Abstract
Objective
Carriers of the PCSK9 R46L genetic variant (rs11591147) are characterized by low levels of low-density lipoprotein cholesterol and a decreased risk of cardiovascular disease (CVD). We studied the impact of the R46L variant on lipoprotein size and composition.
Approach and Results
Lipoprotein-size and composition were measured by nuclear magnetic resonance spectroscopy in 2,373 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study. After adjusting for age, sex and CVD status, carriers of the R46L variant (n=77) were characterized by lower concentrations of very low-density lipoprotein particles (VLDL-P; 85.8±26.2 vs 99.0±33.3 nmol/L, p<0.001), low-density lipoprotein particle (LDL-P; 1479.7±396.8 vs. 1662.9±458.3 nmol/L, p<0.001) and Lipoprotein(a) (11.1[7.2-28.6] vs. 12.4[6.7-29.1] mg/dL, p<0.001) compared to non-carriers. Total high-density lipoprotein particle (HDL-P) as well as VLDL, LDL and HDL particle sizes were comparable in carriers and non-carriers. Carriers were characterized by lower secretory phospholipase A2 (sPLA2; 4.21±0.88 vs 4.61±1.26 nmol/ml/min, p=0.004) and lipoprotein-associated phospholipase A2 activity (Lp-PLA2; 47.5±14.1 vs 52.4±16.2 nmol/ml/min, p=0.02) compared to non-carriers.
Conclusions
Results of this study suggest that carriers of the PCSK9 R46L genetic variant have lower VLDL and LDL particle concentrations, lower Lipoprotein(a) levels and lower sPLA2 and Lp-PLA2 activity compared to non-carriers.
Keywords: R46L, rs11591147, PCSK9, NMR, lipoproteins
Introduction
Proprotein convertase subtilisin/kexin 9 (PCSK9) is a key player in low density lipoprotein (LDL) metabolism1 and a common loss-of-function R46L variant (rs11591147) is associated with both low LDL-cholesterol (LDL-C) levels and low risk of cardiovascular disease (CVD).2 Whether this variant is also associated with other potential CVD risk factors such as measures of plasma lipoprotein subfractions obtained by nuclear magnetic resonance (NMR) spectroscopy is unknown. We hypothesized that carriers of the R46L are characterized by a specific anti-atherogenic lipoprotein-lipid profile measured by nuclear magnetic resonance (NMR) spectroscopy compared to non-carriers. We tested these hypotheses in participants of the European Prospective Investigation of Cancer (EPIC)-Norfolk study.
Methods
The methods are available in the online-only Data Supplement
Results
This analysis comprised 3,821 EPIC-Norfolk participants, previously included in a nested case-control substudy.3 A total of 2174 were incident CVD cases and 1647 were controls, whereas 3700 were non-carriers and 121 were heterozygous carriers of the PCSK9 R46L variant. No homozygous carriers were included. Nuclear Magnetic Resonance (NMR) spectroscopy data were available for 2,296 non-carriers and 77 carriers and the clinical characteristics of these participants are presented in Table 1. As expected, total cholesterol (TC) and LDL-C levels were significantly lower in carriers compared to non-carriers. The heterozygous carriers showed a trend towards a lower CHD risk with an odds ratio (OR) (95% confidence interval (CI) of 0.72 (0.50 – 1.04). Because this cohort was age and sex matched, the age and sex adjusted OR were identical. We measured serum levels of cholesteryl ester transfer protein (CETP), lecithin - cholesterol acyltransferase (LCAT), lipoprotein lipase (LPL), oxidized phospholipids (OxPL), Lipoprotein(a) [Lp(a)], C-reactive protein (CRP), apolipoproteins (apo) A-I, A-II, A-V and B, and NMR measured lipoproteins (presented in Table 2). CETP, LCAT, LPL, OxPL, CRP, ApoA-I, ApoA-II and HDL-P levels as well as HDL size, LDL size, and VLDL size were not different in carriers compared to non-carriers. ApoB, Lp(a), VLDL-P (total, medium and small), intermediate density lipoprotein-particles (IDL-P) and LDL-P levels and sPLA2 and Lp-PLA2 activity were lower in carriers compared to non-carriers.
Table 1.
