- Email: [email protected]
Plasma HDL cholesterol and risk of myocardial infarction
Correspondence
developed the concept of dysfunction of apoA-1 and HDL particles in a milieu of enhanced low-grade inflammation in the population at large.3 We also underlined that a large systematic review of randomised trials4 disclosed a lack of association between treatment-induced change in HDL cholesterol and risk ratios for cardiovascular disease morbidity and mortality, when changes in LDL cholesterol were adjusted for. Evidence is further beginning to emerge that the antioxidant and atheroprotective functions of apoA-1, the major protein constituent of HDL particles, become impaired in the process of autoimmune activation. Such impairment could be linked to excess circulating lipoprotein(a) and its oxidised phospholipids, and could represent a common denominator underlying various different chronic diseases.5 Thus it is time to recognise that the clinical significance of HDL cholesterol concentrations in the general population is markedly heterogeneous, and high concentrations do not necessarily imply reduced cardiometabolic risk. I declare that I have no conflicts of interest.
Altan Onat [email protected]
We declare that we have no conflicts of interest.
Nisbetiye cad. 59/24, Etiler 34335, Istanbul, Turkey
*Carlo Vergani, Tiziano Lucchi
1
[email protected]
2
3
4
5
1990
Population-based studies have shown that a low serum concentration of HDL cholesterol is a risk factor for cardiovascular disease.1 An isolated low HDL cholesterol concentration has also been shown to be strongly predictive of coronary heart disease.2 However, Benjamin Voight and colleagues3 report that raised HDL cholesterol caused by a single nucleotide polymorphism (SNP) in the endothelial lipase gene does not reduce the risk of myocardial infarction. On the basis of this finding, they suggest that raised HDL cholesterol does not correlate ipso facto with clinical benefit. We believe that within such a complex scenario, a key factor to be considered is the specific composition of lipoprotein particles. Individuals who are homozygous for the I405V polymorphism (VV genotype) in the cholesteryl ester transfer protein have less atherosclerosis and exceptional longevity.4 Indeed, this SNP is characterised not only by increased HDL cholesterol concentrations, but also by an increased size of HDL and LDL particles.5 Thus, when investigating the association between HDL cholesterol concentrations and cardiovascular disease, the composition and function of lipoproteins cannot be disregarded.
Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Onat A, Can G, Ayhan E, Kaya Z, Hergenç G. Impaired protection against diabetes and coronary disease by high-density lipoproteins in Turks. Metabolism 2009; 58: 1393–99. Onat A, Hergenç G. Low-grade inflammation and dysfunction of high-density lipoprotein and its apolipoproteins as a major driver of cardiometabolic risk. Metabolism 2011; 60: 499–512. Briel M, Ferreira-Gonzales I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009; 338: b92. Onat A, Direskeneli H. Excess cardiovascular risk in inflammatory rheumatic diseases: pathophysiology and targeted therapy. Curr Pharmaceut Des 2012; 18: 1465–77.
Università degli Studi di Milano, 20122 Milan, Italy (CV); and Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (TL) 1
2
3
4
Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA 1986; 256: 2835–38. Ordovas JM, Schaefer EJ, Salem D, et al. Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia. N Engl J Med 1986; 314: 671–77. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Vergani C, Lucchi T, Caloni M, et al. I405V polymorphism of the cholesteryl ester transfer protein (CETP) gene in young and very old people. Arch Gerontol Geriatr 2006; 43: 213–21.
5
Thompson A, Di Angelantonio E, Sarwar N, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA 2008; 299: 2777–88.
