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. 2023 Dec 1;8(12):1111-1118.
doi: 10.1001/jamacardio.2023.3548.

Concordance of a High Lipoprotein(a) Concentration Among Relatives

Laurens F Reeskamp  1   2 , Tycho R Tromp  1 , Aniruddh P Patel  2   3   4 , Shirin Ibrahim  1 , Mark Trinder  5 , Sara Haidermota  6   7 , G Kees Hovingh  1   8 , Erik S G Stroes  1 , Pradeep Natarajan  2   3   4 , Amit V Khera  2   9
Affiliations

Concordance of a High Lipoprotein(a) Concentration Among Relatives

Laurens F Reeskamp et al. JAMA Cardiol. .

Abstract

Importance: Lipoprotein(a) (Lp[a]) concentrations are a highly heritable and potential causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Recent consensus statements by the European Atherosclerosis Society and American Heart Association recommend screening of relatives of individuals with high Lp(a) concentrations, but the expected yield of this approach has not been quantified in large populations.

Objective: To measure the prevalence of high Lp(a) concentrations among first- and second-degree relatives of individuals with high Lp(a) concentrations compared with unrelated participants.

Design, setting, and participants: In this cross-sectional analysis, pairs of first-degree (n = 19 899) and second-degree (n = 9715) relatives with measured Lp(a) levels from the UK Biobank study and random pairs of unrelated individuals (n = 184 764) were compared. Data for this study were collected from March 2006 to August 2010 and analyzed from December 2021 to August 2023.

Exposure: Serum Lp(a) levels, with a high Lp(a) level defined as at least 125 nmol/L.

Main outcome and measure: Concordance of clinically relevant high Lp(a) levels in first- and second-degree relatives of index participants with high Lp(a) levels.

Results: A total of 52 418 participants were included in the analysis (mean [SD] age, 57.3 [8.0] years; 29 825 [56.9%] women). Levels of Lp(a) were correlated among pairs of first-degree (Spearman ρ = 0.45; P < .001) and second-degree (Spearman ρ = 0.22; P < .001) relatives. A total of 1607 of 3420 (47.0% [95% CI, 45.3%-48.7%]) first-degree and 514 of 1614 (31.8% [95% CI, 29.6%-34.2%]) second-degree relatives of index participants with high Lp(a) levels also had elevated concentrations compared with 4974 of 30 258 (16.4% [95% CI, 16.0%-16.9%]) pairs of unrelated individuals. The concordance in high Lp(a) levels was generally consistent among subgroups (eg, those with prior ASCVD, postmenopausal women, and statin users). The odds ratios for relatives to have high Lp(a) levels if their index relative had a high Lp(a) level compared with those whose index relatives did not have high Lp(a) levels were 7.4 (95% CI, 6.8-8.1) for first-degree relatives and 3.0 (95% CI, 2.7-3.4) for second-degree relatives.

