Lipoprotein(a) Genetic Variants Associated With Coronary and Peripheral Vascular Disease but Not With Stroke Risk in the Heart Protection Study

Hopewell, Jemma C.; Clarke, Robert; Parish, Sarah; Armitage, Jane; Lathrop, Mark; Hager, Jörg; Collins, Rory

doi:10.1161/circgenetics.110.958371

Cited by 49 publications

(38 citation statements)

References 25 publications

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“…At least 1 risk allele was detected in 61.3%, in comparison with only 9.0% and 20.6% in PROCARDIS and the Heart Protection Study. 6,14 There was no difference in event rates between risk allele carriers and those without risk alleles. The difference between Lp(a) concentrations of patients with and without risk alleles was not clinically relevant.…”

Section: Discussionmentioning

confidence: 86%

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Lipoprotein Apheresis in Patients With Maximally Tolerated Lipid-Lowering Therapy, Lipoprotein(a)-Hyperlipoproteinemia, and Progressive Cardiovascular Disease

Leebmann¹,

Roeseler²,

Julius³

et al. 2013

Circulation

283

151

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Background— Lipoprotein(a) (Lp(a)) hyperlipoproteinemia is a major risk factor for cardiovascular disease, which is not affected by treatment of other cardiovascular risk factors. This study sought to assess the effect of chronic lipoprotein apheresis (LA) on the incidence of cardiovascular events in patients with progressive cardiovascular disease receiving maximally tolerated lipid-lowering treatment. Methods and Results— In a prospective observational multicenter study, 170 patients were investigated who commenced LA because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease. Patients were characterized regarding plasma lipid status, lipid-lowering drug treatment, and variants at the LPA gene locus. The incidence rates of cardiovascular events 2 years before (y-2 and y-1) and prospectively 2 years during LA treatment (y+1, y+2) were compared. The mean age of patients was 51 years at the first cardiovascular event and 57 years at the first LA. Before LA, mean low-density lipoprotein cholesterol and Lp(a) were 2.56±1.04 mmol·L −1 (99.0±40.1 mg·dL −1 ) and Lp(a) 3.74±1.63 µmol·L −1 (104.9±45.7 mg·dL −1 ), respectively. Mean annual rates for major adverse coronary events declined from 0.41 for 2 years before LA to 0.09 for 2 years during LA ( P <0.0001). Event rates including all vascular beds declined from 0.61 to 0.16 ( P <0.0001). Analysis of single years revealed increasing major adverse coronary event rates from 0.30 to 0.54 ( P =0.001) for y-2 to y-1 before LA, decline to 0.14 from y-1 to y+1 ( P <0.0001) and to 0.05 from y+1 to y+2 ( P =0.014). Conclusions— In patients with Lp(a)-hyperlipoproteinemia, progressive cardiovascular disease, and maximally tolerated lipid-lowering medication, LA effectively lowered the incidence rate of cardiovascular events. Clinical Trial Registration— URL: https://drks-neu.uniklinik-freiburg.de . Unique identifier: DRKS00003119.

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Section: Discussionmentioning

confidence: 86%

“…Information from the 2 single-nucleotide polymorphisms was combined into a single LPA genotype. 6,14 Outcome Parameter…”

Section: Laboratory Measurementsmentioning

confidence: 99%

Lipoprotein Apheresis in Patients With Maximally Tolerated Lipid-Lowering Therapy, Lipoprotein(a)-Hyperlipoproteinemia, and Progressive Cardiovascular Disease

Leebmann¹,

Roeseler²,

Julius³

et al. 2013

Circulation

283

151

View full text Add to dashboard Cite

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“…33 In prospective studies, rs3798220 was associated (1) with incident MI among 3849 Caucasian men and women age 65 years or older in the Cardiovascular Health Study (CHS), 36 (2) with incident major cardiovascular events (including MI, ischemic stroke, and cardiovascular death) among 25 131 initially healthy women age 45 years or older in the Women's Health Study (WHS), 29 and (3) with incident CHD (a composite of MI, CHD death, and coronary revascularization) among 5330 aspirin nonusers (but not among 1422 aspirin users) age 45 to 64 years in the Atherosclerosis Risk in Communities (ARIC) study. 38 This SNP was not associated with incident CHD among 14 465 participants in the HPS study 39 or with incident CHD among 1328 men and 1552 women in the Framingham Offspring study. 40 In a meta-analysis that combined results from these case-control and prospective studies (see Methods and online-only Data Supplement Materials), carriers of the 4399Met allele had a 57% increased risk of CHD, compared with noncarriers (Pϭ1.04ϫ10 Ϫ11 , Figure 2A).…”

Section: Association Of Lpa Variants With Cardiovascular Diseasementioning

confidence: 95%

“…The intronic rs10455872 SNP was reported to be associated with CHD 30 and with MI 35 in case-control studies and with incident CHD in a prospective study. 39 In a meta-analysis of these studies (see Methods and online-only Data Supplement Materials) the risk of CHD was 42% higher per copy of the minor allele (G) of rs10455872 (11% of the Caucasian populations carry at least 1 G allele; Table) (Pϭ3.80ϫ10 Ϫ6 , Figure 3). The rs10455872 and rs3798220 SNPs are 49 kb apart and are not in linkage disequilibrium (r 2 Ͻ0.01).…”

Section: Association Of Lpa Variants With Cardiovascular Diseasementioning

confidence: 99%

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

Luke

Shiffman

et al. 2011

Circ Cardiovasc Genet

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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...

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“…18 In contrast, a genetic study reported that an LPA genotype score that explains about a third of the variation in Lp(a) levels, and was strongly associated with CHD, was not associated with prevalent or incident IS in those with or without previous CHD. 19 In a subsequent study, Helgadottir et al 20 reported that LPA alleles associated with higher Lp(a) levels were associated with higher risk of large artery IS, but not with either cardioembolic or small vessel IS. Thus, any impact of Lp(a) levels on IS may be subtype specific.…”

Section: Lipoprotein(a)mentioning

confidence: 97%