Genetics
Genetic evidence suggests fatty liver damage lowers Lp(a), not the reverse, while combined high Lp(a) and liver stiffness sharpen carotid plaque risk (Cardiovasc Diabetol 2025)
Original title: Interplay among lipoprotein(a), hepatic and vascular damage in individuals with metabolic dysfunction
This study combined the Liver-Bible cohort of 859 individuals with metabolic dysfunction (808 with genomic data) and the 6,963-person Milan Biobank, using GWAS and polygenic risk scores to disentangle the relationship between Lp(a), liver damage and vascular disease. LPA genetic variation was the strongest determinant of Lp(a), but circulating (not genetically predicted) Lp(a) was inversely related to liver stiffness measurement, suggesting MASLD severity affects Lp(a) secretion rather than the reverse. Among 250 participants with more severe insulin resistance, both Lp(a) (OR 6.7, 95% CI 1.0-53.0, P = 0.046) and liver stiffness (OR 13.7, 95% CI 1.4-172.2, P = 0.023) independently predicted carotid plaque prevalence. In the Milan Biobank, genetically predicted higher Lp(a) tended to raise liver-related outcome risk, while genetically predicted MASLD lowered circulating Lp(a). The authors conclude liver damage more likely reduces plasma Lp(a) than the reverse, and that combining both markers could improve vascular risk prediction.
Original abstract
Background: The relationship between plasma lipoprotein(a) [Lp(a)] levels and metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. The aim of this study was to examine the combined effects of Lp(a) levels on liver and vascular damage.
Methods: The study was conducted using the Liver-Bible cohort of individuals with metabolic dysfunction (n = 859, 808 with genomic information) and the Milan Biobank (n = 6963). Genome-wide association studies (GWAS) and polygenic risk scores (PRS) were used to evaluate the inherited factors influencing plasma Lp(a) levels.
Results: In the Liver-Bible cohort, genetic variation in the LPA gene was the strongest determinant of Lp(a), followed by liver stiffness measurement (LSM). Additionally, circulating Lp(a) levels, but not genetic predisposition, were inversely related to LSM, suggesting that MASLD severity may affect Lp(a) secretion. Among participants with more severe insulin resistance (n = 250), Lp(a) levels (odds ratio 6.7, 95% CI 1.0-53.0, p = 0.046) and LSM (odds ratio 13.7, 95% CI 1.4-172.2, p = 0.023) were associated with greater prevalence of carotid atherosclerotic plaques, regardless of traditional cardiovascular risk factors. In the Milan Biobank, genetically predicted higher Lp(a) levels tended to increase the risk of liver-related outcomes, whereas genetically predicted MASLD was associated with lower circulating Lp(a) levels.
Conclusions: The results of this study suggest that liver damage is more likely the cause of reduced plasma Lp(a) levels rather than a consequence. Assessing plasma Lp(a) levels and the extent of liver damage could improve the prediction of vascular damage.
Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.