PCSK9 SNP rs11591147 is associated with low cholesterol levels but not with cognitive performance or noncardiovascular clinical events in an elderly population

Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a protein involved in LDL-cholesterol metabolism. The single-nucleotide polymorphism (SNP) rs11591147 has been associated with lower LDL-cholesterol and a lower risk of coronary heart disease. Because PCSK9 has high affinity to the LDL receptor, inhibiting PCSK9 is a testable therapeutic target for lipid-lowering therapy. Currently, several approaches to inhibit PCSK9 are under development, but it is unknown what the effects of those inhibitors will be on cognition or noncardiovascular clinical events. In this study, we assessed the association between rs11591147 and cognitive performance, activities of daily living (ADL), and noncardiovascular clinical events within 5,777 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Rs11591147 was associated with 10% to 16% lower LDL cholesterol levels (P = 3.62 × 10−12), but was not associated with cognitive performance, ADL, or noncardiovascular clinical events in the PROSPER study. Our findings suggest that lower cholesterol levels due to genetic variation in the PCSK9 gene are not associated with cognitive performance, functional status, or noncardiovascular clinical events. Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a protein involved in LDL-cholesterol metabolism. The single-nucleotide polymorphism (SNP) rs11591147 has been associated with lower LDL-cholesterol and a lower risk of coronary heart disease. Because PCSK9 has high affinity to the LDL receptor, inhibiting PCSK9 is a testable therapeutic target for lipid-lowering therapy. Currently, several approaches to inhibit PCSK9 are under development, but it is unknown what the effects of those inhibitors will be on cognition or noncardiovascular clinical events. In this study, we assessed the association between rs11591147 and cognitive performance, activities of daily living (ADL), and noncardiovascular clinical events within 5,777 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Rs11591147 was associated with 10% to 16% lower LDL cholesterol levels (P = 3.62 × 10−12), but was not associated with cognitive performance, ADL, or noncardiovascular clinical events in the PROSPER study. Our findings suggest that lower cholesterol levels due to genetic variation in the PCSK9 gene are not associated with cognitive performance, functional status, or noncardiovascular clinical events. Elevated plasma concentration of LDL-cholesterol is a major causal risk factor for cardiovascular disease. Lowering LDL-cholesterol levels is one of the primary goals of therapy in its prevention and treatment (1Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report.Circulation. 2002; 106: 3143-3421Crossref PubMed Scopus (207) Google Scholar). Present lipid-lowering therapy mainly depends on treatment with HMG-CoA reductase inhibitors (statins), but new lipid-lowering drugs are under development that can decrease circulating lipid levels even more (2Brautbar A. Ballantyne C.M. Pharmacological strategies for lowering LDL cholesterol: statins and beyond.Nat Rev Cardiol. 2011; 8: 253-265Crossref PubMed Scopus (79) Google Scholar). A promising new therapeutic target for lipid-lowering therapy is proprotein convertase subtilisin-like/kexin type 9 (PCSK9), a protein involved in LDL-cholesterol metabolism (3Cariou B. Le M.C. Costet P. Clinical aspects of PCSK9.Atherosclerosis. 2011; 216: 258-265Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 4Tibolla G. Norata G.D. Artali R. Meneghetti F. Catapano A.L. Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition.Nutr. Metab. Cardiovasc. Dis. 2011; 21: 835-843Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar, 5Lambert G. Krempf M. Costet P. PCSK9: a promising therapeutic target for dyslipidemias?.Trends Endocrinol. Metab. 2006; 17: 79-81Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). PCSK9 modulates plasma LDL-cholesterol levels by promoting the degradation of LDL receptors (LDLRs) (6Lakoski S.G. Lagace T.A. Cohen J.C. Horton J.D. Hobbs H.H. Genetic and metabolic determinants of plasma PCSK9 levels.J. Clin. Endocrinol. Metab. 2009; 94: 2537-2543Crossref PubMed Scopus (387) Google Scholar). Several “loss-of-function” and “gain-of-function” mutations have been described in the PCSK9 gene (4Tibolla G. Norata G.D. Artali R. Meneghetti F. Catapano A.L. Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition.Nutr. Metab. Cardiovasc. Dis. 2011; 21: 835-843Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Within the Atherosclerosis Risk in Communities study, “loss-of-function” mutations, for example rs11591147, were associated with lower LDL-cholesterol levels through increased LDLR levels, resulting in a lower prevalence of peripheral arterial disease and a reduced risk of coronary heart disease (7Cohen J.C. Boerwinkle E. Mosley Jr., T.H. Hobbs H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N. Engl. J. Med. 2006; 354: 1264-1272Crossref PubMed Scopus (2406) Google Scholar, 8Folsom A.R. Peacock J.M. Boerwinkle E. Variation in PCSK9, low LDL cholesterol, and risk of peripheral arterial disease.Atherosclerosis. 2009; 202: 211-215Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). A recent meta-analysis showed 12% lower LDL-cholesterol levels and 28% lower ischemic heart disease (IHD) risk among carriers of the rs11591147 mutation in the PCSK9 gene (9Benn M. Nordestgaard B.G. Grande P. Schnohr P. Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.J. Am. Coll. Cardiol. 2010; 55: 2833-2842Crossref PubMed Scopus (255) Google Scholar). On the other hand, PCSK9 may be involved in processes associated with neurodegenerative disorders like Alzheimer's disease. A Canadian study found a two-fold increased expression of the PCSK9 in the human frontal cortex of autopsy-confirmed Alzheimer's disease cases compared with age-matched controls (10Bélanger Jasmin, S., 2011. A putative role for PCSK9 in synaptic remodelling and plasticity in response to brain injury: implications for Alzheimer's disease. McGill University (http://digitool.library.mcgill.ca/webclient/StreamGate?folder_id=0&dvs=1352716244239∼284) 59–83Google Scholar). Furthermore, men carrying either the rs2483205-C, rs483462-A, or rs662145-T allele showed a significant increased risk for Alzheimer's disease. However, those single-nucleotide polymorphisms (SNPs) are not known to be associated with LDL-cholesterol levels or with cardiovascular disease risk. Several approaches to inhibit PCSK9 are currently under development, but it is not known whether those inhibitors will have influence on cognitive performance or clinical events. In old age, cholesterol levels are not associated with cognitive performance, and it has previously been shown, in the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), that pravastatin therapy in old age did not affect cognitive decline over a median follow-up of 3.2 years (11Trompet S. van Vliet P. de Craen A.J. Jolles J. Buckley B.M. Murphy M.B. Ford I. Macfarlane P.W. Sattar N. Packard C.J. et al.Pravastatin and cognitive function in the elderly. Results of the PROSPER study.J. Neurol. 2010; 257: 85-90Crossref PubMed Scopus (197) Google Scholar, 12van Vliet P van de Water W. de Craen A.J. Westendorp R.G. The influence of age on the association between cholesterol and cognitive function.Exp. Gerontol. 2009; 44: 112-122Crossref PubMed Scopus (60) Google Scholar). However, to investigate whether lipid lowering via PCSK9 inhibition might have other clinical effects in addition to lipid lowering, we assessed the relation between lower LDL levels associated with genetic variation within the PCSK9 SNP rs11591147 and cognitive function, activities of daily living (ADL), and noncardiovascular clinical events in an elderly population where these events occur frequently. All data come from the PROSPER study. Detailed descriptions of PROSPER have been published elsewhere (13Shepherd J. Blauw G.J. Murphy M.B. Cobbe S.M. Bollen E.L. Buckley B.M. Ford I. Jukema J.W. Hyland M. Gaw A. et al.The design of a prospective study of pravastatin in the elderly at risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.Am. J. Cardiol. 1999; 84: 1192-1197Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar, 14Shepherd J. Blauw G.J. Murphy M.B. Bollen E.L. Buckley B.M. Cobbe S.M. Ford I. Gaw A. Hyland M. Jukema J.W. et al.Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.Lancet. 