Lipoprotein(a) is causally associated with calcific aortic valve disease (CAVD). Lipoprotein(a) carries proinflammatory and procalcific oxidized phospholipids (OxPL). We tested whether the CAVD risk ...is mediated by the content of OxPL on lipoprotein(a).
A case-control study was performed within the Copenhagen General Population Study (n=87 980), including 725 CAVD cases (1977-2013) and 1413 controls free of cardiovascular disease. OxPL carried by apoB (apolipoprotein B-100; OxPL-apoB) or apolipoprotein(a) (OxPL-apo(a)) containing lipoproteins, lipoprotein(a) levels,
kringle IV type 2 repeat, and rs10455872 genetic variants were measured. OxPL-apoB and OxPL-apo(a) levels correlated with lipoprotein(a) levels among cases (
=0.75 and
=0.95; both
<0.001) and controls (
=0.65 and
=0.93; both
<0.001). OxPL-apoB levels associated with risk of CAVD with odds ratios of 1.2 (95% confidence interval CI:1.0-1.6) for 34th to 66th percentile levels, 1.6 (95% CI, 1.2-2.1) for 67th to 90th percentile levels, 2.0 (95% CI, 1.3-3.0) for 91st to 95th percentile levels, and 3.4 (95% CI, 2.1-5.5) for levels >95th percentile, versus levels <34th percentile (trend,
<0.001). Corresponding odds ratios for OxPL-apo(a) were 1.2 (95% CI, 1.0-1.5), 1.2(95% CI, 0.9-1.6), 2.1(95% CI, 1.4-3.1), and 2.9(95% CI, 1.9-4.5; trend,
<0.001) and were similar for lipoprotein(a).
genotypes associated with OxPL-apoB, OxPL-apo(a), and lipoprotein(a) levels and explained 34%, 46%, and 39%, respectively, of the total variation in levels.
genotypes associated with risk of CAVD; a doubling in genetically determined OxPL-apoB, OxPL-apo(a), and lipoprotein(a) levels associated with odds ratio of CAVD of 1.18 (95% CI, 1.10-1.27), 1.09 (95% CI, 1.05-1.13), and 1.09 (95% CI, 1.05-1.14), respectively, comparable to the corresponding observational estimates of 1.27 (95% CI, 1.16-1.39), 1.13 (95% CI, 1.08-1.18), and 1.11 (95% CI, 1.06-1.17).
OxPL-apoB and OxPL-apo(a) are novel genetic and potentially causal risk factors for CAVD and may explain the association of lipoprotein(a) with CAVD.
Elevated lipoprotein(a) levels are associated with myocardial infarction (MI) in some but not all studies. Limitations of previous studies include lack of risk estimates for extreme lipoprotein(a) ...levels, measurements in long-term frozen samples, no correction for regression dilution bias, and lack of absolute risk estimates in the general population. We tested the hypothesis that extreme lipoprotein(a) levels predict MI in the general population, measuring levels shortly after sampling, correcting for regression dilution bias, and calculating hazard ratios and absolute risk estimates.
We examined 9330 men and women from the general population in the Copenhagen City Heart Study. During 10 years of follow-up, 498 participants developed MI. In women, multifactorially adjusted hazard ratios for MI for elevated lipoprotein(a) levels were 1.1 (95% CI, 0.6 to 1.9) for 5 to 29 mg/dL (22nd to 66th percentile), 1.7 (1.0 to 3.1) for 30 to 84 mg/dL (67th to 89th percentile), 2.6 (1.2 to 5.9) for 85 to 119 mg/dL (90th to 95th percentile), and 3.6 (1.7 to 7.7) for > or =120 mg/dL (>95th percentile) versus levels <5 mg/dL (<22nd percentile). Equivalent values in men were 1.5 (0.9 to 2.3), 1.6 (1.0 to 2.6), 2.6 (1.2 to 5.5), and 3.7 (1.7 to 8.0). Absolute 10-year risks of MI were 10% and 20% in smoking, hypertensive women aged >60 years with lipoprotein(a) levels of <5 and > or =120 mg/dL, respectively. Equivalent values in men were 19% and 35%.
We observed a stepwise increase in risk of MI with increasing levels of lipoprotein(a), with no evidence of a threshold effect. Extreme lipoprotein(a) levels predict a 3- to 4-fold increase in risk of MI in the general population and absolute 10-year risks of 20% and 35% in high-risk women and men.
Lipoprotein(a) and risk of type 2 diabetes Mora, Samia; Kamstrup, Pia R; Rifai, Nader ...
