Author + information
- Anette Varbo, MD†,‡,§,
- Marianne Benn, MD, PhD, DMSc‡,§,‖,
- Anne Tybjærg-Hansen, MD, DMSc‡,§,¶,#,
- Anders B. Jørgensen, MD‡,§,#,
- Ruth Frikke-Schmidt, MD, PhD, DMSc‡,§,# and
- Børge G. Nordestgaard, MD, DMSc†,‡,§,¶∗ ()
- †Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- ‡The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- §Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- ‖Department of Clinical Biochemistry, Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- ¶The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
- #Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark
- ↵∗Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark
We thank Würtz and colleagues for their positive comments on our recent paper (1) on remnant cholesterol (remnant-C) as a causal risk factor for ischemic heart disease. We naturally agree that lipoprotein metabolism is very complex, with many subclasses of lipoproteins and different lipid contents of these subclasses, making it difficult, if not impossible, to find genetic instruments completely without pleiotropic effects on the other lipoprotein subclasses. The various lipoprotein subclasses derived from the endogenous pathway are a continuum from large very-low-density lipoproteins excreted from the liver, which are then degraded into intermediate-density lipoproteins by lipolysis and exchange of lipids and apolipoproteins in plasma, which are then degraded further into low-density lipoproteins. The differentiation into these specific subclasses is somewhat arbitrarily defined from the early ultracentrifugation studies (2). Therefore, it seems unlikely that there are genetic variants that exclusively affect levels of just 1 lipoprotein subclass. In our study (1), we used combinations of genetic variants to minimize pleiotropy but of course did not completely avoid it; this limitation was also discussed in our paper and nicely demonstrated by Würtz and colleagues in their letter. Although the allele score of TRIB1 (tribbles homolog-1), GCKR (glucokinase regulatory protein), and APOA5 (apolipoprotein A-V) genetic variants used in our study as an instrument for nonfasting remnant-C alone also had small effects on the cholesterol content in the other lipoprotein subclasses, it was clearly associated with a much larger effect on nonfasting remnant-C levels as demonstrated in our Figure 4. This finding makes it unlikely that our results should be explained by pleiotropic effects only.
Würtz and colleagues have performed an elegant lipoprotein subclass profiling study by using nuclear magnetic resonance (NMR) spectroscopy in 10,547 fasting samples from young adults from the general population of Finland. This method is undoubtedly more detailed in differentiating between subclasses of lipoproteins and their lipid content than our simple calculation of nonfasting remnant-C as nonfasting total cholesterol minus low-density lipoprotein cholesterol minus high-density lipoprotein cholesterol; however, it is exactly the simplicity of our calculation that makes it clinically useful. Clinicians anywhere can use our method to estimate levels of nonfasting remnant-C in patients if they have measured a standard nonfasting lipid profile and, importantly, at no extra cost; lipoprotein subclass profiling with NMR spectroscopy, even though it is very informative, is not suitable for clinical purposes, because of the expenses and requirements of very specialized equipment, and not least because of the complicated interpretation of the results.
In our study (1), we included adults aged 20 to >100 years who were nonfasting at the time of blood sampling. This segment of the population has a broader range and is closer to the everyday state of the entire population (including with respect to other risk factors for ischemic heart disease) than the fasting adolescent and young adult segment examined by Würtz and colleagues; this choice of patient population may have influenced the generalizability of their results. Thus, although they demonstrated pleiotropy of the genetic instruments used by us, they probably did not illustrate the entire variation of lipoprotein subclass profiles as a function of these genetic variants. It is entirely possible that even more pleiotropy could be detected if samples taken at different times after a meal were analyzed, and if, for example, samples were analyzed separately for men and women, young and old. Even more complications can be added if one also considers the influence of remnant-C on other processes likely in the biological pathway; these include from elevated remnant-C to atherosclerosis to ischemic heart disease (i.e., as with inflammation caused by elevated remnant-C and not by elevated low-density lipoprotein cholesterol) (3).
After lowering of low-density lipoprotein cholesterol to recommended levels, there is still a substantial residual risk of ischemic heart disease. Some of this risk is probably explained by elevated levels of cholesterol in the other lipoprotein subclasses than low-density lipoprotein (i.e., remnant-C levels). It is therefore important that clinicians acknowledge and intervene on these other lipid risk factors in addition to low-density lipoprotein cholesterol, and our simple way of estimating levels of nonfasting remnant-C makes this possible.
Please note: The original study was supported by The Danish Medical Research Council, The Danish Heart Foundation, Herlev Hospital, Copenhagen University Hospital, Copenhagen County Foundation, and Chief Physician Johan Boserup and Lise Boserup's Fund, Denmark. Dr. Nordestgaard has received lecture and/or consultancy honoraria from AstraZenecca, Merck, Pfizer, Karo Bio, Omthera, Abbott, Sanofi-Aventis, Regeneron, and ISIS Pharmaceuticals All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- Varbo A.,
- Benn M.,
- Tybjærg-Hansen A.,
- et al.
- Varbo A.,
- Benn M.,
- Tybjærg-Hansen A.,
- Nordestgaard B.G.