Benjamin Voight and colleagues1 found that genetically increased concentrations of HDL cholesterol in plasma do not lower the risk of myocardial infarction, putting into doubt the causal role of HDL cholesterol2 and the potential benefit of interventions to increase it. Their findings seem to contradict those from large long-term prospective studies.3 Like in other Mendelian randomisation studies, the lack of an effect of a genetically increased HDL cholesterol concentration in their study is likely to be a consequence of the weakness and uncertainty of the effect of the Asn396Ser mutation in the endothelial lipase gene (LIPG) on HDL cholesterol.4 Although the instrumental variable odds ratio (table 31) is supposedly unbiased, it does not provide a conclusive picture of the role of HDL cholesterol, since its 95% CI indicates that a genetically induced increase in HDL cholesterol of 0·39 mmol/L could decrease the risk of myocardial infarction by 54% or increase it by 261%. Moreover, values compatible with an unbiased phenotype-disease odds ratio obtained by simulation5 of the distribution of the observational odds ratio (0·70, 95% CI 0·66–0·74) and the instrumental variable odds ratio (1·28, 0·46–3·61) from table 3 ranged from 0·45 to 3·55, reflecting the large uncertainty and the limited value of the instrumental variable odds ratio to assess bias in the observed odds ratio. This uncertainty might be surprising, considering the large sample size of the study. However, simulations4 based on the size of the LIPG Asn396Ser effect on HDL cholesterol (0·29 SD) show that the study had only a 5% chance of detecting a bias of ±20% in the observed odds ratio if there was no actual bias. The results www.thelancet.com Vol 380 December 8, 2012
Correspondence
I declare that I have no conflicts of interest.
Leonelo E Bautista [email protected] Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA 1
2
3
4
5
Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Harrison SC, Holmes MV, Humphries SE. Mendelian randomisation, lipids, and cardiovascular disease. Lancet 2012; 380: 543–45. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302: 1993–2000. Thompson JR, Tobin MD, Minelli C. On the accuracy of estimates of the effect of phenotype on disease derived from Mendelian randomisation studies. Technical Report 2003/ GE1. Leicester: University of Leicester, 2003. http://www2.le.ac.uk/departments/healthsciences/research/gen-epi/reports (accessed Nov 19, 2012). Bautista LE, Smeeth L, Hingorani AD, Casas JP. Estimation of bias in nongenetic observational studies using “Mendelian triangulation”. Ann Epidemiol 2006; 16: 675–80.
Authors’ reply In countless observational epidemiological studies, a higher concentration of HDL cholesterol in plasma has been associated with a lower risk of coronary heart disease (CHD).1 However, the correlation of two variables in a population does not imply that one causes the other. Definition of causal factors in human beings is challenging, but naturally occurring genetic variation and pharmacological intervention studies represent two approaches to it. In our paper,2 we asked whether those who carry HDL-cholesterolboosting gene variants are protected from risk of myocardial infarction. To our surprise, we found that those who carried HDL-cholesterolboosting variants had the same risk of myocardial infarction as those who did not carry these variants. We appreciate Altan Onat’s highlighting earlier work questioning the conventional wisdom that high HDL cholesterol protects against CHD. www.thelancet.com Vol 380 December 8, 2012
Carlo Vergani and Tiziano Lucchi wonder whether the HDL cholesterol phenotype does not capture the complexity of HDL and whether we should pay more attention to aspects of HDL function and composition. Several functions have been assigned to HDL, and the composition of HDL has been studied with a range of methods. We agree that further research is needed to establish which of these more refined HDL phenotypes, if any, has an effect on CHD. Leonelo Bautista wonders whether we had sufficient power to exclude a protective effect for the LIPG Asn396Ser variant. In instrumental variable analysis with LIPG Asn396Ser, there is indeed overlap in the 95% CIs of the effect estimates from observational epidemiology and that from the genetic instrument. To overcome this potential limitation, we assessed multiple genetic variants in combination as an instrument (table 4 in our original report2). In this analysis, there was no overlap in the CIs for the effect estimates from observational epidemiology (0·62, 95% CI 0·58–0·66) and from a genetic score (0·93, 0·68–1·26; p=0·63). A single HDL-cholesterol-raising polymorphism (LIPG Asn396Ser), a genetic risk score comprised of 14 HDL-cholesterolraising polymorphisms, and a drug that purely raised HDL cholesterol all fail to reduce risk of myocardial infarction or CHD.3–5 We disagree with Bautista’s assertion that little has been added to our “current knowledge about the role of HDL cholesterol” and instead suggest that a great deal of evidence now questions whether the association between plasma HDL cholesterol and CHD represents a causal relation. We declare that we have no conflicts of interest.