Clinical chemistry (Baltimore, Md.),
08/2010, Letnik:
56, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Previous studies have demonstrated that cardiovascular risk is higher with increased lipoprotein(a) Lp(a). Whether Lp(a) concentration is related to type 2 diabetes is unclear.
In 26 746 healthy US ...women (mean age 54.6 years), we prospectively examined baseline Lp(a) concentrations and incident type 2 diabetes (n = 1670) for a follow-up period of 13 years. We confirmed our findings in 9652 Danish men and women with prevalent diabetes (n = 419). Analyses were adjusted for risk factors that included age, race, smoking, hormone use, family history, blood pressure, body mass index, hemoglobin A(1c) (Hb A(1c)), C-reactive protein, and lipids.
Lp(a) was inversely associated with incident diabetes, with fully adjusted hazard ratios (HRs) and 95% CIs for quintiles 2-5 vs quintile 1 of 0.87 (0.75-1.01), 0.80 (0.68-0.93), 0.88 (0.76-1.02), and 0.78 (0.67-0.91); P for trend 0.002. The association was stronger in nonfasting women, for whom respective HRs were 0.79 (0.58-1.09), 0.78 (0.57-1.08), 0.66 (0.46-0.93), and 0.56 (0.40-0.80); P for trend 0.001; P for interaction with fasting status 0.002. When we used Lp(a) > or =10 mg/L and Hb A(1c) <5% as reference values, the adjusted HRs were 1.62 (0.91-2.89) for Lp(a) <10 mg/L and Hb A(1c) <5%, 3.50 (3.06-4.01) for Lp(a) > or =10 mg/L and Hb A(1c) 5%-<6.5%, and 5.36 (4.00-7.19) for Lp(a) <10 mg/L and Hb A(1c) 5%-<6.5%. Results were similar in nonfasting Danish men and women, for whom adjusted odds ratios were 0.75 (0.55-1.03), 0.64 (0.46-0.88), 0.74 (0.54-1.01), and 0.58 (0.42-0.79) for Lp(a) quintiles 2-5 vs quintile 1; P for trend 0.002.
Our results indicated that Lp(a) was associated inversely with risk of type 2 diabetes independently of risk factors, in contrast to prior findings of positive associations of Lp(a) with cardiovascular risk.
Objective
For decades, it has been suggested that small dense low‐density lipoprotein (sdLDL) may be particularly atherogenic. High levels of sdLDL are associated with an increased risk of ischemic ...heart disease; however, the association of sdLDL with ischemic stroke has not been explored in a large prospective study on the general population. We tested the hypothesis that high sdLDL cholesterol levels are associated with an increased risk of ischemic stroke.
Methods
This prospective study included 38,319 individuals from the Copenhagen General Population Study with fresh sample measurements of sdLDL cholesterol. Median follow‐up time was 3.1 years. We observed 302 and 74 ischemic and hemorrhagic strokes from baseline in 2013 to 2017 to the end of follow‐up in 2018. For comparison, we included estimates for large buoyant LDL cholesterol and total LDL cholesterol.
Results
Higher levels of sdLDL cholesterol were log‐linearly associated with increased risk of ischemic stroke. Compared with individuals with sdLDL cholesterol in the lowest tertile (≤0.60 mmol/l; ≤23 mg/dl) the multivariable adjusted hazard ratio for ischemic stroke was 1.79 (95% confidence interval = 1.31–2.43) for the highest tertile (≥0.86 mmol/l; ≥33 mg/dl). Multivariable adjusted hazard ratios for ischemic stroke per 1 mmol/l (38.7 mg/dl) higher levels were 1.69 (1.28–2.22) for sdLDL cholesterol, 0.95 (0.78–1.16) for large buoyant LDL cholesterol, and 1.08 (0.93–1.25) for total LDL cholesterol. Hazard ratios were similar when further adjusting for body mass index (BMI) and diabetes mellitus in the biological pathway in combination with related lipids and lipoproteins.
Interpretation
Higher sdLDL cholesterol levels were robustly associated with increased risk of ischemic stroke. ANN NEUROL 2023;93:952–964
The aim of the present study was to determine whether lipoprotein(a) Lp(a), considered a causal risk factor for cardiovascular disease, primarily promotes thrombosis or atherosclerosis.