Conclusions and relevance: The findings of this cross-sectional study suggest that the yield of cascade screening of first-degree relatives of individuals with high Lp(a) levels is over 40%. These findings support recent recommendations to use this approach to identify additional individuals at ASCVD risk based on Lp(a) concentrations.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Reeskamp reported being a cofounder of and owning stock in Lipid Tools and receiving speaker fees from Ultragenyx, Daiichi Sankyo, and Novartis outside the submitted work. Dr Patel reported receiving grant funding from the National Human Genome Research Institute and Harvard Catalyst during the conduct of the study. Dr Hovingh reported being a part-time employee of and holding shares in Novo Nordisk A/S outside the submitted work; receiving funding from Fonds Klinkerpad; receiving institutional research support from Aegerion Pharmaceuticals Inc, Amgen Inc, AstraZeneca, Eli Lilly & Co, Genzyme, Ionis Pharmaceuticals Inc, Kowa Company Ltd, Pfizer Inc, Regeneron Pharmaceuticals Inc, F. Hoffmann–La Roche AG, Sanofi SA, and The Medicines Company; and receiving speaker’s bureau and consulting fees from Amgen Inc, Aegerion Pharmaceuticals Inc, Sanofi SA, and Regeneron Pharmaceuticals Inc until April 2019 (fees paid to the academic institution). Dr Stroes reported receiving fees for lecturing and serving on the advisory board for Amgen Inc and Sanofi SA; receiving grant funding from Ionis Pharmaceuticals Inc and Novo Nordisk A/S; and serving on advisory boards for Merck & Co Inc, AstraZeneca, Esperion Therapeutics Inc, and Novartis AG outside the submitted work. Dr Natarajan reported receiving grant funding from Allelica Inc, Apple Inc, Amgen Inc, Boston Scientific Corporation, Genentech-Roche, and Novartis AG; receiving personal fees from Allelica Inc, Apple Inc, AstraZeneca, Blackstone Life Sciences, Foresite Labs, Genentech-Roche, GV Pharma AS, HeartFlow, Magnet Biomedicine, Novartis AG, Esperion Therapeutics Inc, and TenSixteen Bio; being a shareholder in Preciseli and TenSixteen Bio; scientific advisory board membership at Esperion Therapeutics Inc, Preciseli, and TenSixteen Bio; and spousal employment in Vertex Pharmaceuticals outside the submitted work. Dr Khera reported employment and equity at Verve Therapeutics, receiving personal fees from Amgen Inc, Novartis AG, and Silence Therapeutics, and receiving grant funding from the National Human Genome Research Institute, Broad Institute of MIT and Harvard, and Massachusetts General Hospital during the conduct of the study; receiving personal fees from Third Rock Ventures, Color Health, Illumina Inc, Foresite Labs, and Veritas International outside the submitted work; and having a patent pending for assessment and mitigation of risk associated with 274 perturbations in body fat distribution pending. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Lipoprotein(a) (Lp[a]) Levels, Concordance in High Lp(a) Levels, and Numbers Needed to Screen Among Relatives of Index Participants With High Lp(a) Levels
Concentrations of Lp(a) in relatives of index participants with high Lp(a) levels (≥125 nmol/L [to approximate levels in mg/dL, divide by 2.15]) for first- and second-degree relatives (A) resulted in a high percentage of relatives who also have high Lp(a) levels (B) and a low number needed to screen to identify 1 relative with high Lp(a) levels (C). As a comparator, Lp(a) concentrations in unrelated randomly matched pairs of individuals with high Lp(a) are included in all panels, and the concordance and number needed to screen among relatives is also shown for high levels of low-density lipoprotein cholesterol (LDL-C) (≥190 mg/dL [to convert to mmol/L, multiply by 0.0529]). In panel A, vertical lines indicate medians, boxes indicate IQRs, and error bars indicate the largest and smallest data point, but not further than 1.5 times the IQR.
Figure 2.
Figure 2.. Percentage of First- and Second-Degree Relatives With High Lipoprotein(a) (Lp[a]) Levels for Any Index Cutoff Lp(a) Concentration
High Lp(a) levels were at least 125 nmol/L (to approximate levels in mg/dL, divide by 2.15). The dotted lines indicate the concordance between high Lp(a) (≥125 nmol/L) in index participants and their relatives. Error bars indicate 95% CIs.
Figure 3.
Figure 3.. Subgroup Analysis for Concordance in High Lipoprotein(a) (Lp[a]) Levels Among First-Degree Relatives
High Lp(a) levels were at least 125 nmol/L (to approximate levels in mg/dL, divide by 2.15). Subgroup analysis for high Lp(a) level concordance in first-degree relatives was stratified by the presence or absence of certain traits in index participants. The concordance of high Lp(a) among relatives was largely the same among subgroups and ranged from 28.6% (95% CI, 8.4%-58.1%) in those with no self-reported or other race to 68.8% (95% CI, 60.5%-76.3%) in those with a strong genetic predisposition to high Lp(a). Number of LPA risk alleles is defined as the number of variants (rs1045872 and rs3798220) in the LPA gene, which were previously associated with Lp(a) concentrations and coronary artery disease (CAD). Genetic subgroup analyses were only performed in White participants. For the subgroup analyses including menopause and hormone therapy, only first-degree relative pairs with female index participants were included. The blue dotted line represents the concordance for high Lp(a) levels among all first-degree relatives (47.0%). Error bars indicate 95% CIs. LLT indicates use of therapy to lower lipid levels. aIncludes more than 1 race or ethnicity, other race or ethnicity, unknown race or ethnicity, and race or ethnicity not reported.
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