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

Abstract

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.

Dyslipidaemia management in pregnant patients: a 2024 update

“…Ardissino et al . 84 have introduced a highly innovative approach to assessing whether or not it is plausible that PCSK9 inhibition might be harmful to the developing foetus by using genome-wide association studies including ∼1.3 million patients. Using instrumental variants of PCSK9 that impact serum levels of LDL, these investigators showed that genetically proxied LDL-lowering through PCSK9 correlates with a higher odds of malformations the skin (OR 2.23, 95% CI 1.33–3.75, P = 0.007), and the vertebral, anorectal, cardiovascular, tracheo-oesophageal, renal, and limbs (OR 1.51, 95% CI 1.16–1.96, P = 0.007).…”