Using a ...Mendelian randomization study design, we measured plasma Lp(a) and genetically elevated Lp(a) levels through the LPA kringle IV type 2 repeat genotype in 41231 individuals. We included 2 general population studies of both venous thrombosis and combined thrombosis and atherosclerosis in coronary arteries (=myocardial infarction), and 3 -case--control studies of atherosclerotic stenosis. Neither Lp(a) tertiles nor LPA kringle IV type 2 tertiles associated with the risk of venous thrombosis in general population studies (trend: P=0.12-0.76), but did each associate with risk of coronary, carotid, and femoral atherosclerotic stenosis in -case--control studies (trend: P<0.001 to 0.04). Lp(a) and LPA kringle IV type 2 tertiles also associated with the risk of myocardial infarction in general population studies (trend: P<0.001 to 0.003). For doubling of Lp(a) levels, instrumental variable estimates of hazard/odds ratios were 1.02 (95% CI 0.90-1.15) and 1.04 (0.93-1.16) for venous thrombosis in the 2 general population studies, 1.12 (1.01-1.25), 1.17 (1.05-1.32), and 1.16 (1.01-1.35), respectively, for coronary, carotid, and femoral atherosclerotic stenosis in -case-control studies, and 1.21 (1.10-1.33) and 1.17 (1.05-1.29) for myocardial infarction in general population studies.
This supports that Lp(a) primarily promotes atherosclerotic stenosis rather than venous thrombosis.
Lp(a) (lipoproteina)-lowering therapy to reduce cardiovascular disease is under investigation in phase 3 clinical trials. High Lp(a) may be implicated in peripheral artery disease (PAD), abdominal ...aortic aneurysms (AAAs), and major adverse limb events (MALE).
The authors investigated the association of high Lp(a) levels and corresponding LPA genotypes with risk of PAD, AAA, and MALE.
The authors included 108,146 individuals from the Copenhagen General Population Study. During follow-up, 2,450 developed PAD, and 1,251 AAAs. Risk of MALE was assessed in individuals with PAD at baseline and replicated in the Copenhagen City Heart Study.
Higher Lp(a) was associated with a stepwise increase in risk of PAD and AAA (P for trend <0.001). For individuals with Lp(a) levels ≥99th (≥143 mg/dL, ≥307 nmol/L) vs <50th percentile (≤9 mg/dL, ≤17 nmol/L), multivariable-adjusted HRs were 2.99 (95% CI: 2.09-4.30) for PAD and 2.22 (95% CI: 1.21-4.07) for AAA. For individuals with PAD, the corresponding incidence rate ratio for MALE was 3.04 (95% CI: 1.55-5.98). Per 50 mg/dL (105 nmol/L) genetically higher Lp(a) risk ratios were 1.39 (95% CI: 1.24-1.56) for PAD and 1.21 (95% CI: 1.01-1.44) for AAA, consistent with observational risk ratios of 1.33 (95% CI: 1.24-1.43) and 1.27 (95% CI: 1.15-1.41), respectively. In women smokers aged 70 to 79 years with Lp(a) <50th and ≥99th percentile, absolute 10-year risks of PAD were 8% and 21%, and equivalent risks in men 11% and 29%, respectively. For AAA, corresponding risks were 2% and 4% in women, and 5% and 12% in men.
High Lp(a) levels increased risk of PAD, AAA, and MALE by 2- to 3-fold in the general population, opening opportunities for prevention given future Lp(a)-lowering therapies.
Abstract Objective There are no recommendations in guidelines on measuring lipoprotein(a) in the fasting or nonfasting state, or on the influence of inflammation. We tested the hypotheses that ...lipoprotein(a) levels change only minimally in response to normal food intake, and to inflammation. Also, we tested whether normal food intake or inflammation influenced lipoprotein(a)'s ability to predict ischemic heart disease. Methods We studied 34 829 individuals from the Danish general population using the Copenhagen General Population Study and the Copenhagen City Heart Study. Results Lipoprotein(a) levels did not change in response to normal food intake: median fasting levels were 17.3 mg/dL, while median levels at 3–4 h since last meal were 19.4 mg/dL( p = 0.38). Lipoprotein(a) levels increased minimally with increasing levels of C-reactive protein(CRP): median lipoprotein(a) levels at CRP <1 mg/L were 18.0 mg/dL, while median levels at CRP >10 mg/L were 21.1 mg/dL( p < 0.001). Furthermore, highest versus lowest tertile of lipoprotein(a) at <3 h and ≥3 h since last meal was associated with a 1.4(95%CI:1.2–1.6) and 1.4(1.2–1.6) fold increased risk of ischemic heart disease( p = 0.82), and a 1.8(1.5–2.2) and 1.4(1.1–1.7) fold increased risk of myocardial infarction( p = 0.05). The corresponding odds ratios at CRP levels of <2 mg/L and ≥2 mg/L were 1.3(1.2–1.5) and 1.4(1.2–1.6)( p = 0.80) for ischemic heart disease, and 1.5(1.2–1.8) and 1.7(1.4–2.0)( p = 0.38) for myocardial infarction. Conclusions Lipoprotein(a) levels did not change in response to normal food intake, but were minimally increased at increased levels of CRP. The ability of elevated lipoprotein(a) levels to predict ischemic heart disease and myocardial infarction in the general population was not affected by normal food intake or inflammation.
