rs3798220 — LPA Ile4399Met (I4399M)

Missense variant in the protease-like domain of apolipoprotein(a) causing markedly elevated Lp(a) levels and substantially increased risk of coronary artery disease, peripheral vascular disease, and aortic valve stenosis; carriers show differential benefit from aspirin therapy

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The Lp(a) Missense Variant — Cardiovascular Risk with an Aspirin Twist

Lipoprotein(a), or Lp(a), is an LDL-like particle distinguished by an additional apolipoprotein(a) protein component11 LDL-like particle distinguished by an additional apolipoprotein(a) protein component
making Lp(a) structurally and functionally distinct from ordinary LDL. The rs3798220 variant causes an isoleucine-to-methionine substitution (p.Ile1891Met, also written Ile4399Met in legacy numbering) in the protease-like domain of apolipoprotein(a)22 protease-like domain of apolipoprotein(a)
a region structurally homologous to plasminogen but catalytically inactive. Carriers of the C allele have markedly elevated Lp(a) levels — median 79.5 mg/dL in heterozygotes versus 10.0 mg/dL in non-carriers — and face substantially higher rates of coronary artery disease, peripheral vascular disease, and aortic valve stenosis. This variant is independent of rs10455872 and operates through a distinct mechanism.

The Mechanism

The rs3798220 C allele correlates with smaller apolipoprotein(a) isoforms33 smaller apolipoprotein(a) isoforms
fewer kringle IV-2 repeat copies in the LPA gene, the same feature that drives the Lp(a)-elevating effect of the related rs10455872 variant. However, the Ile4399Met substitution is a coding change in the protease-like domain that appears to independently influence isoform size, secretion efficiency, or metabolic clearance, independently of the KIV-2 repeat number alone.

Elevated Lp(a) contributes to cardiovascular disease through three convergent mechanisms: atherogenic cholesterol delivery to arterial plaques44 cholesterol delivery to arterial plaques
similar to LDL, but resistant to statin therapy; pro-inflammatory oxidized phospholipids (OxPL) carried by the apolipoprotein(a) kringle domains55 pro-inflammatory oxidized phospholipids (OxPL) carried by the apolipoprotein(a) kringle domains
OxPL drives macrophage activation and arterial wall inflammation; and anti-fibrinolytic activity66 anti-fibrinolytic activity
apolipoprotein(a)'s structural similarity to plasminogen allows it to compete with plasminogen for fibrin binding, impairing clot breakdown and increasing thrombotic risk. The thrombotic mechanism is why aspirin provides disproportionate benefit in carriers.

Notably, the Ile4399Met substitution is not associated with elevated Lp(a) in East and Southeast Asian populations77 not associated with elevated Lp(a) in East and Southeast Asian populations
the variant is not in linkage disequilibrium with small KIV-2 alleles in these populations, so the standard risk interpretation does not apply.

The Evidence

The landmark evidence base for rs3798220 is anchored by two large independent studies. Clarke et al. 2009 in the New England Journal of Medicine88 Clarke et al. 2009 in the New England Journal of Medicine
Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease. N Engl J Med 2009;361:2518-28 found rs3798220 associated with coronary disease with an odds ratio of 1.92 (95% CI 1.48-2.49)99 odds ratio of 1.92 (95% CI 1.48-2.49)
a remarkably large effect size for a common variant — the C allele frequency is only ~2% in Europeans, and showed that rs3798220 and rs10455872 together predicted risk with an odds ratio of 4.87 for individuals carrying two or more risk alleles across both variants.

The Chasman et al. 2009 Women's Health Study1010 Chasman et al. 2009 Women's Health Study
Polymorphism in the Apolipoprotein(a) Gene, Plasma Lipoprotein(a), Cardiovascular Disease, and Low-dose Aspirin Therapy. Atherosclerosis 2009;203:371-6 followed 25,131 initially healthy Caucasian women for 9.9 years. The 3.7% who carried the C allele had 2.21-fold higher cardiovascular risk in the placebo group1111 2.21-fold higher cardiovascular risk in the placebo group
HR 2.21, 95% CI 1.39-3.52, but a critical finding emerged: among carriers assigned to low-dose aspirin, cardiovascular risk was reduced by 56% (HR 0.44, p=0.033) versus only 9% in non-carriers1212 56% (HR 0.44, p=0.033) versus only 9% in non-carriers
the gene-aspirin interaction p=0.048, suggesting a genotype-specific aspirin benefit.

The Heart Protection Study (n=12,236)1313 Heart Protection Study (n=12,236)
Lipoprotein(a) Genetic Variants Associated With Coronary and Peripheral Vascular Disease but Not With Stroke Risk. Circ Cardiovasc Genet 2011;4:129-38 confirmed that rs3798220 (as part of an LPA combined score) is strongly associated with coronary disease and peripheral vascular disease but not with ischemic stroke1414 not with ischemic stroke
suggesting the thrombotic and atherogenic mechanisms of Lp(a) are site-specific rather than pan-vascular.

A large-scale EHR study of 44,703 individuals1515 large-scale EHR study of 44,703 individuals
Association of LPA Variants With Aortic Stenosis. JAMA Cardiol 2018;3:400-408 confirmed rs3798220 associated with aortic valve stenosis (OR 1.31, 95% CI 1.09-1.58, p=0.0036), extending the Lp(a) cardiovascular phenotype beyond atherosclerosis to valvular disease.

A meta-analysis of 55,647 participants1616 meta-analysis of 55,647 participants
including 12,406 CHD cases examining both rs3798220 and rs10455872 confirmed significant CHD association under allelic (OR 1.49), dominant (OR 1.53), and other genetic models for rs3798220.

