Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis

Saleheen, Danish; Haycock, Philip; Zhao, Wei; Rasheed, Awais; Taleb, Adam; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Akhtar, Saba; Qamar, Nadeem; Zaman, Khan Shah; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Mallick, Nadeem Hayyat; Ishaq, Mohammad; Rasheed, Syed Zahed; Memon, Fazal-ur-Rehman; Mahmood, Khalid; Ahmed, Naveeduddin; Frossard, Philippe; Tsimikas, Sotirios; Witztum, Joseph L.; Marcovina, Santica M.; Sandhu, Manjinder S.; Rader, Daniel J.; Danesh, John

doi:10.1016/s2213-8587(17)30088-8

Cited by 180 publications

(142 citation statements)

References 30 publications

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“…6,14 LPA kringle IV type 2 repeats and raised lipoprotein(a) concentrations in serum have been associated with increased prevalence of coronary heart disease in a mendelian randomisation analysis. 26 The findings from previous studies and this analysis, therefore, support a causal link between lipoprotein(a) and atherosclerosis development.…”

Section: Discussionsupporting

confidence: 69%

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Zewinger

Kleber

Tragante

et al. 2017

The Lancet Diabetes & Endocrinology

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Summary Background Lipoprotein(a) concentrations in plasma are associated with cardiovascular risk in the general population. Whether lipoprotein(a) concentrations or LPA genetic variants predict long-term mortality in patients with established coronary heart disease remains less clear. Methods We obtained data from 3313 patients with established coronary heart disease in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. We tested associations of tertiles of lipoprotein(a) concentration in plasma and two LPA single-nucleotide polymorphisms ([SNPs] rs10455872 and rs3798220) with all-cause mortality and cardiovascular mortality by Cox regression analysis and with severity of disease by generalised linear modelling, with and without adjustment for age, sex, diabetes diagnosis, systolic blood pressure, BMI, smoking status, estimated glomerular filtration rate, LDL-cholesterol concentration, and use of lipid-lowering therapy. Results for plasma lipoprotein(a) concentrations were validated in five independent studies involving 10 195 patients with established coronary heart disease. Results for genetic associations were replicated through large-scale collaborative analysis in the GENIUS-CHD consortium, comprising 106 353 patients with established coronary heart disease and 19 332 deaths in 22 studies or cohorts. Findings The median follow-up was 9·9 years. Increased severity of coronary heart disease was associated with lipoprotein(a) concentrations in plasma in the highest tertile (adjusted hazard radio [HR] 1·44, 95% CI 1·14–1·83) and the presence of either LPA SNP (1·88, 1·40–2·53). No associations were found in LURIC with all-cause mortality (highest tertile of lipoprotein(a) concentration in plasma 0·95, 0·81–1·11 and either LPA SNP 1·10, 0·92–1·31) or cardiovascular mortality (0·99, 0·81–1·2 and 1·13, 0·90–1·40, respectively) or in the validation studies. Interpretation In patients with prevalent coronary heart disease, lipoprotein(a) concentrations and genetic variants showed no associations with mortality. We conclude that these variables are not useful risk factors to measure to predict progression to death after coronary heart disease is established. Funding Seventh Framework Programme for Research and Technical Development (AtheroRemo and RiskyCAD), INTERREG IV Oberrhein Programme, Deutsche Nierenstiftung, Else-Kroener Fresenius Foundation, Deutsche Stiftung für Herzforschung, Deutsche Forschungsgemeinschaft, Saarland University, German Federal Ministry of Education and Research, Willy Robert Pitzer Foundation, and Waldburg-Zeil Clinics Isny.

