Predicting the impact of low-density lipoprotein cholesterol lowering through different drug targets on risk of congenital heart disease

Abstract

Abstract Background Low-density lipoprotein cholesterol (LDL) lowering in pregnancy has been a controversial topic as observational studies have described an increased risk of congenital malformations. With the advent of new, long-lasting LDL lowering therapies such as silencing RNA therapies that exert clinical effects for up to six months after administration, there is substantial probability that women of childbearing age might conceive during the period of drug activity. Where clinical data is not available, the Mendelian randomization (MR) paradigm can be used to predict effects of drug target perturbation using genetic data. Purpose We aimed to leverage genetic data to explore the predicted impact of LDL lowering via the statin, ezetimibe and PCSK9 drug targets, on congenital heart disease. Methods Uncorrelated genome-wide significant (p<5x10-8) variants for LDL and their association estimates, overall and restricted to the HMGCR, NPC1L1, PCSK9 gene regions +/- 10kB, were extracted from GWAS summary data on the UK Biobank (n=469,897). Gene-outcome association data was extracted from GWAS results of FinnGen 8thRelease (n=342,499) for conotruncal defects, congenital malformations of the great arteries; septal defects; congenital disease of the aortic or mitral valves; and the vertebral, anorectal, cardiovascular, tracheo-esophageal, renal and limb anomaly (VACTERL) association. A drug-target MR analysis was carried out using inverse-variance weighted MR. Results Genetically-proxied LDL-lowering through PCSK9 associated with higher odds of VACTREL association (OR 1.70, 95%ci 1.25-2.32; p<0.001), conotruncal defects (OR 3.97, 95%CI 1.37-11.53, p=0.011) and overall congenital heart disease of any type (OR 1.49, 95%CII 1.08-2.05, p=0.015). Genetically-proxied LDL lowering via HMGCR was associated with higher odds of congenital malformations involving the great arteries (OR 5.85, 95%cCI 1.07-31.84, p=0.041). Genetically-proxied LDL lowering via NPC1L1 drug targets was not associated with differences in risk of congenital heart disease, though the power of these analyses was limited. Conclusions These data provide genetic evidence suggesting that use of LDL-lowering agents during pregnancy might influence risk of congenital heart disease. Importantly, due to underlying assumptions of the analysis, the results of this analysis are only applicable to drugs that are able to cross the placenta and exert direct effects on LDL metabolism in the fetus and they cannot be used to infer the indirect influence of lowering maternal LDL. The data support ongoing caution regarding statin use, and additionally suggest that long-lasting PCSK9-inhibiting agents that are able to cross the placenta, such as monoclonal antibodies and silencing RNA therapies, should be used with utmost caution in women planning to conceive.Figure 1