PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis

ORIGINAL ARTICLE PCSK9 R46L Loss-of-Function Mutation Reduces Lipoprotein(a), LDL Cholesterol, and Risk of Aortic Valve Stenosis Anne Langsted, Børge G. Nordestgaard, Marianne Benn, Anne Tybjærg-Hansen, and Pia R. Kamstrup Department of Clinical Biochemistry (A.L., B.G.N., M.B., P.R.K.) and The Copenhagen General Population Study (A.L., B.G.N., M.B., A.T.-H., P.R.K.), Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark; The Copenhagen City Heart Study (B.G.N., M.B., A.T.-H.), Frederiksberg Hospital, Copenhagen University Hospital, Copenhagen, Denmark; Department of Clinical Biochemistry (A.T.-H.), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Faculty of Health and Medical Sciences (A.L., B.G.N., A.T.-H., P.R.K.), University of Copenhagen, Copenhagen, Denmark Context: Novel, low-density lipoprotein (LDL) cholesterol-lowering proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors also lower lipoprotein(a) levels, but the effect on aortic valve stenosis and myocardial infarction is unknown. Objective: We tested the hypothesis that the PCSK9 R46L loss-of-function mutation is associated with lower levels of lipoprotein(a) and with reduced risk of aortic valve stenosis and myocardial infarction. Design: We used two prospective cohort studies of the general population and one patient-based cohort. Setting: Cohort studies selected at random individuals of Danish descent. Participants: We studied 103 083 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease Study. Main outcome measures: Lipoprotein(a), LDL cholesterol, and PCSK9 R46L genotype and diagnoses of aortic valve stenosis and myocardial infarction from national registries; lipoprotein(a) was measured from 49,617 individuals. Results: Median(interquartilerange)lipoprotein(a)levelswere10(5–30)mg/dlforPCSK9R46Lnoncarriers, 9 (4–32) mg/dl for heterozygotes, and 8 (4–42) mg/dl for homozygotes (trend P ⫽ .02). The corresponding values for LDL cholesterol levels were 124 (101–147) mg/dl, 104 (85–132) mg/dl, and 97 (85–128) mg/dl, respectively(trendP⫽2⫻10⫺52).PCSK9R46Lcarriersvsnoncarriershadanage-andsex-adjustedoddsratio of 0.64 (95% confidence interval, 0.44–0.95) for aortic valve stenosis, 0.77 (0.65–0.92) for myocardial infarction, and 0.76 (0.64–0.89) for aortic valve stenosis or myocardial infarction. Conclusions: PCSK9 R46L carriers have lower levels of lipoprotein(a) and LDL cholesterol as well as reduced riskofaorticvalvestenosisandmyocardialinfarction.ThisindirectlysuggeststhatPCSK9inhibitorsmayhave a role in patients with aortic valve stenosis. (J Clin Endocrinol Metab 101: 3281–3287, 2016) levated lipoprotein(a) levels and elevated low-density lipoprotein (LDL) cholesterol levels are considered causal risk factors for coronary heart disease and aortic E valve stenosis. Genetic variants in the LPA gene, determining elevated lipoprotein(a) levels, are associated with increased risk of myocardial infarction (MI) and aortic ISSN Print 0021-972X ISSN Online 1945-7197 Printed in USA Copyright © 2016 by the Endocrine Society Received January 26, 2016. Accepted May 19, 2016. First Published Online May 24, 2016 Abbreviations: CGPS, Copenhagen General Population Study ; CI, confidence interval; ICD, International Classification of Diseases; KIV-2, Kringle IV type 2; LDL, low-density lipoprotein; MI, myocardial infarction; PCSK8, proprotein convertase subtilisin/kexin type-9. doi: 10.1210/jc.2016-1206 J Clin Endocrinol Metab, September 2016, 101(9):3281–3287 press.endocrine.org/journal/jcem 3281 3282 Langsted et al PCSK9 and Aortic Valve Stenosis valve stenosis (1–10). Lipoprotein(a) consists of an LDL particle with apolipoprotein B100 bound to apolipoprotein(a), a large glycoprotein that resembles plasminogen (7). The exact physiological role of lipoprotein(a) is still unknown, although it has been suggested to have a role in wound healing, in addition to having prothrombotic and/or proatherogenic effects at elevated levels. Proprotein convertase subtilisin/kexin type-9 (PCSK9) is a serine protease that promotes the degradation of the LDL receptor (11, 12). Gain-of-function mutations in PCSK9 result in increased levels of LDL cholesterol and increased risk of cardiovascular disease. Conversely, lossof-function mutations in PCSK9 are associated with less degradation of the LDL receptor, leading to increasing uptake of LDL cholesterol in hepatocytes and thereby to lower levels of LDL cholesterol in the circulation and to protection against cardiovascular disease. Specifically, the PCSK9 R46L loss-of-function mutation has been associated with lower levels of LDL cholesterol and with reduced risk of ischemic heart disease and MI (11, 13, 14). Findings from studies of PCSK9 mutations have spurred development of novel LDL cholesterol-lowering drugs in the form of PCSK9 inhibitors, recently demonstrated in phase II clinical trials to also cause a highly significant and unexpected dose-related reduction in lipoprotein(a) levels (15, 16). However, it is unknown whether treatment with PCSK9 inhibitors will result in reduced risk of aortic valve stenosis and MI. Because PCSK9 inhibitors lower both LDL and lipoprotein(a) and because there is a causal association between lipoprotein(a) and aortic valve stenosis and possibly also between LDL cholesterol and aortic valve stenosis (17), we tested the hypothesis that the PCSK9 R46L lossof-function mutation is associated with lower levels of lipoprotein(a) together with low LDL cholesterol and with reduced risk of aortic valve stenosis and MI. Materials and Methods We studied white individuals of Danish descent. Studies were approved by the Herlev and Gentofte Hospital and by Danish ethical committees and were conducted according to the Declaration of Helsinki with written informed consent from participants. The Copenhagen General Population Study The Copenhagen General Population Study (CGPS) is a prospective study of the general population initiated in 2003 with ongoing enrollment (18). Individuals living in counties near the greater Copenhagen area aged 20 –100 years were identified by the national Danish Civil Registration System, invited, and included if they were of Danish descent, which was defined as Danish citizens born in Denmark where both parents were like- J Clin Endocrinol Metab, September 2016, 101(9):3281–3287 wise Danish citizens and born in Denmark. Data collection included a questionnaire, a physical examination, and blood sampling for biochemical analyses and DNA extraction. We included 88 533 individuals from the CGPS; of these, 39 044 had measurements of both lipoprotein(a) and LDL cholesterol. The Copenhagen City Heart Study The Copenhagen City Heart Study is a prospective study of the general population initiated in 1976 –1978 with follow-up examinations in 1981–1983, 1991–1994, and 2001–2003 (18). Indivi (...truncated)