2002; 360: 1623-1630Abstract Full Text Full Text PDF PubMed Scopus (2980) Google Scholar). Briefly, PROSPER was an investigator-driven, prospective multinational randomized placebo-controlled trial to assess whether treatment with pravastatin reduces the risk of major vascular events in the elderly. Between December 1997 and May 1999, subjects in Scotland (Glasgow), Ireland (Cork), and The Netherlands (Leiden) were screened and enrolled. Men and women aged 70–82 years were recruited if they had preexisting vascular disease or were at increased risk for such disease because of smoking, diabetes, or hypertension. A total of 5,804 subjects were randomly assigned to pravastatin or placebo. The protocol of the PROSPER study was approved by the medical ethics committees of each participating institution. Written informed consent was obtained from all participating subjects. Mean follow-up duration was 3.2 years (range 2.8–4.0), and participants were reviewed every 3 months. During those visits, all endpoints were adjudicated by a study Endpoint Committee. The primary outcome in PROSPER was the combined endpoint of definite or suspected death from coronary heart disease, nonfatal myocardial infarction, and fatal or nonfatal stroke. Furthermore several noncardiovascular clinical events were recorded. Cancer incidence was a tertiary study endpoint. Infections and diabetes were reported as serious adverse effects. Because the association between PCSK9 and cardiovascular events has been investigated previously in PROSPER, the focus in the present paper was on noncardiovascular events, functional status, and cognitive performance. The mini-mental state examination (MMSE) was used to measure global cognitive performance. The MMSE scores range from 0 (very severe cognitive impairment) to 30 points (optimal cognitive function). Participants with poor cognitive performance (MMSE <24) were not eligible for inclusion in the PROSPER study. Four neuropsychological performance tests were used to measure various cognitive domains. The Stroop color-word test for attention and the letter-digit coding test (LDT) for processing speed were used to measure executive function. The outcome parameter for the Stroop test was the total number of seconds to complete the third Stroop card containing 40 items. The outcome variable for the LDT was the total number of correct entries in 60 s. Memory was assessed with the 15-picture learning test testing immediate and delayed recall. The main outcome parameters were the accumulated number of recalled pictures over the three learning trials and the number of pictures recalled after 20 min. To assess change of functional status, the 20-point Barthel and instrumental activities of daily living (IADL) questionnaires, using a modified version of the OARS questionnaire, were performed. The Barthel index is a measure of basic ADL, and the IADL measures extended ADL. The reliability and sensitivity of these tests in an elderly population have been published elsewhere (15Houx P.J. Shepherd J. Blauw G.J. Murphy M.B. Ford I. Bollen E.L. Buckley B. Stott D.J. Jukema W. Hyland M. et al.Testing cognitive function in elderly populations: the PROSPER study. PROspective Study of Pravastatin in the Elderly at Risk.J. Neurol. Neurosurg. Psychiatry. 2002; 73: 385-389Crossref PubMed Scopus (124) Google Scholar). Cognitive performance and ADL were tested at six different time-points during the study: before randomization; at baseline; after 9, 18, and 30 months; and at the end of the study. The time-point of this last measurement was between 36 and 48 months and was different for the participants; therefore, we performed the analyses with their individually varying time-points but report the results for the mean of these time-points (42 months). The prerandomized measurement was discarded in the analysis to preclude possible learning effects. Rs11591147 of the PCSK9 gene was genotyped previously in PROSPER using Taq Man® SNP genotyping assay (Applied Biosystems; Foster City, CA). A detailed description of the genotyping has been published elsewhere (16Polisecki E. Peter I. M. Ford I. Packard Shepherd J. Jukema J.W. Blauw G.J. Westendorp R.G. et variation at the PCSK9 low-density lipoprotein cholesterol levels, but not lower vascular disease risk in an elderly Full Text Full Text PDF PubMed Scopus Google Scholar). Rs11591147 genotyping in 5,777 of the 5,804 PROSPER was on plasma by using the of et de P. J. M. E. A for in Full Text PDF PubMed Google Scholar). To assess the association between other PCSK9 and cholesterol levels, cognitive performance, and clinical events, we used data of the study of in the Elderly at risk a association study in the PROSPER participants S. de Craen A.J. I. Ford I. Sattar N. M. Stott D.J. Buckley B.M. F. et of LDL in as for Med. 2011; PubMed Scopus Google Scholar). The was using the the a were for To the of genetic data and of the to was performed with on the Detailed descriptions of the have been published elsewhere S. de Craen A.J. I. Ford I. Sattar N. M. Stott D.J. Buckley B.M. F. et of LDL in as for Med. 2011; PubMed Scopus Google Scholar). PCSK9 were from the using version S. B. J. P. de et a for association and J. 