rs3798220, also known as I4399M or Ile4399Met, is a SNP in the apolipoprotein(A) LPA gene that has been reported to be associated with elevated plasma lipoprotein(a) [Lp(a)] and increased cardiovascular risk, and in particular, coronary artery disease.
In one study, 25,131 initially healthy Caucasian participants in the Women's Health Study were followed for ~10 years. rs3798220(C) allele carriers (3.7%) in the placebo (i.e. not receiving aspirin) group had a 2x higher risk of major cardiovascular events than non-carriers (age-adjusted hazard ratio (HR) of 2.21, CI: 1.39-3.52). Among rs3798220(C) carriers, the risk was reduced more than twofold by aspirin: for aspirin compared with placebo the age-adjusted HR was 0.44 (CI: 0.20-0.94). The risk was not significantly reduced among non-carriers (age-adjusted HR=0.91, CI: 0.77-1.08). This interaction between carrier status and aspirin allocation was significant (P=0.048). In summary, rs3798220(C) carriers had higher plasma lipoprotein(a) and had double the risk of cardiovascular events, but also benefited more from taking aspirin.[PMID 18775538]
In another study, compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (CI: 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels (P=0.003), leading to the conclusion that the LPA I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.[PMID 17569884]
[PMID 20032323] Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease
celera says rs3798220 is an independent predictor of risk for
Carriers of the rs3798220(C) have higher levels of plasma Lp(a).
[PMID 20605575] Single variants can explain the association between coronary heart disease and haplotypes in the apolipoprotein(a) locus
|Title||Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease|
|Odds Ratio||1.5100 [1.33-1.70]|
[PMID 22192511] KIF6, LPA, TAS2R50, and VAMP8 genetic variation, low density lipoprotein cholesterol lowering response to pravastatin, and heart disease risk reduction in the elderly
[PMID 18682748] Analysis of 17,576 potentially functional SNPs in three case-control studies of myocardial infarction.
[PMID 19060906] Common variants at 30 loci contribute to polygenic dyslipidemia.
[PMID 19880117] The I4399M variant of apolipoprotein(a) is associated with increased oxidized phospholipids on apolipoprotein B-100 particles.
[PMID 21252144] Lipoprotein(a) genetic variants associated with coronary and peripheral vascular disease but not with stroke risk in the Heart Protection Study.
[PMID 21283670] Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans.
[PMID 22560621] Cost-effectiveness model of use of genetic testing as an aid in assessing the likely benefit of aspirin therapy for primary prevention of cardiovascular disease.
|qualified_impact||Insufficiently evaluated pathogenic|
|summary||This variant strongly associated with an increase in Lp(a) lipoprotein levels, associated with an increased risk of coronary disease in a dominant or incomplete dominant manner. This variant is also referred to as I4399M in literature; this discrepancy is due to a highly variable number of kringle repeats in the protein (2-43), our version for inferring amino acid changes from genetic variants uses an assembly with 15 copies.|
[PMID 23735648] Validation and Quantification of Genetic Determinants of Lipoprotein-a Levels and Predictive Value for Angiographic Coronary Artery Disease
[PMID 23978127] Lack of association between lipoprotein(a) genetic variants and subsequent cardiovascular events in Chinese Han patients with coronary artery disease after percutaneous coronary intervention
[PMID 24161338] Elevated Lipoprotein(a) and Risk of Aortic Valve Stenosis in the General Population
[PMID 22898070] Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.
[PMID 23100282] Impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection Study.
[PMID 23278389] Two rare variants explain association with acute myocardial infarction in an extended genomic region including the apolipoprotein(A) gene.
[PMID 23375930] Extreme lipoprotein(a) levels and improved cardiovascular risk prediction.