Practical Implications

Carriers of the C allele should measure serum Lp(a)1717 measure serum Lp(a)
a single test is sufficient as levels are highly stable over time. Because Lp(a) levels are 70-90% genetically determined and statins do not lower Lp(a), this variant represents a source of residual cardiovascular risk that requires targeted attention beyond standard LDL lowering.

The aspirin finding from the Women's Health Study has generated clinical interest in rs3798220 testing as a decision aid for aspirin therapy in primary prevention1818 decision aid for aspirin therapy in primary prevention
particularly relevant given the increased bleeding risk of aspirin, which makes personalized rather than universal aspirin use more attractive. This remains an active area and some health insurers now cover the test for this indication.

Pelacarsen1919 Pelacarsen
an antisense oligonucleotide targeting LPA mRNA in hepatocytes reduces Lp(a) by 80-96% and completed a Phase 3 trial (Lp(a) HORIZON) in 8,323 patients; importantly, pelacarsen's Lp(a)-lowering efficacy is unaffected by whether the patient carries rs3798220 or rs104558722020 pelacarsen's Lp(a)-lowering efficacy is unaffected by whether the patient carries rs3798220 or rs10455872
the antisense mechanism targets all apo(a) mRNA equally regardless of isoform size. PCSK9 inhibitors (evolocumab, alirocumab) provide more modest Lp(a) reduction (~20-27%) plus substantial LDL lowering.

Interactions

The rs3798220 variant interacts additively with rs104558722121 rs10455872
the other major LPA cardiovascular risk variant, located in an intron and associated with fewer KIV-2 repeats through a different mechanism. Together, these two SNPs capture the major genetic determinants of elevated Lp(a) in Europeans. Individuals carrying variant alleles at both positions face dramatically elevated risk2222 dramatically elevated risk
OR 4.87 compared to non-carriers at both variants, which is substantially greater than the sum of individual effects.

The cardiovascular risk from rs3798220 is independent of and additive to LDL cholesterol2323 independent of and additive to LDL cholesterol
meaning Lp(a) contributes residual risk beyond what statins and LDL targets address. Carriers with concurrent elevated LDL face compounded atherosclerotic burden.

For the interaction between rs3798220 and rs10455872 producing amplified Lp(a) risk: both CT/CC genotypes at rs3798220 combined with AG/GG at rs10455872 produce an extremely high-risk haplotype warranting aggressive Lp(a)-targeted therapy, with OR 4.87 for coronary disease representing one of the highest effect sizes for common variant combinations in cardiovascular genetics.

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal Lp(a) Risk Normal

Common genotype with no rs3798220-related elevation in Lp(a) or cardiovascular risk

You carry two copies of the common T allele at rs3798220, meaning this specific variant does not elevate your lipoprotein(a) levels or increase your cardiovascular risk above baseline. About 96% of people of European ancestry share your genotype. Your Lp(a) levels are determined by other genetic factors — primarily the KIV-2 repeat count and other LPA variants — and are likely in the population-typical range (median ~10 mg/dL in Europeans). A one-time Lp(a) measurement remains clinically useful as independent assessment of this important risk factor.

CT Elevated Lp(a) Risk High Risk

One C allele markedly elevates Lp(a) levels and approximately doubles cardiovascular event risk

The Ile4399Met substitution in apolipoprotein(a)'s protease-like domain is linked to smaller LPA isoforms that are produced more efficiently, resulting in persistently elevated circulating Lp(a). Because Lp(a) levels are largely genetically fixed and unresponsive to diet or standard lipid-lowering drugs, this genotype creates a source of residual cardiovascular risk that operates independently of LDL cholesterol.

The aspirin interaction is mechanistically coherent: elevated Lp(a) promotes thrombosis by competing with plasminogen for fibrin binding and inhibiting clot dissolution. Aspirin's antiplatelet and anti-thrombotic actions specifically counter this mechanism, which may explain why carriers derive disproportionate benefit. This gene-aspirin interaction had an interaction p=0.048 in the Women's Health Study — statistically meaningful in a pre-specified analysis.

In East and Southeast Asian individuals, the rs3798220 C allele is not in linkage disequilibrium with small KIV-2 alleles, meaning it does not elevate Lp(a) or predict cardiovascular risk in those populations. This profile is specifically for individuals of European or similar ancestry.

CC Very High Lp(a) Risk High Risk

Two C alleles produce extremely elevated Lp(a) and the highest genetic cardiovascular risk from this variant

CC homozygosity for rs3798220 is rare enough that most published studies do not separately report CC outcomes — typically only one or a handful of CC carriers appear in any given cohort. However, the dose-response relationship seen across TT, CT, and CC genotypes is clear: each additional C allele multiplies Lp(a) levels and cardiovascular risk. With Lp(a) levels typically exceeding 150 mg/dL, your cardiovascular risk profile approaches the highest tier where Lp(a)-specific interventions — PCSK9 inhibitors, aspirin, and emerging RNA-based therapies — are most warranted.

Emerging therapies are particularly relevant at this level. Pelacarsen (an antisense oligonucleotide targeting apolipoprotein(a) mRNA) reduces Lp(a) by 80-96% and its efficacy is unaffected by rs3798220 genotype status. The Phase 3 Lp(a) HORIZON trial (n=8,323) results are awaited; compassionate use or trial enrollment may currently be an option. PCSK9 inhibitors provide interim Lp(a) lowering (~20-27%) alongside powerful LDL reduction.