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I. Ford I. Sattar N. M. Stott D.J. Buckley B.M. F. et of LDL in as for Med. 2011; PubMed Scopus Google Scholar). and were associated with LDL-cholesterol levels P However, of these were associated with cognitive performance, functional status, or noncardiovascular clinical events we combined the PCSK9 were between the cholesterol levels, cognitive performance, functional status, or clinical events not In this study, we assessed the association between the PCSK9 SNP rs11591147, cognitive performance, functional and noncardiovascular clinical events in the PROSPER study. association between rs11591147 and cognitive performance, functional status, or clinical events was Because the SNP was associated with lower cholesterol and with cardiovascular disease protection (7Cohen J.C. Boerwinkle E. Mosley Jr., T.H. Hobbs H.H. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.N. Engl. J. Med. 2006; 354: 1264-1272Crossref PubMed Scopus (2406) Google Scholar, M. Nordestgaard B.G. Grande P. Schnohr P. Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.J. Am. Coll. Cardiol. 2010; 55: 2833-2842Crossref PubMed Scopus (255) Google Scholar, E. Peter I. M. Ford I. Packard Shepherd J. Jukema J.W. Blauw G.J. Westendorp R.G. et variation at the PCSK9 low-density lipoprotein cholesterol levels, but not lower vascular disease risk in an elderly Full Text Full Text PDF PubMed Scopus Google these data not that drugs inhibiting PCSK9 will have other effects. The association between the PCSK9 SNP rs11591147 and lipid levels and vascular disease risk has been investigated previously in PROSPER (16Polisecki E. Peter I. M. Ford I. Packard Shepherd J. Jukema J.W. Blauw G.J. Westendorp R.G. et variation at the PCSK9 low-density lipoprotein cholesterol levels, but not lower vascular disease risk in an elderly Full Text Full Text PDF PubMed Scopus Google Scholar). In this carriers of the of rs11591147 had 10% lower LDL-cholesterol levels (P lower LDL-cholesterol levels are in with the findings of a meta-analysis population studies with a total of carriers of the rs11591147 allele and (9Benn M. Nordestgaard B.G. Grande P. Schnohr P. Tybjaerg-Hansen A. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.J. Am. Coll. Cardiol. 2010; 55: 2833-2842Crossref PubMed Scopus (255) Google Scholar). In this rs11591147 was associated with 12% lower LDL-cholesterol levels in The reported a meta-analysis studies that investigated the risk of cases and subjects. The rs11591147 SNP was associated with a in risk of of 28% is the previously reported results in PROSPER where rs11591147 was associated with a reduced risk of vascular disease of The LDLR an role in cholesterol metabolism by the of lipoprotein from the blood (2Brautbar A. Ballantyne C.M. Pharmacological strategies for lowering LDL cholesterol: statins and beyond.Nat Rev Cardiol. 2011; 8: 253-265Crossref PubMed Scopus (79) Google Scholar). PCSK9 is involved in the cholesterol metabolism by promoting the degradation of LDLR (6Lakoski S.G. Lagace T.A. Cohen J.C. Horton J.D. Hobbs H.H. Genetic and metabolic determinants of plasma PCSK9 levels.J. Clin. Endocrinol. Metab. 2009; 94: 2537-2543Crossref PubMed Scopus (387) Google Scholar). are that cholesterol metabolism is associated with cognitive performance. total cholesterol levels have been to be associated with lower levels of and of in brain studies (11Trompet S. van Vliet P. de Craen A.J. Jolles J. Buckley B.M. Murphy M.B. Ford I. Macfarlane P.W. Sattar N. Packard C.J. et al.Pravastatin and cognitive function in the elderly. Results of the PROSPER study.J. Neurol. 