Very high concentrations of lipoprotein(a) substantially increase long-term cardiovascular risk in healthy women, according to 30-year data from the Women’s Health Study, prompting renewed debate on whether routine population screening for this genetic biomarker should be adopted more widely.
This major cohort analysis examined whether baseline lipoprotein(a) levels, analysed as continuous variables, clinical thresholds and population percentiles, predicted major cardiovascular events over three decades. The researchers also assessed the rs3798220 genotype – a known determinant of elevated lipoprotein(a).
The study included 27,748 female healthcare professionals free from cardiovascular disease, cancer and other chronic conditions at recruitment, with a median baseline age of 53 years. Lipoprotein(a) levels were measured from blood samples collected between 1992 and 1995, and participants were followed for a median of 27.8 years.
Over this period, 3,707 major cardiovascular events occurred in the lipoprotein(a) cohort. A further 3,165 major cardiovascular events occurred among 23,279 women of verified European ancestry with the rs3798220 genotype, who were included in the genetic analyses.
Dose–response effects for lipoprotein(a)-related outcomes
Lipoprotein(a) levels above 30 mg/dL – or above the 75th percentile of 31 mg/dL – were linked with a higher 30-year risk of major cardiovascular events and coronary heart disease, with risk rising steeply at extreme concentrations.
Women with levels of at least 120 mg/dL, or above the 99th percentile of 131 mg/dL, had a multivariable-adjusted hazard ratio (HR) of 1.54 for major cardiovascular events compared with those with levels below 10 mg/dL. The association was strongest for coronary heart disease, with HRs of 1.80 for the ≥120 mg/dL group and 2.06 for those above the 99th percentile relative to the lowest half of the cohort.
In contrast, ischaemic stroke and cardiovascular death showed increased risk only at the highest lipoprotein(a) levels. For women with concentrations at or above 120 mg/dL, HRs were 1.41 for stroke and 1.63 for cardiovascular mortality compared with those below 10 mg/dL.
The genetic analysis mirrored these findings. Increased lipoprotein(a) levels, from 10 to 82 mg/dL, due to carrying the rs3798220 minor allele, were associated with a 27% higher risk of major cardiovascular events than in non-carriers. Despite these associations, the authors noted that only a modest proportion of women had lipoprotein(a) levels high enough to confer clinically significant risk.
Screening may be warranted
The authors acknowledged several study limitations, including indications that the proportional hazards assumption was not met in some analyses and the possibility that menopausal changes in lipoprotein(a) may have influenced the results. The findings may not be generalisable to populations of non-European ancestry, they added, and these associations need to be confirmed in men.
Despite these limitations, the authors concluded that their findings support the case for lipoprotein(a) screening in the general population, especially given that the highest-risk individuals represent a small subgroup that may derive particular benefit from future targeted interventions.
Reference
Nordestgaard AT et al. Thirty-Year Risk of Cardiovascular Disease Among Healthy Women According to Clinical Thresholds of Lipoprotein(a). JAMA Cardiol 2026;7 Jan:doi 10.1001/jamacardio.2025.5043.