High lipoprotein(a) (Lpa) is the most common genetic dyslipidemia and is a causal factor for myocardial infarction (MI) and aortic stenosis (AS). We sought to estimate the population impact of Lp(a) ...lowering that could be achieved in primary prevention using the therapies in development.
We used published data from 2 prospective cohorts. High Lp(a) was defined as ≥50 mg/dL (≈20th percentile). Relative risk, attributable risk, the attributable risk percentage, population attributable risk, and the population attributable risk percentage were calculated as measures of the population impact. For MI, the event rate was 4.0% versus 2.8% for high versus low Lp(a) (relative risk, 1.46; 95% confidence interval CI, 1.45-1.46). The attributable risk was 1.26% (95% CI, 1.24-1.27), corresponding to 31.3% (95% CI, 31.0-31.7) of the excess MI risk in those with high Lp(a). The population attributable risk was 0.21%, representing a population attributable risk percentage of 7.13%. For AS, the event rate was 1.51% versus 0.78% for high versus low Lp(a) (relative risk, 1.95; 95% CI, 1.94-1.97). The attributable risk was 0.74% (95% CI, 0.73-0.75), corresponding to 48.8% (95% CI, 48.3-49.3) of the excess AS risk in those with high Lp(a). The population attributable risk was 0.13%, representing a population attributable risk percentage of 13.9%. In sensitivity analyses targeting the top 10% of Lp(a), the population attributable risk percentage was 5.2% for MI and 7.8% for AS.
Lp(a) lowering among the top 20% of the population distribution for Lp(a) could prevent 1 in 14 cases of MI and 1 in 7 cases of AS, suggesting a major impact on reducing the burden of cardiovascular disease. Targeting the top 10% could prevent 1 in 20 MI cases and 1 in 12 AS cases.
The physiological role of lipoprotein(a) is unclear; however, lipoprotein(a) may play a role in hemostasis and wound healing. We tested the hypothesis that high lipoprotein(a) concentrations are ...associated with low risk of major bleeding in the brain and airways both observationally and causally (from human genetics).
We examined 109169 individuals from the Copenhagen City Heart Study and the Copenhagen General Population study, 2 similar prospective studies conducted in the Danish general population. Individuals had information on plasma lipoprotein(a) concentrations (n = 59980),
kringle-IV type 2 (KIV-2) number of repeats (n = 98965), and/or
single-nucleotide polymorphism rs10455872 associated with high lipoprotein(a) concentrations (n = 109 169), and information on hospital contacts or death due to major bleeding in brain and airways from registers.
Using extreme phenotypes or genotypes, the multifactorially adjusted hazard ratio for major bleeding in the brain and airways was 0.84 (95%CI: 0.71-0.99) for lipoprotein(a), >800 mg/L vs <110 mg/L; 0.83 (0.73-0.96) for KIV-2, <24 vs >35 number of repeats; and 0.89 (0.81-0.97) for rs10455872 carriers (heterozygotes + homozygotes) vs noncarriers. The corresponding hazard ratios were 0.89 (0.82-0.98) for heterozygotes and 0.59 (0.36-0.98) for homozygotes separately vs rs10455872 noncarriers. Also, for a 1 standard deviation higher lipoprotein(a) (= 310 mg/L), the hazard ratio for major bleeding in the brain and airways was 0.95 (95%CI: 0.91-1.00) observationally, 0.89 (0.80-0.98) causally based on
KIV-2 number of repeats, and 0.94 (0.87-1.02) causally based on
rs10455872.
High lipoprotein(a) concentrations were associated with lower risk of major bleeding in the brain and airways observationally and causally. This indicates that lipoprotein(a) may play a role in hemostasis and wound healing.
Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
We determined genomewide associations with the ...presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval CI, 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently.
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
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