Benjamin F Voight, *Sekar Kathiresan [email protected] Cardiovascular Disease Prevention Center, Massachusetts General Hospital, Boston, MA 02114, USA 1
Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302: 1993–2000.
2
3
4
5
Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009; 158: 896–901. Kathiresan S. Will cholesteryl ester transfer protein inhibition succeed primarily by lowering low-density lipoprotein cholesterol?: insights from human genetics and clinical trials. J Am Coll Cardiol 2012; 60: 2049–52. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; published online Nov 5. http://dx.doi.org/ 10.1056/NEJMoa120679.
Science Photo Library
of this study therefore add little to our current knowledge about the role of HDL cholesterol.
My turn and my right In his essay “Not my turn” (Sept 15, p 968),1 Arthur Caplan finds a bioethical conundrum in a not uncommon type of clinical ethical issue. An 88-year-old widower who has become heavily dependent on hospital nursing care after an extensive stroke develops pressure sores despite good nursing care. He now refuses to be turned in bed because it is painful, despite the capacious knowledge that it means he will die of septicaemia. As a result he requires more resourceintensive nursing care, provokes controversy among his carers, and has a deleterious effect on the quality of life of a fellow patient. Caplan uses this example to question the pre-eminence of informed autonomy of competent patients to refuse treatment. The ethicist Daniel Sokol2 describes bioethics as being dominated by philosophy, which inclines towards abstraction, as exhibiting bullying tendencies, and as treating clinicians as an ethically deficient species. Informed patient autonomy is a cornerstone of medical ethics, and more importantly of the fundamental international human right to the highest attainable standard of health ratified by four in every five countries worldwide.3 This patient should have been referred urgently to a palliativecare physician for transfer to a hospice for intensive symptom control, and, 1991
developed the concept of dysfunction of apoA-1 and HDL particles in a milieu of enhanced low-grade inflammation in the population at large.3 We also underlined that a large systematic review of randomised trials4 disclosed a lack of association between treatment-induced change in HDL cholesterol and risk ratios for cardiovascular disease morbidity and mortality, when changes in LDL cholesterol were adjusted for. Evidence is further beginning to emerge that the antioxidant and atheroprotective functions of apoA-1, the major protein constituent of HDL particles, become impaired in the process of autoimmune activation. Such impairment could be linked to excess circulating lipoprotein(a) and its oxidised phospholipids, and could represent a common denominator underlying various different chronic diseases.5 Thus it is time to recognise that the clinical significance of HDL cholesterol concentrations in the general population is markedly heterogeneous, and high concentrations do not necessarily imply reduced cardiometabolic risk. I declare that I have no conflicts of interest.
Altan Onat [email protected]
We declare that we have no conflicts of interest.
Nisbetiye cad. 59/24, Etiler 34335, Istanbul, Turkey
*Carlo Vergani, Tiziano Lucchi
1
[email protected]
2
3
4
5
1990
Population-based studies have shown that a low serum concentration of HDL cholesterol is a risk factor for cardiovascular disease.1 An isolated low HDL cholesterol concentration has also been shown to be strongly predictive of coronary heart disease.2 However, Benjamin Voight and colleagues3 report that raised HDL cholesterol caused by a single nucleotide polymorphism (SNP) in the endothelial lipase gene does not reduce the risk of myocardial infarction. On the basis of this finding, they suggest that raised HDL cholesterol does not correlate ipso facto with clinical benefit. We believe that within such a complex scenario, a key factor to be considered is the specific composition of lipoprotein particles. Individuals who are homozygous for the I405V polymorphism (VV genotype) in the cholesteryl ester transfer protein have less atherosclerosis and exceptional longevity.4 Indeed, this SNP is characterised not only by increased HDL cholesterol concentrations, but also by an increased size of HDL and LDL particles.5 Thus, when investigating the association between HDL cholesterol concentrations and cardiovascular disease, the composition and function of lipoproteins cannot be disregarded.
Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Onat A, Can G, Ayhan E, Kaya Z, Hergenç G. Impaired protection against diabetes and coronary disease by high-density lipoproteins in Turks. Metabolism 2009; 58: 1393–99. Onat A, Hergenç G. Low-grade inflammation and dysfunction of high-density lipoprotein and its apolipoproteins as a major driver of cardiometabolic risk. Metabolism 2011; 60: 499–512. Briel M, Ferreira-Gonzales I, You JJ, et al. Association between change in high density lipoprotein cholesterol and cardiovascular disease morbidity and mortality: systematic review and meta-regression analysis. BMJ 2009; 338: b92. Onat A, Direskeneli H. Excess cardiovascular risk in inflammatory rheumatic diseases: pathophysiology and targeted therapy. Curr Pharmaceut Des 2012; 18: 1465–77.
Università degli Studi di Milano, 20122 Milan, Italy (CV); and Fondazione Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy (TL) 1
2
3
4
Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. JAMA 1986; 256: 2835–38. Ordovas JM, Schaefer EJ, Salem D, et al. Apolipoprotein A-I gene polymorphism associated with premature coronary artery disease and familial hypoalphalipoproteinemia. N Engl J Med 1986; 314: 671–77. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Vergani C, Lucchi T, Caloni M, et al. I405V polymorphism of the cholesteryl ester transfer protein (CETP) gene in young and very old people. Arch Gerontol Geriatr 2006; 43: 213–21.
5
Thompson A, Di Angelantonio E, Sarwar N, et al. Association of cholesteryl ester transfer protein genotypes with CETP mass and activity, lipid levels, and coronary risk. JAMA 2008; 299: 2777–88.
Benjamin Voight and colleagues1 found that genetically increased concentrations of HDL cholesterol in plasma do not lower the risk of myocardial infarction, putting into doubt the causal role of HDL cholesterol2 and the potential benefit of interventions to increase it. Their findings seem to contradict those from large long-term prospective studies.3 Like in other Mendelian randomisation studies, the lack of an effect of a genetically increased HDL cholesterol concentration in their study is likely to be a consequence of the weakness and uncertainty of the effect of the Asn396Ser mutation in the endothelial lipase gene (LIPG) on HDL cholesterol.4 Although the instrumental variable odds ratio (table 31) is supposedly unbiased, it does not provide a conclusive picture of the role of HDL cholesterol, since its 95% CI indicates that a genetically induced increase in HDL cholesterol of 0·39 mmol/L could decrease the risk of myocardial infarction by 54% or increase it by 261%. Moreover, values compatible with an unbiased phenotype-disease odds ratio obtained by simulation5 of the distribution of the observational odds ratio (0·70, 95% CI 0·66–0·74) and the instrumental variable odds ratio (1·28, 0·46–3·61) from table 3 ranged from 0·45 to 3·55, reflecting the large uncertainty and the limited value of the instrumental variable odds ratio to assess bias in the observed odds ratio. This uncertainty might be surprising, considering the large sample size of the study. However, simulations4 based on the size of the LIPG Asn396Ser effect on HDL cholesterol (0·29 SD) show that the study had only a 5% chance of detecting a bias of ±20% in the observed odds ratio if there was no actual bias. The results www.thelancet.com Vol 380 December 8, 2012
Correspondence
I declare that I have no conflicts of interest.
Leonelo E Bautista [email protected] Department of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726, USA 1
2
3
4
5
Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Harrison SC, Holmes MV, Humphries SE. Mendelian randomisation, lipids, and cardiovascular disease. Lancet 2012; 380: 543–45. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302: 1993–2000. Thompson JR, Tobin MD, Minelli C. On the accuracy of estimates of the effect of phenotype on disease derived from Mendelian randomisation studies. Technical Report 2003/ GE1. Leicester: University of Leicester, 2003. http://www2.le.ac.uk/departments/healthsciences/research/gen-epi/reports (accessed Nov 19, 2012). Bautista LE, Smeeth L, Hingorani AD, Casas JP. Estimation of bias in nongenetic observational studies using “Mendelian triangulation”. Ann Epidemiol 2006; 16: 675–80.
