Variation in Serum PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9), Cardiovascular Disease Risk, and an Investigation of Potential Unanticipated Effects of PCSK9 Inhibition
2019; Wolters Kluwer; Volume: 12; Issue: 1 Linguagem: Inglês
10.1161/circgen.118.002335
ISSN2574-8300
AutoresBen Brumpton, Lars G. Fritsche, Jie Zheng, Jonas B. Nielsen, Maria Mannila, Ida Surakka, Humaira Rasheed, Gunnhild Åberge Vie, Sarah E. Graham, Maiken E. Gabrielsen, Lars Erik Laugsand, Pål Aukrust, Lars J. Vatten, Jan Kristian Damås, Thor Ueland, Imre Janszky, John‐Anker Zwart, Ferdinand M. van’t Hooft, Nabil G. Seidah, Kristian Hveem, Cristen J. Willer, George Davey Smith, Bjørn Olav Åsvold,
Tópico(s)Atherosclerosis and Cardiovascular Diseases
ResumoHomeCirculation: Genomic and Precision MedicineVol. 12, No. 1Variation in Serum PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9), Cardiovascular Disease Risk, and an Investigation of Potential Unanticipated Effects of PCSK9 Inhibition Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBVariation in Serum PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9), Cardiovascular Disease Risk, and an Investigation of Potential Unanticipated Effects of PCSK9 InhibitionA Genome-Wide Association Study and Mendelian Randomization Study in the HUNT, Norway Ben M. Brumpton, PhD, Lars G. Fritsche, PhD, Jie Zheng, PhD, Jonas Bille Nielsen, MD, PhD, Maria Mannila, MD, PhD, Ida Surakka, PhD, Humaira Rasheed, PhD, Gunnhild Åberge Vie, MD, PhD, Sarah E. Graham, PhD, Maiken Elvestad Gabrielsen, PhD, Lars Erik Laugsand, MD, PhD, Pål Aukrust, MD, PhD, Lars Johan Vatten, MD, PhD, Jan Kristian Damås, MD, PhD, Thor Ueland, PhD, Imre Janszky, MD, PhD, John-Anker Zwart, MD, PhD, Ferdinand M. van't Hooft, MD, PhD, Nabil Georges Seidah, PhD, Kristian Hveem, MD, PhD, Cristen Willer, PhD, George Davey Smith, MD, DSc, Bjørn Olav Åsvold, MD, PhD and INVENT Consortium Ben M. BrumptonBen M. Brumpton Ben M. Brumpton, PhD, Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Postbox 8905, MTFS, NO-7491 Trondheim, Norway. Email E-mail Address: [email protected] Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology (B.M.B., L.G.F., H.R., G.Å.V., M.E.G., K.H., B.O.Å.), NTNU, Norwegian University of Science and Technology, Trondheim. MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom (B.M.B., J.Z., H.R., G.D.S.). Clinic of Thoracic and Occupational Medicine (B.M.B.), St. Olavs Hospital, Trondheim University Hospital, Norway. , Lars G. FritscheLars G. Fritsche Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology (B.M.B., L.G.F., H.R., G.Å.V., M.E.G., K.H., B.O.Å.), NTNU, Norwegian University of Science and Technology, Trondheim. Department of Biostatistics and Center for Statistical Genetics (L.G.F., C.W.), University of Michigan, Ann Arbor, MI. , Jie ZhengJie Zheng MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom (B.M.B., J.Z., H.R., G.D.S.). , Jonas Bille NielsenJonas Bille Nielsen Department of Internal Medicine (J.B.N., I.S., S.E.G., C.W.), University of Michigan, Ann Arbor, MI. , Maria MannilaMaria Mannila Cardiology Unit (M.M.), Karolinska Institutet, Stockholm, Sweden. Cardiovascular Medicine Unit, Department of Medicine Solna, Center for Molecular Medicine (M.M., F.M.v.H.), Karolinska Institutet, Stockholm, Sweden. , Ida SurakkaIda Surakka Department of Internal Medicine (J.B.N., I.S., S.E.G., C.W.), University of Michigan, Ann Arbor, MI. , Humaira RasheedHumaira Rasheed Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology (B.M.B., L.G.F., H.R., G.Å.V., M.E.G., K.H., B.O.Å.), NTNU, Norwegian University of Science and Technology, Trondheim. MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom (B.M.B., J.Z., H.R., G.D.S.). , Gunnhild Åberge VieGunnhild Åberge Vie Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology (B.M.B., L.G.F., H.R., G.Å.V., M.E.G., K.H., B.O.Å.), NTNU, Norwegian University of Science and Technology, Trondheim. Department of Public Health and Nursing (G.