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J Am Coll Cardiol, 2005; 45:1620-1621, doi:10.1016/j.jacc.2005.02.056 © 2005 by the American College of Cardiology Foundation |
Department of Vascular Medicine, Academic Medical Center at the University of Amsterdam, Amsterdam, the Netherlands.
* Reprint requests and correspondence: Dr. John J. P. Kastelein, Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, P.O. Box 22700, 1100 DE Amsterdam, the Netherlands. (Email: e.vandongen{at}amc.uva.nl).
Until very recently, it was fair to say that in most populations approximately 65% of the cases of inherited hypercholesterolemia could be explained by mutations in the LDL receptor gene and in 10% by mutations in the apoB gene. The underlying genetic cause of the remaining 25% of individuals suffering from inherited hypercholesterolemia now appears to be partly resolved with the finding that proprotein convertase subtilisin/kexin 9, or PCSK9, likely plays an important role in cholesterol metabolism.
The question now is: does PCSK9 hold the same promise as apoB and the LDL receptor 15 and 30 years ago? Will the elucidation of the role of PCSK9 equally contribute to the improvement of diagnosis, risk estimation, and the development of new therapeutic targets in cardiovascular disease prevention? Unfortunately, the situation surrounding PCSK9 is, at minimal, conflicting and confusing. Let us review how this situation has arisen.
In 1999, a French group identified a locus on chromosome 1 that was linked to inherited hypercholesterolemia (7) and in May 2003, the same group pinpointed PCSK9 to chromosome 1p32 (8). PCSK9 is a protease whose precise function is not fully understood. It probably can activate or deactivate other proteins by proteolytic cleavage. The French group reported two mutations in the coding region of the PCSK9 gene that segregated with a hypercholesterolemic phenotype, in which the LDL receptor and the apoB genes were excluded as the cause of inherited hypercholesterolemia. These researchers also introduced the term autosomal-dominant hypercholesterolemia (ADH) to refer to the three genetically distinct forms of hypercholesterolemia that are inherited in an autosomal dominant fashion, but that are clinically undistinguishable: FH caused by mutations in the LDL-receptor gene, FDB caused by mutations in the apoB-gene, and FH3, caused by a, up to that time, unknown genes. Since the time that PCSK9 was reported as the putative third locus involved in ADH, several studies have been published, including the study by Chen et al. (9) in this issue of the Journal. These colleagues investigated the role of PCSK9 and the molecular variation in this gene in the metabolism of LDL-cholesterol (8,10–13). Regretfully, these recent studies have not been able to unequivocally confirm PCSK9 as the third gene causing ADH, and the reported results vary from definitely causative, e.g., Timms et al. (10) and Leren (11) to definitely not causative (14). The essential difference between the first report by Abifadel et al. (8) and the investigations that followed, lies in the fact that Abifadel et al. (8) identified a chromosomal segment on chromosome 1 that harbored the PCSK9 gene, plus 42 other known genes, whereas other researchers were focused directly onto the PCSK9 gene. The study by Abifadel et al. (8) does not rule out the possibility that the missense mutations that were identified in PCSK9 are in fact not the cause of ADH but that they might be in linkage disequilibrium with other genetic variants on the same chromosomal segment of 5.2 megabases. Such reasonable doubt is strengthened by the fact that functional assays of the effects of these mutations on PCSK9 function have not been performed so far. Nevertheless, PCSK9 has emerged as a candidate for the third ADH gene because a role for PCSK9 in cholesterol metabolism is evident.
Recent gene expression data obtained from hepatic tissue of cholesterol-fed mice have shown that PCSK9 expression is significantly down-regulated by dietary cholesterol (15). In agreement with these findings, up-regulation becomes evident when human liver cells are cholesterol depleted (13). Also, overexpression of PCSK9 in mice results in a similar phenotype as in mice lacking the LDL receptor (15). This severely elevated cholesterol phenotype is supposed to be the result of rapid degradation of the LDL receptor protein because overexpression of PCSK9 caused a 72% decrease in LDL receptor protein, whereas LDL receptor mRNA levels were in the normal range (16,17). This notion is further strengthened by the observation that overexpression of PCSK9 in LDL receptor-deficient mice does not result in additional elevation of cholesterol levels (15). Despite these solid data in animals, the mechanism by which genetic variants in PCSK9 affect LDL cholesterol levels in humans is still poorly understood. The obvious conflicting situation has now arisen insofar that high PCSK9 activity levels in mice result in elevated cholesterol levels, whereas in contrast in humans, reduced PCSK9 activity leads to an elevated cholesterol phenotype.
Therefore, novel attempts, such as the study by Chen et al. (9) in this issue of the Journal, to further clarify the role of PCSK9 in cholesterol metabolism have been eagerly awaited. In this study, several novel and known genetic variants in the PCSK9 gene were assessed. One variant, E670G, a substitution of glutamic acid by glycin at amino acid position 670, indeed explained as much as 3.5% of the variation in LDL cholesterol levels, confirming a role for PCSK9. Nevertheless, a gene dosage effect, which might have indicated a direct functional influence on enzyme activity in human lipoprotein metabolism, was not observed. Lipoprotein levels associated with wild type (EE) and the heterozygous (EG) form were essentially similar, and only the homozygous (GG) form was associated with elevated LDL cholesterol levels. However, these findings might have been the result of reduced power because of limited sample size. In view of the modest elevation of LDL cholesterol by the homozygous GG form, the clinical implications of these findings seem to be limited. The risk of coronary atherosclerosis only showed an upward trend in GG carriers and the response to cholesterol lowering treatment with fluvastatin was not influenced by presence or absence of the G variant. Therefore, the currently gathered knowledge does not seem to provide the final answer to the questions that have arisen since the implication of PCSK9 in hereditary defects in human lipoprotein metabolism. The study by Chen et al. (9) should be replicated in other populations, ideally with a large enough sample size to generate the definitive data. So far, a significant impact on cardiovascular risk or treatment of cardiovascular disease has not been part of the PCSK9 story.
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