Baseline characteristics
| Non-carriers | Carriers | P | |
|---|---|---|---|
| n=2296 | n=77 | ||
| Age, years | 65.1(±7.8) | 66.2(±7.3) | 0.25 |
| Male sex | 67.7% (1554) | 62.3% (48) | 0.33 |
| Current smoker | 11.1% (251) | 12.0% (9) | 0.35 |
| Body mass index, kg/m2 | 26.7(±3.7) | 26.4(±3.6) | 0.52 |
| Diabetes mellitus | 3.9% (89) | 3.9% (3) | 0.99 |
| Systolic blood pressure, mmHg | 140.5(±18.2) | 140.0(±17.1) | 0.79 |
| Diastolic blood pressure, mmHg | 84.3(±11.4) | 83.8(±11.2) | 0.79 |
| Total cholesterol, mmol/L | 6.4(±1.2) | 5.8(±0.9) | <0.001 |
| LDL cholesterol, mmol/L | 4.2(±1.0) | 3.7(±0.8) | <0.001 |
| HDL cholesterol, mmol/L | 1.3(±0.4) | 1.4(±0.4) | 0.49 |
| Triglycerides, mmol/L | 2.0(±1.1) | 1.8(±0.9) | 0.08 |
The baseline characteristics were based on variables from participants whose NMR data was available. Data are presented as mean ± standard deviation for continuous variables with a normal distribution, median (interquartile range) for continuous variables with a non-normal distribution, and number (percentage) for categorical variables. LDL = low-density lipoprotein. HDL = high-density lipoprotein.
Table 2.
CETP, LCAT, LPL, OxPL, apolipoproteins and nuclear magnetic resonance spectroscopy-measured lipid levels and size of participants of the EPIC-Norfolk study classified on the basis of PCSK9 R46L carrier status.
| Non-carriers | N | Carriers | N | D (%) | D (SD) | P*2 | |
|---|---|---|---|---|---|---|---|
| CETP, mg/L | 2.9(2.2-3.8) | 2099 | 2.9(1.9-4.0) | 71 | 0.3% | 0.00 | 1.00 |
| LCAT, µg/ml | 8.9(±2.2) | 2071 | 8.7(±2.3) | 68 | -2.2% | -0.09 | 0.47 |
| LPL, ng/ml | 62.5(44.1-88.8) | 2239 | 61.4(51.8-81.2) | 76 | -1.7% | 0.04 | 0.95 |
| OxPL, RLU | 1694.0(1167.0-2670.0) | 1997 | 1573.5(1093.0-3128.0) | 66 | -7.1% | -0.04 | 0.83 |
| CRP, mg/L | 1.7 (0.8-14.0) | 2296 | 1.9(0.8-14.2) | 77 | 11.8% | 0.03 | 0.72 |
| WBC, 10^3/µl | 6.7(±1.9) | 2852 | 6.9(±2.0) | 96 | 2.9% | 0.10 | 0.20 |
| sPLA2, nmol/ml/min* | 4.6(±1.3) | 2373 | 4.2(±0.9) | 77 | -8.7% | -0.33 | 0.0036 |
| Lp-PLA2, nmol/ml/min* | 52.4(±16,2) | 2373 | 47.5(±14.1) | 77 | -9.4% | -0.30 | 0.0154 |
| Apolipoprotein B, mg/dL* | 133.9(±32.5) | 2105 | 119.6(±31.9) | 75 | -10.7% | -0.44 | <0.001 |
| Apolipoprotein A-I, mg/dL | 158.6(±28.4) | 1971 | 160.2(±27.5) | 73 | 1.1% | 0.06 | 0.79 |
| Apolipoprotein A-II, mg/L | 35.2(±6.1) | 2280 | 34.5(±5.3) | 77 | -2.1% | -0.12 | 0.22 |
| Apolipoprotein A-V, ng/mL | 180.0(141.6-235.6) | 2236 | 193.7(159.2-266.5) | 76 | 7.6% | 0.17 | 0.15 |
| Lipoprotein(a), mg/dL* | 12.4(6.7-29.1) | 2296 | 11.1(7.2-28.6) | 77 | -10.3% | -0.04 | <0.001 |
| VLDL Size, nm | 51.8(±8.7) | 2296 | 52.6(±10.0) | 77 | 1.4% | 0.09 | 0.30 |
| LDL Size, nm | 21.0(±0.6) | 2296 | 21.0(±0.7) | 77 | 0.3% | 0.09 | 0.73 |
| HDL Size, nm | 8.9(±0.5) | 2296 | 9.0(±0.4) | 77 | 1.3% | 0.24 | 0.12 |
| VLDL-P (total), nmol/L* | 99.0(±33.3) | 2296 | 85.8(±26.2) | 77 | -13.3% | -0.40 | <0.001 |