Å.V., L.E.L., L.J.V., I.J.), NTNU, Norwegian University of Science and Technology, Trondheim. , Sarah E. GrahamSarah E. Graham Department of Internal Medicine (J.B.N., I.S., S.E.G., C.W.), University of Michigan, Ann Arbor, MI. , Maiken Elvestad GabrielsenMaiken Elvestad Gabrielsen Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology (B.M.B., L.G.F., H.R., G.Å.V., M.E.G., K.H., B.O.Å.), NTNU, Norwegian University of Science and Technology, Trondheim. , Lars Erik LaugsandLars Erik Laugsand Department of Public Health and Nursing (G.Å.V., L.E.L., L.J.V., I.J.), NTNU, Norwegian University of Science and Technology, Trondheim. Department of Circulation and Medical Imaging (L.E.L.), NTNU, Norwegian University of Science and Technology, Trondheim. Department of Cardiology (L.E.L.), St. Olavs Hospital, Trondheim University Hospital, Norway. , Pål AukrustPål Aukrust Research Institute of Internal Medicine (P.A., T.U.), Oslo University Hospital, Rikshospitalet. Section of Clinical Immunology and Infectious Diseases (P.A.), Oslo University Hospital, Rikshospitalet. Institute of Clinical Medicine (P.A.), University of Oslo, Norway. , Lars Johan VattenLars Johan Vatten Department of Public Health and Nursing (G.Å.V., L.E.L., L.J.V., I.J.), NTNU, Norwegian University of Science and Technology, Trondheim. , Jan Kristian DamåsJan Kristian Damås Department of Clinical and Molecular Medicine, Centre of Molecular Inflammation Research (J.K.D.), NTNU, Norwegian University of Science and Technology, Trondheim. Department of Infectious Diseases (J.K.D.), St. Olavs Hospital, Trondheim University Hospital, Norway. , Thor UelandThor Ueland Research Institute of Internal Medicine (P.A., T.U.), Oslo University Hospital, Rikshospitalet. University of Oslo, Norway (T.U.). K.G. Jebsen TREC, University of Tromsø, Norway (T.U.). , Imre JanszkyImre Janszky Department of Public Health and Nursing (G.Å.V., L.E.L., L.J.V., I.J.), NTNU, Norwegian University of Science and Technology, Trondheim. , John-Anker ZwartJohn-Anker Zwart Division of Clinical Neuroscience, Oslo University Hospital (J.-A.Z.), University of Oslo, Norway. , Ferdinand M. van't HooftFerdinand M. van't Hooft Cardiovascular Medicine Unit, Department of Medicine Solna, Center for Molecular Medicine (M.M., F.M.v.H.), Karolinska Institutet, Stockholm, Sweden. , Nabil Georges SeidahNabil Georges Seidah Laboratory of Biochemical Neuroendocrinology, IRCM, Montreal, Quebec, Canada (N.G.S.). , Kristian HveemKristian Hveem Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology (B.M.B., L.G.F., H.R., G.Å.V., M.E.G., K.H., B.O.Å.), NTNU, Norwegian University of Science and Technology, Trondheim. , Cristen WillerCristen Willer Department of Biostatistics and Center for Statistical Genetics (L.G.F., C.W.), University of Michigan, Ann Arbor, MI. Department of Internal Medicine (J.B.N., I.S., S.E.G., C.W.), University of Michigan, Ann Arbor, MI. Department of Human Genetics (C.W.), University of Michigan, Ann Arbor, MI. , George Davey SmithGeorge Davey Smith MRC Integrative Epidemiology Unit, University of Bristol, United Kingdom (B.M.B., J.Z., H.R., G.D.S.). , Bjørn Olav ÅsvoldBjørn Olav Åsvold Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology (B.M.B., L.G.F., H.R., G.Å.V., M.E.G., K.H., B.O.Å.), NTNU, Norwegian University of Science and Technology, Trondheim. Department of Endocrinology (B.O.Å.), St. Olavs Hospital, Trondheim University Hospital, Norway. and INVENT Consortium Originally published15 Jan 2019https://doi.org/10.1161/CIRCGEN.118.002335Circulation: Genomic and Precision Medicine. 