers with low HDL-C concentrations (one man and six women), participants with the CA and AA genotypes were combined and compared with homozygous CC carriers. Homozygous CC men had a significantly higher risk of low HDL-C concentrations than did carriers of the A allele (p=0.014). The combined analysis, including samples from the Ansung study and KoCAS, showed that male carriers of the C allele had a significantly increased risk of low HDL-C concentrations (AA used as the reference, p=0.012 for CA and p=0.007 for CC). No differences in HDL-C risk across PCSK5 genotypes were observed in the women.

    View this table:
    Table 3

    Association between PCSK5 genotypes and the risk of low HDL-C

    PCSK5 polymorphism and dietary PUFA intake interaction effects on serum HDL-C concentrations

    To evaluate the influence of dietary PUFAs on the effects of PCSK5 polymorphisms on HDL-C concentrations, we first examined total PUFA intake according to the median distributions of the populations in the Ansung study and KoCAS (3.98% and 4.06% of total energy intake, respectively). We detected an interaction effect between PCSK5 polymorphisms and dietary PUFA intakes including n-3 and n-6 intakes on HDL-C concentrations in male participants of both studies (p for interaction=0.001 and 0.008; n-3, 0.0055 and 0.0050; n-6, 0.0010 and 0.0035, respectively) (table 4 and figure 1). These results were significant after correcting for multiple testing. The C allele was associated with a decrease in HDL-C concentrations in individuals consuming less than the median PUFA intake; however, there was no significant genotype-related difference in those consuming greater than the median intake. Similar to PUFAs, individuals with low intake of n-3 and n-6 showed a tendency to decrease of HDL-C concentration in the presence of the C allele, whereas the opposite effect was observed in the presence of the AA genotype.

    View this table:
    Table 4

    Interaction between rs1029035 polymorphism and PUFAs for HDL-C levels in male participants

    Figure 1
    Figure 1

    Interaction of proprotein convertase subtilisin/kexin type 5 (PCSK5) genotypes and dietary polyunsaturated fatty acid (PUFA) on serum high-density lipoprotein cholesterol (HDL-C) level in men. Performed by general linear model analysis with adjustment for age and body mass index. KoCAS, Korean Children-Adolescents Study.

    Discussion

    In this study, we found that PCSK5 polymorphisms influence serum HDL-C concentrations, in accordance with an earlier report.8 To identify the effects of PCSK5 genetic variants on HDL-C concentrations, they used a two-stage-design study consisting of French Canadian individuals with HDL-C concentrations in the <5th and >95th centiles (Stage 1) and Finnish families with low HDL-C concentrations (Stage 2). Our study confirmed these findings in adults and children of the general Korean population. Men with the AA genotype showed significantly higher HDL-C concentrations, whereas the presence of the C allele increased the risk of low HDL-C concentrations. These findings reinforce the notion of a causal link between PCSK5 and HDL-C concentrations.

    Possible explanations for such effects include the following; EL plays a role in HDL metabolism by promoting the turnover of HDL components and increasing the catabolism of apolipoprotein A-I4; in turn, this leads to smaller-sized HDL particles with reduced phospholipid contents, resulting in decreased blood HDL-C concentrations. This is in agreement with an in vivo study in which EL−/− mice had elevated plasma HDL-C and apolipoprotein A-I concentrations, as well as an abundance of large HDL particles.25 These data indicate that EL is a major determinant of HDL concentrations. The PCSK5 gene product, PC5/6, upregulates HDL-C concentrations through direct inactivation of EL via cleavage of the N-terminal catalytic and C-terminal lipid-binding domains or through activation of ANGPTL3, an endogenous inhibitor of EL.6–8 In support, our study showed that genetic variations in PCSK5 modulate HDL concentrations in men. The loss of PC5/6 and/or ANGPTL3 activity could lead to overexpression of EL and lipoprotein lipase,6 ,7 ,26 resulting in reduced HDL, very-low-density lipoprotein and TG concentrations. Moreover, PCSK9, a natural post-transcriptional inhibitor of the LDL receptor, is degraded by PC5/6A,27 which correlates with LDL-C concentrations. These results suggest that PCSK5 genetic variants could influence lipoprotein metabolism. However, we could not find an association among TC, TG and LDL-C in our study. Further studies are required to elucidate the influence of PCSK5 on lipoprotein metabolism.

    Many studies have found that dietary PUFAs are associated with improved blood lipid concentrations related to CVD. Randomised controlled trials showed that replacing a SFA diet with 16.4–17% energy from PUFA diet28 and high PUFA snack chips (36.3% of energy from fat, 9.7% of energy from PUFAs)29 improved serum lipid concentrations. In our study, a higher intake of PUFAs was associated with lower TG (only in children) and higher HDL-C concentrations (data not shown). A pooled analysis of 11 prospective cohort studies demonstrated that the risks of coronary events and coronary death were lowest when 5% lower energy intake from SFAs were replaced by higher intake from PUFAs in the diet.30 Thus, a better understanding of the mechanisms of action of fatty acids is a priority in cardiometabolic studies.

