A Polymorphism in the Protease-Like Domain of Apolipoprotein(a) Is Associated With Severe Coronary Artery Disease

Abstract

Objectives-The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD). Methods and Results-We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12 077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in LPA, CALM1, HAP1, AP3B1, and ABCG2) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD: LPA I4399M (rs3798220). LPA encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels (Pϭ0.003). Key Words: coronary arteriosclerosis Ⅲ genetics Ⅲ single nucleotide polymorphism Ⅲ lipoprotein(a) Ⅲ risk factors S evere coronary artery disease (CAD), characterized by occlusive epicardial coronary stenosis, and its consequences such as myocardial infarction (MI) are the leading causes of death in the United States. 1 Several major risk factors for coronary disease are well established and form the basis of current risk assessment algorithms. 2,3 However, some risk factors for coronary disease have not yet been identified, because some of the patients with coronary disease do not have traditional risk factors, 4 and traditional risk factors do not reliably predict premature MI. 5 The unidentified risk factors probably include genetic variants because genetics is considered to have an important role in coronary disease, 6,7 and a family history of cardiovascular disease is an independent risk factor. 8 One approach to identify genetic variants associated with complex diseases, such as coronary disease, is to use multiple association studies. We have previously identified genetic variants associated with MI and early-onset MI by testing thousands of putative functional SNPs in 3 case-control studies. 7,9 Thus, we have taken the same approach for angiographically defined severe CAD in 3 casecontrol studies, and asked if we could identify genetic variants associated with severe CAD. Conclusions-The Methods Study DesignBecause testing 12 077 SNPs for association with severe CAD could result in false-positives, we used 3 consecutive case-control studies. We generated a limited number of hypotheses in the first 2 studies by identifying a subset of SNPs that were nominally associated with severe CAD and had the same risk alleles in both studies and then tested these hypotheses in a third study. Angiographic Assessme...

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.…”

“…Under neutral expectations, the rather narrow range of KIV CNV sizes associated with rs3798220 C in Europeans [21,22] together with the variant's lower population frequency could be interpreted as a younger age of the mutation in Europe than in Asia, where it is far more frequent and associated with a wider CNV size range. Our haplotype analyses comprising other SNPs in LPA indicated that the more common background haplotype of rs3798220 variant alleles in Asians is comparatively old, as it was frequent (42.5%) and has acquired further mutations restricted to this haplotype.…”

“…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].…”

“…Since rs3798220 induces an amino acid change from Isoleucine to Methionine (I4399M) in the protease-like domain of apo(a), it has been suggested that its pathophysiological significance extends beyond its role as a marker for short apo(a) isoforms but rather confers risk on its own [21,28].…”

Lipoprotein(a) and Cardiometabolic Diseases: The Mystery Continues

“…2. It has been reported that a minor allele variant of Apo(a) (rs3798220) is associated with both increased Lp(a) plasma concentrations and increased cardiovascular risk (12 ). In WHS, 3.7% of the study population carried the minor allele (13 ).…”