Context: Lipoprotein(a) is a cardiovascular risk factor. Levels of lipoprotein(a) are predominantly determined by apolipoprotein(a) gene variation, including a pentanucleotide repeat promoter ...polymorphism.
Objective: We tested the hypothesis that apolipoprotein(a) pentanucleotide repeat genotype predicts elevated lipoprotein(a) levels and risk of myocardial infarction (MI) and ischemic heart disease (IHD) in the general population.
Design: We used a cohort study of the Danish general population, The Copenhagen City Heart Study, including 10,276 individuals of which 860 and 1,781 developed MI and IHD, respectively, during up to 31 yr of follow-up, and a case-control study including 1,814 IHD patients and 5,076 controls. Follow-up was 100% complete.
Results: Allele frequencies were 0.0018, 0.0018, 0.6750, 0.1596, 0.1465, 0.0146, and 0.0004 for 6, 7, 8, 9, 10, 11, and 12 repeats, respectively. Mean lipoprotein(a) levels were 40, 36, and 27 mg/dl for individuals with 14–15, 16, and 17–22 repeats (sum of repeats on both alleles), respectively (trend, P < 0.001). Cumulative incidence of MI and IHD was increased for individuals with 14–15 vs. at least 16 repeats (log rank, P < 0.001 and P = 0.002). Multifactorially adjusted hazard ratios for 14–15 and 17–22 vs. 16 repeats were 3.1 (95% confidence interval, 1.6–5.8) and 1.0 (0.9–1.2) for MI and 2.2 (1.3–3.6) and 1.0 (0.9–1.1) for IHD. In the case-control study, multifactorially adjusted odds ratios for 14–15 and 17–22 vs. 16 repeats were 2.9 (1.1–7.8) and 0.9 (0.8–1.0) for MI and 2.5 (1.0–6.0) and 0.9 (0.8–1.0) for IHD.
Conclusions: Apolipoprotein(a) 14–15 pentanucleotide repeats predict elevated levels of lipoprotein(a) and a 3- and 2-fold increased risk of MI and IHD in the general population.
Abstract APOE ε2/3/4 genotypes affect plasma lipoprotein(a); however, the effects of APOE genotypes on the prediction of myocardial infarction and aortic valve stenosis by lipoprotein(a) are unknown. ...We tested the hypothesis that APOE ε 2/3/4 genotype affects plasma lipoprotein(a), the contribution of plasma apoE levels to this association as well as the associated risk of myocardial infarction and aortic valve stenosis. In 46,615 individuals from the general population, we examined plasma lipoprotein(a), APOE ε2/3/4 , and incidence of myocardial infarction (n = 1807) and aortic valve stenosis (n = 345) over 37 years of follow-up (range: 0.3 to 38 years). Compared with ε 33, age- and sex-adjusted lipoprotein(a) concentrations were lower by 15% in ε 23, by 24% in ε 24, and by 36% in ε 22; adjusted for plasma apolipoprotein E, corresponding values were 22%, 28%, and 62%. These reductions were independent of LPA genotypes. Compared with ε 2 carriers with lipoprotein(a) ≤50 mg/dL, the hazard ratio for myocardial infarction was 1.26 (95% confidence interval: 1.06 to 1.49) for ε 2 noncarriers with lipoprotein(a) ≤50 mg/dL, 1.68 (1.21 to 2.32) for ε 2 carriers with lipoprotein(a) >50 mg/dL, and 1.92 (1.59 to 2.32) for ε 2 noncarriers with lipoprotein(a) >50 mg/dL (interaction, P = 0.57); corresponding values for aortic valve stenosis were 1.05 (0.74 to 1.51), 1.49 (0.72 to 3.08), and 2.04 (1.46 to 2.26) (interaction, P = 0.50). Further adjustment for APOE ε2/3/4 genotype had minimal influence on these risk estimates. APOE ε2 is a strong genetic determinant of low lipoprotein(a) concentrations but does not modify the causal association of lipoprotein(a) with myocardial infarction or aortic valve stenosis. We measured APOE ε genotypes and lipoprotein(a). APOE ε genotypes affect lipoprotein(a) concentrations but not the associated risk of myocardial infarction and aortic valve stenosis.