    All population of our study did not respond to the dietary questionnaires (refusal or inability to recall) which were obtained by self-report. This raises the potential for non-response and overestimation bias. We used validated questionnaires via pilot study and representative sampling strategies to ensure the quality of the results by controlling for recall bias via limiting the recall period and adjusting for confounders via using only validated survey instruments. Also, because our studies were performed with cohort data surveyed in Seoul and Kyunggi province, the participants do not represent the general population in Korea. However, when PUFA intakes (Ansung: 9.2±5.49 g/day, KoCAS: 7.9±2.91 g/day) were compared with the 2005 Korean National Health and Nutrition Examination Survey (50–64 years: 8.5±9.9 g/day, 9–11 years: 7.4±6.6 g/day), our populations’ intakes met the proper ratio of energy (≤10%) by the KSLA to maintain a healthy body weight.

    In this study, we identified an effect of the interaction between PCSK5 genetic variants and dietary PUFA intake on serum HDL-C concentrations in male adults and children. Our study showed that low intake of PUFAs was associated with lower concentrations of HDL-C in C allele carriers, whereas the opposite effect was observed for the AA genotype. Moreover, the C allele significantly influenced HDL-C concentrations according to PUFA intake in an adult population. The C allele carriers with high PUFA intake had higher HDL-C concentrations than did the C allele carriers with low PUFA intake, while there was no significant difference in children. This discrepancy may be due to the relatively longer period of dietary exposure and impact in adults compared with children. Our data suggest that the influence of PCSK5 on serum HDL-C concentrations is associated with the consumption of dietary PUFAs.

    However, the biological mechanisms underlying the PCSK5 and dietary PUFA intake interaction effect on HDL-C concentrations have not yet been elucidated. One potential pathway involves the activation of peroxisome proliferator-activated receptor-α (PPAR-α), a transcriptional regulator. PUFAs or their metabolites regulate certain genes through the activation of PPAR-α.31–33 In cells and in vivo, hepatic PPAR-α responds to changes in dietary fats and newly synthesised fats (de novo lipogenesis).33 ,34 This response leads to changes in the expression of multiple genes involved in HDL metabolism. A previous study showed that PC5/6A is upregulated by fibrates in a PPAR-α-dependent manner.35 Similar to fibrates, PUFAs act as ligands for PPARs. We propose that the regulation of PCSK5 by PUFAs and PPAR-α contributes to its beneficial effects on HDL-C.

    Another finding of this research was the sex difference associated with PCSK5 genotypes and genotype-PUFA intake interactions. In male carriers of the C allele, lower PUFA intakes were associated with lower HDL-C concentrations, whereas no such effects were observed in women. In vivo studies have reported an influence of gender on the regulation of lipoprotein metabolism by PPAR-α.36 ,37 The PPAR-α mRNA level was found to be higher in male rats than in female rats.36 Mice lacking PPAR-α showed differential effects on obesity and lipid metabolism between men and women.38 ,39 Yoon et al40 reported that fenofibrate, a PPAR-α ligand, decreases weight gain, adipose tissue mass and plasma TC levels in male mice, but did not reduce them in female mice. Jeong et al41 also showed that fenofibrate reduced weight gain and adiposity in ovariectomised female mice, but not in female mice with functioning ovaries. In our study, women aged ≥65 years, who could be considered as menopausal status and less exposed to oestrogen dose, had significant PCSK5 genotype-related difference in HDL-C levels after adjustment for age and BMI (p=0.046; data not shown). Also, among our children population, over 77% of girls meet with sexual maturation (≥Tanner stage 2, data not shown). These findings suggest the possibility that the action of PPAR-α on lipid metabolism may be influenced by oestrogen in women. The biological mechanisms underlying this gender dimorphism have not been elucidated. One possible explanation is that ovarian hormones inhibit the expression of PPAR-α target gene, implicating lipid metabolism in the oestrogen-signalling pathway.38 ,39

    In summary, we showed interaction effects between PCSK5 genetic variants and dietary PUFA consumption on serum HDL-C concentrations in Korean adults and children. According to these results, individuals carrying the C allele were associated with low HDL-C concentrations and might exert beneficial effects on HDL-C concentrations following consumption of a high-PUFA diet. These findings suggest that evaluation of PCSK5 genotypes is useful for the development of individualised therapies to modulate serum HDL-C concentrations.

    Acknowledgments

    The authors thank all the participating adults and children.

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    Footnotes

    • HBJ and J-YH contributed equally.

    • Contributors HBJ: designed the study and wrote the article; J-YH: designed the study and performed genotyping; JEP, YJA, J-HK and K-HP: provided phenotypical information; JHO: performed genotyping; B-GH, BJK and SIP: data interpretation; H-JL: designed, analysed and interpreted data.

    • Funding This work was supported by intramural grants from the Korea National Institute of Health, Korea Center for Disease Control (project no: 4845-302-210/4845-300-260/4851-302-210/4845-301-210).

    • Competing interests None.

    • Provenance and peer review Not commissioned; externally peer reviewed.