Genetic Variants in the Apolipoprotein(a) Gene and Coronary Heart Disease

Abstract

T wo independent single-nucleotide polymorphisms (SNPs) in the gene encoding apolipoprotein(a) (LPA) have been shown to be associated with coronary heart disease (CHD) and lipoprotein(a) levels in Caucasians. For the missense SNP rs3798220 (Ile4399Met), carriers of 1 or 2 copies of the minor allele (Met) were at 57% increased risk of CHD. For the intronic SNP rs10455872, the risk of CHD increased by 42% for each copy of the minor allele. The rs3798220 SNP was also associated with differential response to aspirin therapy in the Women's Health Study; carriers of the minor allele had a significant reduction in CHD events from aspirin therapy, whereas noncarriers did not have a significant reduction.Lipoprotein(a) [Lp(a)] is a lipoprotein particle that consists of an apolipoprotein(a) [apo(a)] molecule covalently linked by a disulfide bond to the apolipoprotein B-100 (apoB-100) component of a low-density lipoprotein (LDL)-like particle (Figure 1, modified on the Albers et al 1 figure). The LPA gene, which encodes apo(a), is thought to have been generated by a duplication of the neighboring plasminogen gene. 2 Like the plasminogen protein, the apo(a) has a protease-like domain and multiple kringle domains. Different variants of the LPA gene can affect the plasma level of Lp(a), encode apo(a) size variants (ie, kringle repeat length variations), or both.Lp(a) may contribute to cardiovascular disease through complex mechanisms that involve proatherogenic and prothrombotic pathways. 3,4 Lp(a) accumulates in the arterial wall of patients with coronary heart disease (CHD) 5 and contributes to cholesterol deposition, induction of endothelial adhesion molecules, chemotaxis of monocytes, foam cell formation, and also to smooth muscle cell proliferation and dedifferentiation. 6 Lp(a) binds oxidized phospholipids that are capable of modulating inflammation and progression of atherosclerosis. 7 In addition, the structural homology between apo(a) and plasminogen suggests that Lp(a) promotes thrombosis. 8 For example, several studies have suggested that Lp(a) can interfere with plasminogen activation by competing for binding to fibrin and consequently attenuate fibrinolysis. 9,10 Lp(a) may also promote thrombosis by a mechanism independent of plasminogen. 11Apo(a) size, kringle repeat number, and Lp(a) plasma levels are all associated with CHD. [12][13][14] For example, depending on the gene variant, the LPA gene can encode apo(a) that contains from 3 to Ͼ40 kringle IV type 2 (KIV-2) repeats, and the risk of CHD or stroke was 2-fold higher among individuals having small apo(a) molecules (Յ22 KIV-2 repeats) compared with those having larger apo(a) molecules (Ͼ22 repeats) in a recent meta-analysis of 40 studies involving Ͼ11 000 patients and Ͼ46 000 control subjects. 15 Elevated Lp(a) plasma levels are also a risk factor for CHD: a recent meta-analysis of 36 prospective studies involving Ͼ126 000 individuals found "continuous, independent, and modest associations of Lp(a) concentration with risk of CHD and stroke." 16 Howeve...

Structure, function, and genetics of lipoprotein (a)

“…The strongest association was observed for rs10455872 (an intronic SNP) and rs3798220 (a nonsynonymous SNP in the PD) (157). A subsequent meta-analysis of these findings reported that CHD risk in the carriers of the minor alleles of rs10455872 and rs3798220 was increased by 42 and 57%, respectively (217).…”

“…As outlined, GWASs and candidate gene approaches have identified SNPs within LPA associated with CHD (157,196,197,217,218). The question of whether the results of such association studies in one population (i.e., Europeans) are valid for other ethnic groups has recently been addressed for the nonsynonymous SNP, rs3798220 (201).…”

Recent advances in physiological lipoprotein metabolism

“…In addition to apo(a) and apoB100, Lp(a) particles also contain apoAI, apoE and traces of apoAII [168]. Single nucleotide polymorphisms in the LPA gene locus and repeat polymorphisms in the promoter region of the LPA gene which increase Lp(a) levels have been shown to be associated with increased CHD risk [169,170]. Further, the risk for CHD increased continuously with a decreasing number of kringle 4 repeats [171].…”

Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a)

“…7B ). OxPLs were clearly present in apo(a) captured from the 17K and 17K ⌬ VP constructs, which are missing KV and KV and the protease domain respectively, the I4399M r-apo(a) construct, which represents the LPA single nucleotide polymorphism (SNP) rs3798220 with an isoleucine to methionine substitution associated with CAD ( 45,46 ) and high OxPL/apoB levels ( 47 ), and human plasma. No OxPLs were detectable on 17K ⌬ Asp 57 r-apo(a) (chimpanzee and gorilla variant) that contains KV but has a substitution of alanine to aspartate 57 on KIV 10 .…”