See article vol. 28: 329–337
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is recognized as a key factor of familial hypercholesterolemia since 2003 1). Afterward, the association of PCSK9 genetic variance was found with low-density lipoprotein (LDL) cholesterol level and risk of coronary heart disease (CHD)2), and PCSK9 has been a novel therapeutic target. Recently, two monoclonal antibodies to PCSK9 (Evolocumab and Airocumab) have been available especially for high cholesterol patients resistant to statins and other lipid-lowering medication, and clinical and research interests are increasing on PCSK9. Although PCSK9 has a vital role in lipid metabolism and CHD risk, the interpretation of serum PCSK9 level remains not well known.
Presently, Hamamura et al. examined the association of serum PCSK9 levels with lipid metabolism and insulin resistance in the Japanese general population with a cross-sectional study design3). Higher serum PCSK9 level was associated with serum levels of triglycerides and lipoprotein(a) and insulin resistance among the Japanese population that has relatively low CHD risk. Regarding serum LDL cholesterol levels, a positive association was not observed in univariate linear regression analysis among the overall population. However, this finding did not deny a positive association between serum PCSK9 level and LDL cholesterol level in the general population because the beta coefficient of serum LDL cholesterol level in relation to serum PCSK9 level was quite similarly positive among both individuals who were using lipid-lowering medication and those who were not using such medication. The current research provides a clue for the interpretation of the high serum PCSK9 level.
To my knowledge, only one study examines the association between serum PCSK9 levels and the risk of cardiovascular disease (CVD). Among 4,232 Swedish men and women aged 60 years with 485 ischemic CVD events during 15 years of follow-up, serum PCSK9 levels were linearly positively associated with incident ischemic CVD including myocardial infarction, angina pectoris, chronic CHD, sudden cardiac death, and ischemic stroke4). Although Swedish population has generally higher CVD risk than Japanese population5), serum PCSK9 level was not higher in the Swedish study (median level: 94.3 ng/ml measured with ELISA)4) than that in the Japanese population (mean level: 211.2 ng/ml measured with ELISA)3). In a Kenyan study with 698 middle-aged adults which reported the positive association of serum PCSK9 level with hepatic enzyme levels and fatty liver disease, serum PCSK9 level was approximately 150 ng/ml in the median6). These findings suggest that there may be racial differences on serum PCSK9 levels.
Furthermore, from a meta-analysis of previous intervention studies, moderate-to-vigorous physical activities increase plasma PCSK9 levels, especially among statin users7). Additionally, in an intervention study, alteration of saturated fat intake with unsaturated fat intake, which will lower CHD risk, improved LDL cholesterol levels but not serum PCSK9 levels8). These findings suggest that serum PCSK9 level could not be modified by improving physical activity and dietary intake although CHD risk could be modified. To interpret the meaning of high serum PCSK9 level on CHD risk in the general population, further investigation is warranted. Additionally, the assessment of the CHD risk prediction performance and the cost–benefit balance by adding serum PCSK9 level to the Suita score9), which is adopted in the Japan Atherosclerosis Society Guideline for Prevention of Atherosclerotic Cardiovascular Diseases 2017 10), has been waited for to determine whether serum PCSK9 level is useful for CHD risk assessment.
Conflict of Interests
The author has no conflict of interest in this paper.
References
- 1). Abifadel M, Varret M, Rabès JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derré A, Villéger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet, 2003; 34: 154-156 [DOI] [PubMed] [Google Scholar]
- 2). Cohen SM, Arnold LL, Eldan M, Lewis AS, Beck BD. Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit Rev Toxicol, 2006; 36: 99-133 [DOI] [PubMed] [Google Scholar]
- 3). Hamamura H, Adachi H, Enomoto M, Fukami A, Nakamura S, Nohara Y, Morikawa N, Sakaue A, Toyomasu K, Yamamoto M, Fukumoto Y. Serum Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is Independently Associated with Insulin Resistance, Triglycerides, Lipoprotein(a) Levels but not Low-Density Lipoprotein Cholesterol Levels in a General Population. J Atheroscler Thromb, 2021; 28: 329-337 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4). Leander K, Mälarstig A, Van't Hooft FM, Hyde C, Hellénius ML, Troutt JS, Konrad RJ, Öhrvik J, Hamsten A, de Faire U. Circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Predicts Future Risk of Cardiovascular Events Independently of Established Risk Factors. Circulation, 2016; 133: 1230-1239 [DOI] [PubMed] [Google Scholar]
- 5). Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, Djousse L, Elkind MSV, Ferguson JF, Fornage M, Khan SS, Kissela BM, Knutson KL, Kwan TW, Lackland DT, Lewis TT, Lichtman JH, Longenecker CT, Loop MS, Lutsey PL, Martin SS, Matsushita K, Moran AE, Mussolino ME, Perak AM, Rosamond WD, Roth GA, Sampson UKA, Satou GM, Schroeder EB, Shah SH, Shay CM, Spartano NL, Stokes A, Tirschwell DL, VanWagner LB, Tsao CW, American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association. Circulation, 2020; 141: e139-e596 [DOI] [PubMed] [Google Scholar]
- 6). Paquette M, Gauthier D, Chamberland A, Prat A, De Lucia Rolfe E, Rasmussen JJ, Kaduka L, Seidah NG, Bernard S, Christensen DL, Baass A. Circulating PCSK9 is associated with liver biomarkers and hepatic steatosis. Clin Biochem, 2020; 77: 20-25 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7). Kuo W, Stevens JM, Ersig AL, Johnson HM, Tung TH, Bratzke LC. Does 24-h Activity Cycle Influence Plasma PCSK9 Concentration? A Systematic Review and Meta-Analysis. Curr Atheroscler Rep, 2020; 22: 30 [DOI] [PubMed] [Google Scholar]
- 8). Tindall AM, Kris-Etherton PM, Petersen KS. Replacing Saturated Fats with Unsaturated Fats from Walnuts or Vegetable Oils Lowers Atherogenic Lipoprotein Classes Without Increasing Lipoprotein(a). J Nutr, 2020; 150: 818-825 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9). Nishimura K, Okamura T, Watanabe M, Nakai M, Takegami M, Higashiyama A, Kokubo Y, Okayama A, Miyamoto Y. Predicting coronary heart disease using risk factor categories for a Japanese urban population, and comparison with the framingham risk score: the suita study. J Atheroscler Thromb, 2014; 21: 784-798 [DOI] [PubMed] [Google Scholar]
- 10). Kinoshita M, Yokote K, Arai H, Iida M, Ishigaki Y, Ishibashi S, Umemoto S, Egusa G, Ohmura H, Okamura T, Kihara S, Koba S, Saito I, Shoji T, Daida H, Tsukamoto K, Deguchi J, Dohi S, Dobashi K, Hamaguchi H, Hara M, Hiro T, Biro S, Fujioka Y, Maruyama C, Miyamoto Y, Murakami Y, Yokode M, Yoshida H, Rakugi H, Wakatsuki A, Yamashita S, Committee for Epidemiology and Clinical Management of Atherosclerosis. Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017. J Atheroscler Thromb, 2018; 25: 846-984 [DOI] [PMC free article] [PubMed] [Google Scholar]