2019;12:e002335Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 15, 2019: Previous Version of Record PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce serum LDL (low-density lipoprotein) cholesterol (LDL-C) by increasing uptake in the liver.1 Although some long-term trials have evaluated their safety, broad investigations of outcomes over the lifetime, leveraging genetic variation in serum PCSK9, have seldomly been conducted. We investigated effects of these variants on a range of outcomes to explore unanticipated effects of long-term PCSK9 inhibition.We linked genotype and phenotype data from 69 422 participants in the population-based HUNT (Nord-Trøndelag Health Study) with hospital records. Coronary heart disease, myocardial infarction, heart failure, venous thrombosis, diabetes mellitus, asthma, chronic obstructive pulmonary disease, allergic rhinitis, and mood disorders were indicated by International Classification of Diseases–NinthorTenth Revision codes recorded between September 1987 and March 2016 or self-report in HUNT2 (1995–1997) or HUNT3 (2006–2008). Using self-report in HUNT, we assessed anxiety, depression, musculoskeletal pain, headaches, pain or stiffness in muscles or joints in at least 3 consecutive months during the last year, gastrointestinal pain, pain in either leg while walking, and pain in the legs while at rest.Blood pressure, height, weight, and lung function were measured in HUNT by trained nurses or technicians. Nonfasting serum levels of total cholesterol, HDL (high-density lipoprotein) cholesterol, triglycerides, glucose, and C-reactive protein were measured, and LDL-C was calculated. All-cause mortality was updated from the National Population Registry.Serum concentrations of PCSK9 were measured in a subsample by ELISA with antibodies obtained from R&D Systems (Minneapolis, MN) as described elsewhere.2 Because of the sensitive nature of the data, requests to access the dataset from qualified researchers may be sent to HUNT (www.ntnu.edu/hunt). The regional committee for ethics in medical research approved the study, and participants gave informed consent.We performed a genome-wide association study of serum PCSK9 in 3697 adults using BOLT-LMM adjusted for sex, age, genotyping batch, and 4 principal components. Serum PCSK9 measurements were rank-transformed to normality. The replication cohort included 5304 adults from the TwinGene Study recruited between 2004 and 2008.3 We defined a new genetic risk score for serum PCSK9 and regressed this and an existing score (rs11206510, rs2479409, rs2149041, rs2479394, rs10888897, rs7552841, and rs562556) on a range of outcomes.1 For comparision, we used LDL-C–associated variants on HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase; rs12916, rs17238484, rs5909, rs2303152, rs10066707, and rs2006760)—the target of statins.1 The associations of PCSK9 and HMGCR genetic risk scores with outcomes in HUNT were assessed using linear regression for continuous and logistic regression for binary outcomes, adjusted for age and sex. We performed 2-sample Mendelian randomization on 48 outcomes using large biobanks available in MR-Base.4We assessed 11.67 million single-nucleotide and indel variants imputed from a combined reference panel, including 2202 low-pass sequenced HUNT genomes and the Haplotype Reference Consortium panel. We identified genome-wide significant associations at 2 loci—PCSK9 and PCSK2. Three independent genome-wide significant variants were identified; the most strongly associated variant was rs11591147 in PCSK9 (p.R46L), which was associated with a 1.30-unit decrease in rank-transformed serum PCSK9 (P=2.9×10−31) per effect allele (SD of original PCSK9 measurements, 47.5 ng/mL; interquartile range, 100.6–154.9), followed by the intronic rs499883 in PCSK9 (β=0.19; P=2.3×10−15) and rs192265866 in PCSK2 (β=−1.05; P=2.8×10−8) of which the 2 variants in PCSK9 (but not the variant in PCSK2) replicated in TwinGene and were used to construct a new genetic risk score for PCSK9.Our results demonstrated probable causal associations between lower serum PCSK9 and both lower serum LDL-C (P=2.8×10−43) and lower risk of coronary heart disease (P=8.9×10−4; Figure [A]). Because analyses within HUNT suggested associations between PCSK9 and HMGCR genetic risk scores