Genetically proxied low-density lipoprotein cholesterol lowering via PCSK9-inhibitor drug targets and risk of congenital malformations.

Autor:	Ardissino M; National Heart and Lung Institute, Imperial College London, Hammersmith Campus, London, UK.; Department of Medicine, School of Clinical Medicine, University of Cambridge, London, UK., Slob EAW; MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.; Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, The Netherlands.; Erasmus University Rotterdam Institute for Behavior and Biology, Erasmus University Rotterdam, Rotterdam, The Netherlands., Reddy RK; National Heart and Lung Institute, Imperial College London, Hammersmith Campus, London, UK., Morley AP; Department of Medicine, School of Clinical Medicine, University of Cambridge, London, UK., Schuermans A; Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium., Hill P; Royal Oldham Hospital, Northern Care Alliance NHS Foundation Trust, Manchester, UK., Williamson C; Institute of Reproductive and Developmental Biology, Imperial college London, London, UK., Honigberg MC; Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.; Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.; Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA., de Marvao A; British Heart Foundation Centre of Research Excellence, School of Cardiovascular Medicine and Sciences, King's College London, London, UK.; Medical Research Council, London Institute of Medical Sciences, Imperial College London, London, UK., Ng FS; National Heart and Lung Institute, Imperial College London, Hammersmith Campus, London, UK.
Jazyk:	angličtina
Zdroj:	European journal of preventive cardiology [Eur J Prev Cardiol] 2024 Jun 03; Vol. 31 (8), pp. 955-965.
DOI:	10.1093/eurjpc/zwad402
Abstrakt:	Aims: Current guidelines advise against the use of lipid-lowering drugs during pregnancy. This is based only on previous observational evidence demonstrating an association between statin use and congenital malformations, which is increasingly controversial. In the absence of clinical trial data, we aimed to use drug-target Mendelian randomization to model the potential impact of fetal LDL-lowering, overall and through PCSK9 drug targets, on congenital malformations. Methods and Results: Instrumental variants influencing LDL levels overall and through PCSK9-inhibitor drug targets were extracted from genome-wide association study (GWAS) summary data for LDL on 1 320 016 individuals. Instrumental variants influencing circulating PCSK9 levels (pQTLs) and liver PCSK9 gene expression levels (eQTLs) were extracted, respectively, from a GWAS on 10 186 individuals and from the genotype-tissue expression project. Gene-outcome association data was extracted from the 7th release of GWAS summary data on the FinnGen cohort (n = 342 499) for eight categories of congenital malformations affecting multiple systems. Genetically proxied LDL-lowering through PCSK9 was associated with higher odds of malformations affecting multiple systems [OR 2.70, 95% confidence interval (CI) 1.30-5.63, P = 0.018], the skin (OR 2.23, 95% CI 1.33-3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal, and limb association (VACTERL) (OR 1.51, 95% CI 1.16-1.96, P = 0.007). An association was also found with obstructive defects of the renal pelvis and ureter, but this association was suggestive of horizontal pleiotropy. Lower PCSK9 pQTLs were associated with the same congenital malformations. Conclusion: These data provide genetic evidence supporting current manufacturer advice to avoid the use of PCSK9 inhibitors during pregnancy. Competing Interests: Conflict of interest: C.W. is a consultant for Mirum Pharmaceuticals and GlaxoSmithKline. M.C.H. has received consulting fees from CRISPR Therapeutics, reports advisory board service for Miga Health, and receives research support from Genentech, all unrelated to this work. All authors have no conflicts of interest to report. (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)
Databáze:	MEDLINE
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