Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Schmidt, A. F. et al. (2019) Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. BMC Cardiovascular Disorders, 19, 240. (doi: 10.1186/s12872-019-1187-z) (PMID:31664920) (PMCID:PMC6820948)

Abstract

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer’s disease – outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ward, Dr Joey and Padmanabhan, Professor Sandosh and Young, Dr Robin and Pell, Professor Jill and Sattar, Professor Naveed and Ford, Professor Ian
• Authors: Schmidt, A. F., Holmes, M. V., Preiss, D., Swerdlow, D., Denaxas, S., Fatemifar, G., Faraway, R., Finan, C., Lumbers, T., Henry, A., Valentine, D., Fairhurst-Hunter, Z., Hartwig, F. P., Horta, B. L., Hypponen, E., Power, C., Moldovan, M., van Iperen, E., Hovingh, K., Demuth, I., Norman, K., Steinhagen-Thiessen, E., Demuth, J., Bertram, L., Lill, C. M., Coassin, S., Willeit, J., Kiechl, S., Willeit, K., Mason, D., Wright, J., Morris, R., Wanamethee, G., Whincup, P., Ben-Shlomo, Y., McLachlan, S., Price, J. F., Kivimaki, M., Welch, C., Sanchez-Galvez, A., Marques-Vidal, P., Nicolaides, A., Panayiotou, A. G., Onland-Moret, N. C., van der Schouw, Y. T., Matullo, G., Fiorito, G., Guarrera, S., Sacerdote, C., Wareham, N. J., Langenberg, C., Scott, R. A., Luan, J.’a., Bobak, M., Malyutina, S., Pajak, A., Kubinova, R., Tamosiunas, A., Pikhart, H., Grarup, N., Pedersen, O., Hansen, T., Linneberg, A., Jess, T., Cooper, J., Humphries, S. E., Brilliant, M., Kitchner, T., Hakonarson, H., Carrell, D. S., McCarty, C. A., Lester, K. H., Larson, E. B., Crosslin, D. R., Andrade, M. d., Roden, D. M., Denny, J. C., Carty, C., Hancock, S., Attia, J., Holliday, E., Scott, R., Schofield, P., O’Donnell, M., Yusuf, S., Chong, M., Pare, G., van der Harst, P., Said, M. A., Eppinga, R. N., Verweij, N., Snieder, H., Christen, T., Mook-Kanamori, D.O., Gustafsson, S., Lind, L., Ingelsson, E., Pazoki, R., Franco, O., Hofman, A., Uitterlinden, A., Dehghan, A., Teumer, A., Baumeister, S., Dörr, M., Lerch, M. M., Völker, U., Völzke, H., Ward, J., Pell, J. P., Meade, T., Christophersen, I. E., Maitland-van der Zee, A. H., Baranova, E. V., Young, R., Ford, I., Campbell, A., Padmanabhan, S., Bots, M. L., Grobbee, D. E., Froguel, P., Thuillier, D., Roussel, R., Bonnefond, A., Cariou, B., Smart, M., Bao, Y., Kumari, M., Mahajan, A., Hopewell, J. C., Seshadri, S., Dale, C., Costa, R. P. E., Ridker, P. M., Chasman, D. I., Reiner, A. P., Ritchie, M. D., Lange, L. A., Cornish, A. J., Dobbins, S. E., Hemminki, K., Kinnersley, B., Sanson, M., Labreche, K., Simon, M., Bondy, M., Law, P., Speedy, H., Allan, J., Li, N., Went, M., Weinhold, N., Morgan, G., Sonneveld, P., Nilsson, B., Goldschmidt, H., Hemminki, K., Sud, A., Engert, A., Hansson, M., Hemingway, H., Asselbergs, F. W., Patel, R. S., Keating, B. J., Sattar, N., Houlston, R., Casas, J. P., and Hingorani, A. D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: BMC Cardiovascular Disorders
• Publisher: BioMed Central
• ISSN: 1471-2261
• ISSN (Online): 1471-2261
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in BMC Cardiovascular Disorders 19:240
• Publisher Policy: Reproduced under a Creative Commons License