and risk of venous thrombosis and asthma, respectively, we investigated associations using summary-level data from the INVENT (International Network against Thrombosis) Consortium and GABRIEL (A Multidisciplinary Study to Identify the Genetic and Environmental Causes of Asthma in the European Community).4,5 Neither associations replicated (venous thrombosis, inverse-variance weighted: odds ratio [OR], 1.38; 95% confidence interval [CI], 0.88–2.20; asthma, inverse-variance weighted: OR, 1.13; 95% CI, 0.64–1.98). We did not observe any other convincing associations across a range of cardiovascular, respiratory, mental, diabetes mellitus, or pain-related outcomes.Download figureDownload PowerPointFigure. The association between genetic risk scores for PCSK9 (proprotein convertase subtilisin/kexin type 9) or HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) and a wide range of outcomes in HUNT (Nord-Trøndelag Health Study) and 2-sample MR of serum PCSK9 and a range of outcomes in MR-Base. A, The association between PCSK9 and HMGCR genetic risk scores and a range of continuous traits (left) and diseases or traits (right) in the HUNT, scaled to a genetic risk score–determined 0.259 mmol/L (10 mg/dL) decrease in LDL (low-density lipoprotein) cholesterol. The PCSK9 genetic risk score is defined from the discovery genome-wide association study in this study. The existing PCSK9 score and HMGCR score are defined and weighted using results for LDL cholesterol–associated variants from the Global Lipids Genetics Consortium. B, The association between genetically determined serum PCSK9 and a range of continuous traits (amygdala volume, birth weight, body fat, body mass index, caudate volume, chronotype, depressive symptoms, father's age at death, HDL [high-density lipoprotein] cholesterol, hip circumference, hippocampus volume, intracranial volume, LDL cholesterol, mean platelet volume, mother's age at death, neuroticism, nucleus accumbens volume, pallidum volume, parents' age at death, platelet count, putamen volume, sitting height ratio, sleep duration, thalamus volume, top 1% survival, total cholesterol, triglycerides, waist circumference, waist-to-hip ratio, and years of schooling; left) and diseases or traits (alcohol dependence, Alzheimer disease, amyotrophic lateral sclerosis, autism, bulimia nervosa, coronary heart disease, Crohn disease, eczema, inflammatory bowel disease, lung adenocarcinoma, lung cancer, multiple sclerosis, myocardial infarction, rheumatoid arthritis, schizophrenia, squamous cell lung cancer, type 2 diabetes mellitus, and ulcerative colitis; right) in MR-Base. The new PCSK9 genetic risk score had an r2 and F statistics of 2.1% and 80.55 for serum PCSK9. BMI indicates body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; HADS, Hospital Anxiety and Depression Scale; and OR, odds ratio.Utilizing genome-wide association study summary statistics and 2-sample MR, the PCSK9 genetic risk score was associated with LDL-C, HDL cholesterol, and total cholesterol as expected (Figure [B]). Moreover, genetically decreased serum PCSK9 was associated with higher father's age at death (β=0.04; 95% CI, 0.01–0.08), parents age at death (β=0.05; 95% CI, 0.01–0.10), and waist-to-hip ratio (β=0.03; 95% CI, 0.01–0.06; Figure [B]). Additionally, genetically decreased serum PCSK9 was associated with decreased risk of coronary heart disease (OR, 0.84; 95% CI, 0.78–0.89) and myocardial infarction (OR, 0.81; 95% CI, 0.70–0.93) and an increased risk of Alzheimer disease (OR, 1.27; 95% CI, 1.04–1.55; Figure [B]).In summary, we confirmed 2 independent genetic variants associated with serum PCSK9 and causal associations of lower serum PCSK9 with lower LDL-C and reduced risk of coronary heart disease. Additionally, we did not observe any other consistent unexpected associations when investigating a range of outcomes. The lack of association with a range of potential adverse outcomes is reassuring for