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Section: Discussionsupporting

confidence: 69%

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Zewinger

Kleber

Tragante

et al. 2017

The Lancet Diabetes & Endocrinology

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“…8b). Our model ascribed greatest importance to rs10455872, a previously described SNP associated with KIV2-CN 14,15 . The full 61-variant model in our validation dataset explained 60% of variation in genotyped KIV2-CN (Supplemental Table 5, Supplemental Fig.…”

Section: Structural Variant Analyses: Discovery and Imputation Of Kivmentioning

confidence: 97%

“…Genetic variation at the LPA locus is an optimal instrument for Mendelian randomization (MR) as it strongly and specifically influences circulating Lp(a) levels. Past studies have performed Lp(a) MR across clinical and metabolic traits using genetic risk scores comprised of between 1-18 variants 14,39,40 . Here, we performed MR using three different genetic instruments per cohort to distinguish variant classes influencing Lp(a) phenotypes: 1) an expanded genetic risk score, "GRS," comprised of the sum of the KIV2-CN-adjusted variant effects from LD-pruned variants in a ~4MB window around LPA with sub-threshold significance (P < 1x10 -4 ); 2) a "KIV2-CN" score using the directly genotyped or imputed KIV2-CN; and 3) a combined "GRS+KIV2-CN" score combining scores from (1) and (2).…”

Section: Mendelian Randomizationmentioning

confidence: 99%

“…However, the most recent genome-wide association studies have only explained approximately half of the genetic heritability 11 . Epidemiologic studies and genetic analyses in European and Asian populations have causally linked Lp(a) concentrations with atherosclerotic cardiovascular disease, independent of other plasma lipids including LDL cholesterol [12][13][14][15] . As a result, Lp(a) has emerged as a promising therapeutic target for atherosclerotic cardiovascular diseases.Plasma Lp(a) distributions vary significantly among ethnicities but these differences are not explained by known differential KIV2-CN distributions between the ethnicities and are posited to be related to primary sequence 16 .…”

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confidence: 99%

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Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

Zekavat

Ruotsalainen

Handsaker

et al. 2017

Preprint

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Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle where apolipoprotein(a) (protein product of the LPA gene) is covalently attached to apolipoprotein B. Lp(a) is a highly heritable, causal risk factor for cardiovascular diseases and varies in concentrations across ancestries. To comprehensively delineate the inherited basis for plasma Lp(a), we performed deep-coverage whole genome sequencing in 8,392 individuals of European and African American ancestries. Through whole genome variant discovery and direct genotyping of all structural variants overlapping LPA, we quantified the 5.5kb kringle IV-2 copy number (KIV2-CN), a known LPA structural polymorphism, and developed a model for its imputation. Through common variant analysis, we discovered a novel locus (SORT1) associated with Lp(a)-cholesterol, and also genetic modifiers of KIV2-CN. Furthermore, in contrast to previous GWAS studies, we explain most of the heritability of Lp(a), observing Lp(a) to be 85% heritable among African Americans and 75% among Europeans, yet with notable inter-ethnic heterogeneity. Through analyses of aggregates of rare coding and non-coding variants with Lp(a)-cholesterol, we found the only genome-wide significant signal to be at a non-coding SLC22A3 intronic window also previously described to be associated with Lp(a); however, this association was mitigated by adjustment with KIV2-CN. Finally, using an additional imputation dataset (N=27,344), we performed Mendelian randomization of LPA variant classes, finding that genetically regulated Lp(a) is more strongly associated with incident cardiovascular diseases than directly measured Lp(a), and is significantly associated with measures of subclinical atherosclerosis in African Americans.

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“…Single nucleotide polymorphisms (SNP) at the LPA locus like rs10455872 and rs3798220 were also associated with an increased level of Lp(a) (13,14). Several studies using Mendelian randomization approaches have demonstrated that LPA variants were associated with the risk of coronary heart disease (CHD) and myocardial infarction (14)(15)(16)(17), which supports a causal role of Lp(a) in ischemic cardiovascular disease.…”

Section: Introductionmentioning

confidence: 89%

LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk

Muhanhali¹,

Zhai²,

Ling

et al. 2018

Journal of Lipid Research

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Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis

Cited by 180 publications

References 30 publications

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Relations between lipoprotein(a) concentrations, LPA genetic variants, and the risk of mortality in patients with established coronary heart disease: a molecular and genetic association study

Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries

LPA kringle IV type 2 is associated with type 2 diabetes in a Chinese population with very high cardiovascular risk

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