2010; 257: 85-90Crossref PubMed Scopus (197) Google Scholar). The of PCSK9 in cholesterol metabolism the of whether PCSK9 is associated with cognitive function. A Canadian study investigated the relation between PCSK9 and Alzheimer's disease. In this study, variations in and were associated with an increased Alzheimer's disease risk (10Bélanger Jasmin, S., 2011. A putative role for PCSK9 in synaptic remodelling and plasticity in response to brain injury: implications for Alzheimer's disease. McGill University (http://digitool.library.mcgill.ca/webclient/StreamGate?folder_id=0&dvs=1352716244239∼284) 59–83Google Scholar). However, those are not known to be associated with cholesterol levels or in with one of associated with A study with Alzheimer's disease found association between the PCSK9 and and Alzheimer's disease N. S. M. R. A. A. et genetic association between PCSK9 polymorphisms and Alzheimer's disease and plasma cholesterol in PubMed Scopus Google Scholar). In study, rs11591147 was not associated with cognitive performance. Because PCSK9 has high affinity for the inhibiting PCSK9 might be a promising therapeutic target for lipid-lowering therapy in addition to therapy. Several approaches to inhibit PCSK9 are currently under development, but it is unknown what the of those inhibitors will be on cognitive function or noncardiovascular events (2Brautbar A. Ballantyne C.M. Pharmacological strategies for lowering LDL cholesterol: statins and beyond.Nat Rev Cardiol. 2011; 8: 253-265Crossref PubMed Scopus (79) Google Scholar). In study, rs11591147 associated with LDL-cholesterol levels did not affect cognitive performance, functional status, or noncardiovascular clinical events. On the of one may that drugs inhibiting PCSK9 J. R. R. R. R. of a to PCSK9, to low-density lipoprotein cholesterol in with on with or a randomised controlled trial.Lancet. Full Text Full Text PDF PubMed Scopus Google Scholar, J.M. D.J. and of a to proprotein convertase subtilisin/kexin type 9 in with primary Am. Coll. Cardiol. PubMed Scopus Google Scholar, P. R. F. B. S. S.M. et and of the a placebo-controlled study of the and of a of PCSK9 in subjects with on Cardiol. PubMed Scopus Google to an to the rs11591147 to a aged 70–82 years with a or increased risk of cardiovascular disease, are not to affect cognitive performance. that cholesterol lowering by PCSK9 inhibition may be a and to cardiovascular disease risk. However, because the inhibitors in development may LDL-cholesterol compared with the rs11591147 definite the adverse effects of cholesterol lowering due to PCSK9 inhibition be assessed by this study. of the of study is population have prospective data for over subjects on lipid cognitive function, and clinical we have a follow-up of months with to Furthermore, population is an study population to measure cognitive function, as subjects with a MMSE points were eligible for it a study for cognitive function. A possible of study is the to the PROSPER study is one of the studies to investigate the association between genetic variations and lipid levels, cognitive function, and clinical events, we not have to effects. we that it is that we have effects. possible is the of the ADL may have to significant between the PCSK9 mutation and ADL performance. However, analyses of the have that the PROSPER study is for genetic on cognition and ADL C.J. Westendorp R.G. Stott D.J. Shepherd J. Blauw G.J. Murphy M.B. Bollen E.L. Buckley B.M. et between and cognitive decline in elderly Am. 55: PubMed Scopus Google Scholar). A last possible is the of the PROSPER Participants were recruited they had vascular disease or increased risk of such disease (13Shepherd J. Blauw G.J. Murphy M.B. Cobbe S.M. Bollen E.L. Buckley B.M. Ford I. Jukema J.W. Hyland M. Gaw A. et al.The design of a prospective study of pravastatin in the elderly at risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.Am. J. Cardiol. 1999; 84: 1192-1197Abstract Full Text Full Text PDF PubMed Scopus (257) Google Scholar). to the mutation not to low LDL-cholesterol but for cardiovascular disease may have been in study. In it has previously been that the PCSK9 SNP rs11591147 is associated with lower LDL-cholesterol levels and lower cardiovascular risk. In study, we to between the and cognitive The of is that it is that lowering LDL-cholesterol via inhibiting PCSK9 to an to the of the mutation in study population will affect cognitive performance, functional status, or noncardiovascular clinical events. was performed as of an of the PROSPER study in the of and with activities of daily living association study instrumental activities of daily living ischemic heart disease LDL letter-digit coding test mini-mental state examination proprotein convertase subtilisin-like/kexin type 9 study of in the Elderly at risk PROspective Study of Pravastatin in the Elderly at Risk single-nucleotide polymorphism

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