| Large VLDL/Chylomicrons, nmol/L | 4.7(1.8-7.8) | 2296 | 3.6(1.7-6.9) | 77 | -22.1% | -0.21 | 0.11 |
| Medium VLDL, nmol/L* | 34.6(±17.7) | 2296 | 29.0(±14.6) | 77 | -16.4% | -0.32 | 0.0082 |
| Small VLDL, nmol/L* | 59.1(±18.7) | 2296 | 52.4(±18.7) | 77 | -11.2% | -0.35 | 0.0021 |
| NMR LDL-P, nmol/L* | 1662.9(±458.3) | 2296 | 1479.7(±396.8) | 77 | -11.0% | -0.40 | <0.001 |
| IDL, nmol/L* | 38.3(16.4-71.7)) | 2296 | 31.5(11.0-61.1) | 77 | -17.8% | -0.24 | 0.0393 |
| Large LDL, nmol/L* | 565.9(±206.4) | 2296 | 517.0(±192.1) | 77 | -8.7% | -0.24 | 0.0088 |
| Medium small LDL, nmol/L | 191.8(141.6-264.4) | 2296 | 164.7(124.9-230.5) | 77 | -14.1% | -0.22 | 0.12 |
| Very small LDL, nmol/L | 764.5(565.9-1044.6) | 2296 | 654.5(480.2-909.2) | 77 | -14.4% | -0.26 | 0.06 |
| NMR HDL-P, µmol/L | 33.8(±5.6) | 2296 | 34.3(±4.7) | 77 | 1.6% | 0.10 | 0.51 |
| Large HDL, µmol/L | 5.0(2.8-7.7) | 2296 | 6.1(3.9-8.3) | 77 | 23.2% | 0.24 | 0.11 |
| Medium HDL, µmol/L | 2.6(1.1-4.9) | 2296 | 3.4(1.4-5.0) | 77 | 29.5% | 0.05 | 0.64 |
| Small HDL, µmol/L | 24.9(±5.0) | 2296 | 24.4(±4.3) | 77 | -1.8% | -0.09 | 0.54 |
| LDL cholesterol, mmol/L |
Data are presented as mean ± standard deviation for variables with a normal distribution and median with interquartile range for variables with a non-normal distribution. N= number, D = difference, D (SD) = difference as proportion of standard deviation, NMR = nuclear magnetic resonance, CETP = cholesteryl ester transfer, LCAT = lecithin - cholesterol acyltransferase, LPL = lipoprotein lipase, OxPL = oxidized phospholipids, RLU = relative light units, CRP = C-reactive protein, secretory phospholipase A2= sPLA2, lipoprotein-associated phospholipase A2 = Lp-PLA2, WBC = white blood cells, VLDL = very low density lipoprotein, LDL = low-density lipoprotein, IDL = intermediate-density lipoprotein, HDL = high-density lipoprotein, SD = standard deviation.
significant difference.
P*2 values calculated with a linear regression model, adjusted for age, sex and CVD status.
Discussion
Our study shows that carriers of the PCSK9 R46L variant are characterized by lower levels of NMR measured atherogenic lipoproteins and subfractions compared to non-carriers. The most prominent differences based on percentage change between carriers and non-carriers were observed with IDL-P (-18%) and medium VLDL-P (-16%). The most prominent differences based on change in standard deviation (SD) between carriers and non-carriers were observed with apoB (-0.44 SD), VLDL-P (-0.40 SD) and LDL-P (-0,40 SD). Our results extent those of Cohen et al.2 who have reported a 15% reduction in LDL-C in carriers of the PCSK9 R46L variant in the ARIC study. The effect on other parameters of the lipoprotein-lipid profile was comparable, with in both studies significant lower levels of total cholesterol, and no effect on high-density lipoprotein-cholesterol.