long-term use of PCSK9 inhibitors.AcknowledgmentsThe HUNT (Nord-Trøndelag Health Study) is a collaboration between HUNT Research Center (Faculty of Medicine and Health Sciences, NTNU, Norwegian University of Science and Technology), Nord-Trøndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health.Sources of FundingDrs Brumpton and Åsvold work in a research unit funded by Stiftelsen Kristian Gerhard Jebsen; Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU); the Liaison Committee for Education, Research, and Innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. The genotyping in HUNT (Nord-Trøndelag Health Study) was financed by the National Institutes of Health; University of Michigan; the Research Council of Norway; the Liaison Committee for Education, Research, and Innovation in Central Norway; and the Joint Research Committee between St. Olavs Hospital and the Faculty of Medicine and Health Sciences, NTNU. Dr Seidah was supported by a Leducq Foundation grant No. 13 CVD 03, a Canadian Institutes of Health Research Foundation grant No. 148363, and a Canada Research Chair No. 950-231335. Dr Nielsen was supported by grants from the Danish Heart Foundation and the Lundbeck Foundation. Dr Vie was supported by a research grant from the Norwegian Research Council (grant No. 250335). Drs Smith and Brumpton work in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council and the University of Bristol (MC_UU_12013/1). Drs Mannila and van't Hooft were supported by the Swedish Heart-Lung Foundation and the Leducq Foundation. Dr Willer was supported by HL135824, HL109946, and HL127564.DisclosuresNone.Footnotes*Drs Willer, Smith, and Åsvold contributed equally to this work.https://www.ahajournals.org/journal/circgenBen M. Brumpton, PhD, Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, Norwegian University of Science and Technology, Postbox 8905, MTFS, NO-7491 Trondheim, Norway. Email ben.[email protected]noReferences1. Ference BA, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes.N Engl J Med. 2016; 375:2144–2153. doi: 10.1056/NEJMoa1604304CrossrefMedlineGoogle Scholar2. Laugsand LE, et al. Circulating PCSK9 and risk of myocardial infarction: the HUNT study in Norway.JACC Basic Transl Sci. 2016; 1:568–575. doi: 10.1016/j.jacbts.2016.06.007CrossrefMedlineGoogle Scholar3. Magnusson PK, et al. The Swedish Twin Registry: establishment of a biobank and other recent developments.Twin Res Hum Genet. 2013; 16:317–329. doi: 10.1017/thg.2012.104CrossrefMedlineGoogle Scholar4. Hemani G, et al. The MR-base platform supports systematic causal inference across the human phenome.Elife. 2018; 7:e34408.CrossrefMedlineGoogle Scholar5. Germain M, et al; Cardiogenics Consortium. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism.Am J Hum Genet. 2015; 96:532–542. doi: 10.1016/j.ajhg.2015.01.019CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Bensenor I, Padilha K, Lima I, Santos R, Lambert G, Ramin-Mangata S, Bittencourt M, Goulart A, Santos I, Mill J, Krieger J, Lotufo P and Pereira A (2021) Genome-Wide Association of Proprotein Convertase Subtilisin/Kexin Type 9 Plasma Levels in the ELSA-Brasil Study, Frontiers in Genetics, 10.3389/fgene.2021.728526, 12 Åsvold B, Langhammer A, Rehn T, Kjelvik G, Grøntvedt T, Sørgjerd E, Fenstad J, Heggland J, Holmen O, Stuifbergen M, Vikjord S, Brumpton B, Skjellegrind H, Thingstad P, Sund E, Selbæk G, Mork P, Rangul V, Hveem K, Næss M and Krokstad S (2022) Cohort Profile Update: The HUNT Study, Norway, International Journal of Epidemiology, 10.1093/ije/dyac095 January 2019Vol 12, Issue 1 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCGEN.118.002335PMID: 30645169 Originally publishedJanuary 15, 2019 Keywordscardiovascular diseasesmental healthhospital recordspainlipidslungPDF download Advertisement SubjectsCardiovascular DiseaseEpidemiologyGenetic, Association StudiesLipids and CholesterolRisk Factors
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