Authors’ reply In countless observational epidemiological studies, a higher concentration of HDL cholesterol in plasma has been associated with a lower risk of coronary heart disease (CHD).1 However, the correlation of two variables in a population does not imply that one causes the other. Definition of causal factors in human beings is challenging, but naturally occurring genetic variation and pharmacological intervention studies represent two approaches to it. In our paper,2 we asked whether those who carry HDL-cholesterolboosting gene variants are protected from risk of myocardial infarction. To our surprise, we found that those who carried HDL-cholesterolboosting variants had the same risk of myocardial infarction as those who did not carry these variants. We appreciate Altan Onat’s highlighting earlier work questioning the conventional wisdom that high HDL cholesterol protects against CHD. www.thelancet.com Vol 380 December 8, 2012
Carlo Vergani and Tiziano Lucchi wonder whether the HDL cholesterol phenotype does not capture the complexity of HDL and whether we should pay more attention to aspects of HDL function and composition. Several functions have been assigned to HDL, and the composition of HDL has been studied with a range of methods. We agree that further research is needed to establish which of these more refined HDL phenotypes, if any, has an effect on CHD. Leonelo Bautista wonders whether we had sufficient power to exclude a protective effect for the LIPG Asn396Ser variant. In instrumental variable analysis with LIPG Asn396Ser, there is indeed overlap in the 95% CIs of the effect estimates from observational epidemiology and that from the genetic instrument. To overcome this potential limitation, we assessed multiple genetic variants in combination as an instrument (table 4 in our original report2). In this analysis, there was no overlap in the CIs for the effect estimates from observational epidemiology (0·62, 95% CI 0·58–0·66) and from a genetic score (0·93, 0·68–1·26; p=0·63). A single HDL-cholesterol-raising polymorphism (LIPG Asn396Ser), a genetic risk score comprised of 14 HDL-cholesterolraising polymorphisms, and a drug that purely raised HDL cholesterol all fail to reduce risk of myocardial infarction or CHD.3–5 We disagree with Bautista’s assertion that little has been added to our “current knowledge about the role of HDL cholesterol” and instead suggest that a great deal of evidence now questions whether the association between plasma HDL cholesterol and CHD represents a causal relation. We declare that we have no conflicts of interest.
Benjamin F Voight, *Sekar Kathiresan [email protected] Cardiovascular Disease Prevention Center, Massachusetts General Hospital, Boston, MA 02114, USA 1
Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009; 302: 1993–2000.
2
3
4
5
Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572–80. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009; 158: 896–901. Kathiresan S. Will cholesteryl ester transfer protein inhibition succeed primarily by lowering low-density lipoprotein cholesterol?: insights from human genetics and clinical trials. J Am Coll Cardiol 2012; 60: 2049–52. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012; published online Nov 5. http://dx.doi.org/ 10.1056/NEJMoa120679.
Science Photo Library
of this study therefore add little to our current knowledge about the role of HDL cholesterol.
My turn and my right In his essay “Not my turn” (Sept 15, p 968),1 Arthur Caplan finds a bioethical conundrum in a not uncommon type of clinical ethical issue. An 88-year-old widower who has become heavily dependent on hospital nursing care after an extensive stroke develops pressure sores despite good nursing care. He now refuses to be turned in bed because it is painful, despite the capacious knowledge that it means he will die of septicaemia. As a result he requires more resourceintensive nursing care, provokes controversy among his carers, and has a deleterious effect on the quality of life of a fellow patient. Caplan uses this example to question the pre-eminence of informed autonomy of competent patients to refuse treatment. The ethicist Daniel Sokol2 describes bioethics as being dominated by philosophy, which inclines towards abstraction, as exhibiting bullying tendencies, and as treating clinicians as an ethically deficient species. Informed patient autonomy is a cornerstone of medical ethics, and more importantly of the fundamental international human right to the highest attainable standard of health ratified by four in every five countries worldwide.3 This patient should have been referred urgently to a palliativecare physician for transfer to a hospice for intensive symptom control, and, 1991