Genetic Variants Associated with Lp(a) Lipoprotein Level and Coronary Disease

Abstract

BACKGROUND: An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. METHODS: We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. RESULTS: Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. CONCLUSIONS: We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease

Lack of association of rs3798220 with small apolipoprotein(a) isoforms and high lipoprotein(a) levels in East and Southeast Asians

“…This is in contrast to individuals of European descent, where the association of the C allele with small KIV CNV sizes and high Lp(a) concentrations was consistently demonstrated with similar numbers of variant alleles studied [21,23,28]. In East and Southeast Asians, rs3798220 C rather seems to be associated with KIV CNV sizes larger than their population mean.…”

“…In these populations the variant allele of rs3798220 is associated with high Lp(a) and short KIV-2 CNV alleles, and linked to an about 70% increased risk for coronary artery disease (CAD) [21][22][23]. An allele frequency of 13% was reported in German CAD patients undergoing lipid apheresis for very high Lp(a) [24].…”

Genetics: Implications for Prevention and Management of Coronary Artery Disease

“…Well-powered studies using this array firmly established associations between CAD and genetic variants in LPA, the gene encoding lipoprotein(a), and confirmed several early GWAS discoveries for CAD (9p21, COL4A1/COL4A2, ZC3HC1, and CYP17A1) (72,73). However, these studies also confirmed a lack of association for a vast majority of variants within candidate genes related to CAD (72,73).…”

Lipoprotein(a) and the Apolipoprotein B/A1 Ratio Independently Associate With Surgery for Aortic Stenosis Only in Patients With Concomitant Coronary Artery Disease

“…It has been suggested that Lp(a) plays a causal role in the development of atherosclerotic diseases, and high circulating levels of Lp(a) were prospectively associated with coronary heart disease and ischemic stroke. In addition, genetically determined small isoforms of Lp(a), as a result of either kringle repeats or the above‐mentioned SNPs, were associated with cardiovascular events; that is, Mendelian randomization studies have supported a causal relationship 11, 21, 22, 23. This concept was further supported by the finding that genetically determined low levels of Lp(a) due to loss of function of the proprotein convertase subtilisin/kexin type‐9 protein were associated with reduced risks of both MI and AS 24.…”