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Variation in Serum PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9), Cardiovascular Disease Risk, and an Investigation of Potential Unanticipated Effects of PCSK9 Inhibition: A Genome-Wide Association Study and Mendelian Randomization Study in the HUNT, Norway

Circ Genom Precis Med. 2019;12:e002335. DOI: 10.1161/CIRCGEN.118.002335 January 2019 Ben M. Brumpton, PhD et al 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–Ninth or Tenth Revision codes recorded between September 1987 and March 2016 or selfreport 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. 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 LDLC–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 RESEARCH LETTER