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

Q: What is the clinical evidence from this study?

Study design: Observational. Population: Lipoprotein(a) deficiency (LPA loss-of-function variants) (n=173303). Intervention: Homozygous or heterozygous LPA loss-of-function (LoF) genetic variants vs. Homozygous reference (non-carrier) genotype. Primary outcome: Odds of pregnancy resulting in a livebirth (additive model in recall-by-genotype study) (OR 0.95, 95% CI 0.68-1.34, p=0.67).

Q: What does this research mean for the field?

Lifelong complete LPA deficiency caused by loss-of-function variants is not associated with impaired fertility, reduced livebirth odds, or adverse maternal and child health outcomes. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

Christopher Koch; John E. Dominy; Allan M. Gurtan; Maleeha Zaman Khan; Shareef Khalid; Yoav Timsit; JP Casas; Carolina Hache; Huilei Xu; Michael Mendelson; Ieuan Jones; Allison B. Goldfine; Danish Saleheen

doi:10.64898/2026.11.05.764746

November 6, 2026Open Access

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

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Key result

Lifelong LPA deficiency from loss-of-function variants was not associated with reduced livebirth odds (OR 0.95, 95% CI 0.68-1.34, P=0.67), fertility, or adverse maternal and child outcomes.

Why the study?

Because the LPA gene is absent in most model organisms, preclinical studies have limited value for assessing the reproductive safety of therapies that markedly lower circulating Lp(a). Analyzing naturally occurring human LPA loss-of-function variants was needed to evaluate the reproductive outcomes of on-target Lp(a) lowering.

Does lifelong complete LPA deficiency due to naturally occurring LPA loss-of-function variants adversely affect fertility, pregnancy outcomes, or child health in Pakistani participants?

Key Points

To assess whether lifelong genetic deficiency of lipoprotein(a) caused by loss-of-function variants in the LPA gene impairs human fertility, pregnancy outcomes, or child health.
Identified carriers of predicted loss-of-function LPA variants in the Pakistan Genome Resource to evaluate Hardy-Weinberg equilibrium and perform burden testing for fertility traits.
Conducted a recall-by-genotype study surveying 19 homozygous loss-of-function females (107 pregnancies, 87 children), 31 heterozygous females (141 pregnancies), and 86 non-carrier control females (401 pregnancies).
Total pregnancies did not differ by LPA loss-of-function genotype under additive (β = -0.09, 95% CI [-0.62, 0.45], P = 0.75) or recessive models (β = -0.31, 95% CI [-1.45, 0.84], P = 0.60), with all 19 homozygous women reporting at least one pregnancy.
Genotype showed no significant association with odds of miscarriage (ORadditive = 1.05, 95% CI [0.73, 1.52], P = 0.78), maternal complications (ORadditive = 1.19, 95% CI [0.25, 5.62], P = 0.83), or delivery complications (ORadditive = 1.62, 95% CI [0.37, 6.97], P = 0.52).
Offspring outcomes did not differ by genotype for total number of children (βadditive = -0.09, 95% CI [-0.54, 0.36], P = 0.69) or neonatal intensive care unit admission (ORadditive = 1.88, 95% CI [0.54, 6.51], P = 0.32; ORrecessive = 0.93, 95% CI [0.05, 15.95], P = 0.96).

Study Design

Type

Observational (n=173,303)

Multicenter

Yes

Structured PICO

Does lifelong complete LPA deficiency due to naturally occurring LPA loss-of-function variants adversely affect fertility, pregnancy outcomes, or child health in Pakistani participants?

P

Population

173,303 participants (38.8% female) in the Pakistan Genome Resource biobank, including a recall-by-genotype cohort of 19 homozygous LPA loss-of-function women, 31 heterozygotes, and 86 non-carrier controls surveyed for lifelong reproductive and offspring outcomes.

E

Exposure

Lifelong genetic lipoprotein(a) [Lp(a)] deficiency due to carriage of high-confidence LPA loss-of-function (LoF) variants (homozygous or heterozygous, including rs41272114, rs559580002, and rs533200556) as a genetic proxy for on-target pharmacological Lp(a)-lowering.

C

Comparator

Homozygous reference (non-carrier) and heterozygous family member controls, as well as female controls matched for age, autozygosity, self-reported ethnicity, and case/control recruitment status not carrying any LPA variant with minor allele frequency < 5%.

O

Outcome

Fertility-related traits (ever having a child and total number of children) in the PGR biobank, and self-reported reproductive, pregnancy, and offspring outcomes (number of pregnancies, livebirth, stillbirth, miscarriage, abortion, preterm birth, maternal complications [preeclampsia, hypertension, gestational diabetes], delivery complications, neonatal intensive care unit admission, birth defects, and child survival and health at 6 months, 1 year, and 5 years) in the recall-by-genotype study.safety

Main Result

Odds Ratio: 0.95 (95% CI 0.68–1.34)

p-value: p=0.67

Complete lifelong genetic deficiency of Lp(a) in humans is not associated with adverse fertility, pregnancy, or offspring health outcomes, providing genetic reassurance for the reproductive safety of pharmacological Lp(a)-lowering therapies.

Limitations

High consanguinity in the Pakistan Genome Resource cohort may mask subtle effects on Hardy-Weinberg equilibrium and reproductive fitness
Male overrepresentation in the biobank due to cardiovascular disease-focused recruitment
Retrospective self-reported reproductive history in the recall-by-genotype study
Small sample size of homozygous LPA loss-of-function women (n=19) in the recall-by-genotype survey
High consanguinity in the population may mask subtle effects on homozygote depletion relative to Hardy-Weinberg equilibrium
Male over-representation in the PGR cohort due to cardiovascular disease-focused recruitment
Statistical models for stillbirth showed boundary (singular) fit warnings and were not reported
Recessive model for abortion failed to converge due to no homozygous LoF cases

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Implication

Supports reproductive safety of Lp(a) deficiency; hypothesis-generating for targeted therapies and requires prospective confirmation.

Abstract

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).

Discussion

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Cite This Study

Koch et al. (2026) conducted an observational in Lipoprotein(a) deficiency (LPA loss-of-function variants) (n=173,303). Homozygous or heterozygous LPA loss-of-function (LoF) genetic variants vs. Homozygous reference (non-carrier) genotype was evaluated on Odds of pregnancy resulting in a livebirth (additive model in recall-by-genotype study) (OR 0.95, 95% CI 0.68-1.34, p=0.67). Lifelong LPA deficiency from loss-of-function variants was not associated with reduced livebirth odds (OR 0.95, 95% CI 0.68-1.34, P=0.67), fertility, or adverse maternal and child outcomes.

synapsesocial.com/papers/6aefbd4950d2071ffda4bc20 https://doi.org/10.64898/2026.11.05.764746

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

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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

Key Points

Study Design

Structured PICO

Main Result

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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