Analysis of reproductive traits associated with lipoprotein(a) deficiency in participants from the Pakistan Genome Resource
Aims. Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease, driving development of LPA-targeting therapies that markedly lower circulating Lp(a). Because LPA?the gene encoding apolipoprotein(a)?is absent in most model organisms, preclinical studies have limited value for assessing effects such as reproductive safety. Therefore, naturally occurring human LPA ?knockouts? were analyzed to evaluate reproductive outcomes of on-target Lp(a) lowering. Methods and Results. Individuals carrying high-confidence LPA loss-of-function (LoF) variants which reduce Lp(a) in a gene-dosage?dependent manner within the Pakistan Genome Resource were identified. LoF variants showed no depletion of homozygotes relative to Hardy?Weinberg expectations. LPA LoF associations with fertility-related traits (ever having a child and number of children) under additive and recessive models were assessed using regenie-based burden testing, including sex-stratified analyses, and no significant associations were observed. A recall-by-genotype study of female LoF homozygotes alongside heterozygous and non-carrier family member controls was performed, surveying reproductive histories and offspring outcomes. Across 107 pregnancies and 87 children in 19 homozygous LoF women, rates of miscarriage, maternal complications (including preeclampsia, hypertension, and gestational diabetes), delivery complications, neonatal intensive care admission, birth defects, and child health problems were comparable across genotypes with no statistically significant genotype?outcome associations. Conclusions. These genetic and by-genotype analyses indicate that complete lifelong LPA deficiency due to high-confidence LPA loss-of-function variants is not associated with overt adverse maternal fertility, pregnancy or child health outcomes. These findings offer human genetic reassurance regarding reproductive and developmental safety in the context of sustained Lp(a)-lowering, with implications for long-term therapies targeting Lp(a).