Evidence on ustekinumab safety in pregnancy is gradually expanding, but its clearance in the postnatal period is unknown. The aim of this study was to investigate ustekinumab concentrations in ...umbilical cord blood and rates of clearance after birth, as well as how these correlate with maternal drug concentrations, risk of infection, and developmental milestones during the first year of life.
Pregnant women with inflammatory bowel disease were prospectively recruited from 19 hospitals in Denmark and the Netherlands between 2018 and 2022. Infant infections leading to hospitalization/antibiotics and developmental milestones were assessed. Serum ustekinumab concentrations were measured at delivery and specific time points. Nonlinear regression analysis was applied to estimate clearance.
In 78 live-born infants from 76 pregnancies, we observed a low risk of adverse pregnancy outcomes and normal developmental milestones. At birth, the median infant-mother ustekinumab ratio was 2.18 (95% confidence interval, 1.69–2.81). Mean time to infant clearance was 6.7 months (95% confidence interval, 6.1–7.3 months). One in 4 infants at 6 months had an extremely low median concentration of 0.015 μg/mL (range 0.005–0.12 μg/mL). No variation in median ustekinumab concentration was noted between infants with (2.8 range 0.4–6.9 μg/mL) and without (3.1 range 0.7–11.0 μg/mL) infections during the first year of life (P = .41).
No adverse signals after intrauterine exposure to ustekinumab were observed with respect to pregnancy outcome, infections, or developmental milestones during the first year of life. Infant ustekinumab concentration was not associated with risk of infections. With the ustekinumab clearance profile, live attenuated vaccination from 6 months of age seems of low risk.
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One in four pregnancies end in a pregnancy loss. Although the effect on couples is well documented, evidence-based treatments and prediction models are absent. Fetal aneuploidy is associated with a ...higher chance of a next successful pregnancy compared with euploid pregnancy loss in which underlying maternal conditions might be causal. Ploidy diagnostics are therefore advantageous but challenging as they require collection of the pregnancy tissue. Cell-free fetal DNA (cffDNA) from maternal blood has the potential for evaluation of fetal ploidy status, but no large-scale validation of the method has been done.
In this prospective cohort study, women with a pregnancy loss were recruited as a part of the Copenhagen Pregnancy Loss (COPL) study from three gynaecological clinics at public hospitals in Denmark. Women were eligible for inclusion if older than 18 years with a pregnancy loss before gestational age 22 weeks (ie, 154 days) and with an intrauterine pregnancy confirmed by ultrasound (including anembryonic sac), and women with pregnancies of unknown location or molar pregnancies were excluded. Maternal blood was collected while pregnancy tissue was still in situ or within 24 h after pregnancy tissue had passed and was analysed by genome-wide sequencing of cffDNA. Direct sequencing of the pregnancy tissue was done as reference.
We included 1000 consecutive women, at the time of a pregnancy loss diagnosis, between Nov 12, 2020, and May 1, 2022. Results from the first 333 women with a pregnancy loss (recruited between Nov 12, 2020, and Aug 14, 2021) were used to evaluate the validity of cffDNA-based testing. Results from the other 667 women were included to evaluate cffDNA performance and result distribution in a larger cohort of 1000 women in total. Gestational age of fetus ranged from 35–149 days (mean of 70·5 days SD 16·5, or 10 weeks plus 1 day). The cffDNA-based test had a sensitivity for aneuploidy detection of 85% (95% CI 79–90) and a specificity of 93% (95% CI 88–96) compared with direct sequencing of the pregnancy tissue. Among 1000 cffDNA-based test results, 446 (45%) were euploid, 405 (41%) aneuploid, 37 (4%) had multiple aneuploidies, and 112 (11%) were inconclusive. 105 (32%) of 333 women either did not manage to collect the pregnancy tissue or collected a sample classified as unknown tissue giving a high risk of being maternal.
This validation of cffDNA-based testing in pregnancy loss shows the potential and feasibility of the method to distinguish euploid and aneuploid pregnancy loss for improved clinical management and benefit of future reproductive medicine and women's health research.
Ole Kirks Foundation, BioInnovation Institute Foundation, and the Novo Nordisk Foundation.
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