In a cross-sectional study of 52 healthy subjects, PCSK9 levels were found to correlate with TC, non-HDL-C, LDL-C, TG and VLDL-P and LDL-P concentrations.4 In a subsequent multivariable regression analysis, PCSK9 levels were only related to LDL-P concentration. Interestingly, in an analysis which included the 3 LDL subfractions, PCSK9 was only associated with IDL-P. The R46L variant examined in our study has been shown to be associated with lower levels of PCSK95 and therefore we expected a similar effect on NMR lipoprotein subfractions. Our study suggests that there is not only an association between PCSK9 and IDL-P, but also on the other lipoproteins, as all clinical characteristics (except cholesterol related parameters) were comparable between carriers and non-carriers. The effect of the R46L variant on lipoproteins in our study appeared to be comparable with the results of Chasman et al6, who showed a significant effect of the SNP on large LDL-P, total LDL_P, small LDL-P, IDL-P, LDL-C, total VLDL-P and small VLDL-P. Other groups also documented the effect of different SNPs at the PCSK9 locus on plasma lipids.7,8 A recent analysis of the Copenhagen general population study showed that carriers of the R46L variant had lower Lp(a) than non-carriers.9 Recently, Koren et al10 documented the impact of the PCSK9 inhibitor alirocumab on NMR lipoprotein subfractions in 60 patients with hypercholesterolemia. Alirocumab therapy resulted in a 63.3% decrease of LDL-P concentration, whereas IDL-P concentration fell by 52.8%. Although the effect of alirocumab on Lp(a) was not determined by Koren et al,10 Lp(a) reductions up to 30% were demonstrated in phase 2 trials.11 The effect of alirocumab on CETP, LCAT, LPL, OxPL, sLPA2 and Lp-LPA2 has not been reported. Our study extends the results of Koren et al. by showing that PCSK9 inhibition could be associated with lower LDL-P and Lp(a) in patients without hypercholesterolemia.10
The relationship between LDL-C and CVD risk is strong and consistent but evidence suggest that LDL-P concentrations could be more closely associated with CVD risk than LDL-C.12 Due to a possible discordance between LDL-C and LDL-P concentrations, patients with LDL-C levels on target could be at increased CVD risk due to high LDL-P levels.13 The American Association of Clinical Chemistry has suggested to strive for a LDL-P concentration treatment goal of <1100 nmol/L14 or an equivalent LDL-C level of <100 mg/dl in patients at high CVD risk according to the National Cholesterol Education Program Adult Treatment Panel III.15
As was shown by Ference et al,16 a life-long exposition to lower LDL-C levels, resulted in a 3-fold greater reduction in CHD per mmol/L than in the statin trials. Also it was recently shown that plasma Lp-PLA2 are inversely correlated with PCSK9 levels.17 This enzyme is positively associated with the development of CHD, stroke and aortic stenosis.18,19 R46L carriers had both lower levels of sPLA2 and Lp-PLA2 than non-carriers, which could be an additional explanation of the lower CHD risk in R46L carriers. Results of our genetic association study are however more likely to imply a causal role for PCSK9 in Lp-PLA2 than an association between blood levels of both factors based on correlations.
In conclusion, our results suggest that carriers of the PCSK9 R46L genetic variant have a lifelong lower exposure to all atherogenic lipoproteins, including Lp(a), sPLA2 and Lp-PLA2, which presumably explains their reduced CHD risk.
Supplementary Material
Highlights.
Carriers of the PCSK9 R46L genetic variant have, compared to non-carriers:
-
-
lower apoB concentrations
-
-
lower VLDL and LDL particle concentrations
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lower Lipoprotein(a) concentrations
-
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lower sPLA2 and Lp-PLA2 activity
Acknowledgements
We would like to thank participants, general practitioners and staff of the EPIC-Norfolk study.
Source of funding: The EPIC-Norfolk Study is funded by Cancer Research UK grant number 14136 and the Medical Research Council grant number G1000143. R.V. is supported by a grant from the European Union [TransCard: FP7-603091-2]. B.J.A. holds a junior scholar award from the Fonds de recherche du Québec: Santé (FRQS). J.J.P.K. is a recipient of the Dutch Heart Foundation Lifetime Achievement Award (2010).
Abbreviations
- Apolipoproteins
apo
- CVD
cardiovascular disease
- EPIC-Norfolk
European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk
- VLDL-P
very low-density lipoprotein particle
- sPLA2
secretory phospholipase A2
- Lp-PLA2
lipoprotein-associated phospholipase A2
- NMR
nuclear magnetic resonance
- CETP
Cholesteryl ester transfer
- LCAT
Lecithin - cholesterol acyltransferase
- LPL
Lipoprotein lipase
- OxPL
Oxidized phospholipids
- CRP
C-reactive protein
Footnotes
Disclosures: no potential conflicts of interests.
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