Genetic insights into lipoprotein(a) lowering and reproductive and offspring health outcomes

Aims Lipoprotein(a) lowering therapies are being investigated to reduce atherosclerotic cardiovascular disease risk. However, their implications on women’s reproductive health are unknown and pre-clinical models offer limited insight towards understanding such effects. We evaluated potential causal effects of genetically proxied lipoprotein(a) lowering on reproductive and offspring health outcomes. Methods and Results We analyzed common and rare variants in the LPA region using two-sample Mendelian randomization, genetic risk scores, and gene-based tests. Additionally, performing individual-level analyses using UK Biobank and All of Us cohorts, with genome sequencing linked to biomarkers and electronic health records, we investigated outcomes spanning maternal health during pregnancy, labor and delivery complications, pregnancy outcomes, and congenital malformations in 236,228 UK Biobank and 122,038 All of Us women, and recorded female infertility in 102,549 All of Us women. In summary-level analyses, no significant adverse associations of genetically predicted low lipoprotein(a) with reproductive and offspring health outcomes were detected. Nominal associations were present across Mendelian randomization, genetic risk score and gene-based analyses, but no adverse reproductive findings survived the multiple-testing corrections. Confidence intervals for all fertility and reproductive-count estimates included the null. Controls showed expected associations for higher lipoprotein(a) with low-density lipoprotein cholesterol (p-value = 2×10−19) and triglycerides (p-value = 4×10−9). Conclusion In summary, we found no robust or multiplicity-adjusted evidence of adverse reproductive or offspring health effects related to genetically proxied lipoprotein(a) lowering. These findings provide genetic evidence relevant to assessing the reproductive and offspring health implications of targeting lipoprotein(a).