Analysis of reproductive traits associated with lipoprotein(a) deficiency in participants from the Pakistan Genome Resource

High-confidence LPA loss-of-function variants that produce lifelong, gene-dosage–dependent Lp(a) deficiency in Pakistan Genome Resource participants show no significant association with fertility traits or pregnancy/child outcomes.

• Why it matters: Because LPA is absent in most model organisms, preclinical reproductive safety evidence is limited, creating a need for human genetic reassurance for Lp(a)-lowering therapies.
• What they did: Researchers identified Pakistan Genome Resource carriers of high-confidence LPA LoF variants and tested associations with ever having a child and number of children using regenie-based burden testing under additive and recessive models, including sex-stratified analyses. They also ran a recall-by-genotype study in 19 female LoF homozygotes with family controls, evaluating 107 pregnancies and 87 children across miscarriage, maternal complications, delivery issues, NICU admission, birth defects, and child health problems.
• The result: LoF variants showed no depletion of homozygotes versus Hardy–Weinberg expectations, and no statistically significant genotype–outcome associations emerged for fertility, pregnancy, or offspring measures, supporting reproductive and developmental safety implications for sustained Lp(a)-lowering.

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