Danish Population-based Studies Research Articles

RF13 | PMON59 Tracking and Cumulative Lifetime Exposure to Circulating IGF-I in 6,459 Healthy Individuals and in SGA Children Treated with GH

Abstract Background: /objective Insulin-like-growth-factor-I (IGF-I) levels in the lower or upper normal range have been proposed as a biomarker of risk for later disease in healthy adults, specifically cardiovascular disease and cancer. In addition, concern has been raised about the frequently observed supraphysiological IGF-I levels in non-growth-hormone-deficient children treated with growth hormone (GH). However, whether a single IGF-I measurement is a valid indicator of cumulative lifetime exposure to IGF-I and thus disease risk is not established. We aimed to evaluate intra-individual longitudinal tracking of IGF-I and IGF-binding-protein-3 (IGFBP-3) levels and to estimate cumulative lifetime exposure to IGF-I in healthy and GH-treated individuals. We hypothesized that individuals follow a certain IGF-I trajectory throughout life and that GH therapy in childhood does not increase lifetime IGF-I exposure substantially. Methods We performed a combined cross-sectional (n=5,326) and longitudinal (n=1,133) study of 6,459 healthy participants (49% male) aged 0­­­–76 years recruited as part of six Danish population-based studies, resulting in a total of 9,963 serum samples. In addition, we included 238 samples from nine short children born small-for-gestational-age (SGA) before, during and after GH treatment. Serum samples were analyzed for IGF-I and IGFBP-3 with the IDS-iSYS immunoassay and anthropometric measures were obtained. Intra-individual tracking was determined by intraclass correlation coefficients (ICC) derived from a linear mixed model with IGF-I (SDS) or IGFBP-3 (SDS) as dependent variable and subject as random effect, unadjusted and adjusted for BMI-changes. Cumulative lifetime exposure to IGF-I was estimated by calculating area under the curve of the predicted SD trajectory from 0-76 years. Results Sex- and age-specific reference curves for IGF-I and IGFBP-3 were established. For IGF-I, ICCs were 0.50 (95% CI: 0.47–0.53) and 0.53 (0.50–0.56) for male and female participants, respectively. ICCs for IGFBP-3 were 0.52 (0.49–0.55) for male participants and 0.59 (0.56–0.62) for female. Cumulative lifetime IGF-I exposure was significantly higher in female (mean ± SD, 12,723 ± 3,691) than in male participants (12,563 ± 3,393); p=0.02. The SGA patients had a mean (range) GH-treatment duration of 9.2 years (5.2–11.9). Treatment caused an increase in estimated cumulative lifetime IGF-I exposure of 1,759 ± 556 shifting them from a mean estimated lifetime exposure without treatment of 9,512 ± 1,889 to 11,271 ± 1,689 with treatment. This corresponded to a rise in IGF-I trajectory (SDS) of 0.55 SD ± 0.18, from -0.89 SD ± 0.57 to -0.35 SD ± 0.49. Conclusion Our results suggest that IGF-I and IGFBP-3 levels are tracking throughout life and that a single measurement reliably reflects lifetime exposure. We, for the first time, estimated lifetime exposure to IGF-I in healthy individuals and show that pediatric GH therapy only slightly increases lifetime exposure and not beyond levels commonly found in the reference population. Presentation: Sunday, June 12, 2022 12:42 p.m. - 12:47 p.m., Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Fish Oil and Vitamin D Supplementations in Pregnancy Protect Against Childhood Croup

Croup is a prevalent respiratory disorder in early childhood most often caused by parainfluenza virus infections. There are no preventive strategies; therefore, we investigated the potential effects of prenatal micronutrient supplementations. To investigate the supplementation effects of (1) 2.4-g n-3 long-chained polyunsaturated fatty acid (n-3 LCPUFA) (fish oil) versus olive oil and (2) high-dose (2800 IU/d) versus standard-dose (400 IU/d) of vitamin D from pregnancy week 24 until 1 week after birth on the risk for offspring croup during the double-blinded first 3 years of life in a secondary analysis of a 2× 2 factorial designed randomized controlled trial. The study was completed in the Danish population-based single-center Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort, which included 736 pregnant women. Croup was diagnosed by physicians' clinical examinations and medical record checks. Potential mediating mechanisms were investigated using blood metabolomics, airway cytokines, and airway microbiome. Of 695 children, 97 had croup before age 3 years (14%). The risk of croup was reduced in the n-3 LCPUFA (ncases / ntotal= 38/346; 11%) versus olive oil group (59 of 349 children; 17%) (hazard ratio= 0.62; 95% CI, 0.41-0.93; P= .02) and in the high-dose vitamin D group (32 of 295 children; 11%) versus the standard-dose group (51 of 286 children; 18%) (hazard ratio= 0.60; 95% CI, 0.38-0.93; P= .02). There was no evidence of interaction or additive effects between the supplements (Pinteraction= .56). Furthermore, the results did not change when they were adjusted for each other, persistent wheeze, and lower respiratory tract infection. This analysis of the double-blinded period of the Copenhagen Prospective Studies on Asthma in Childhood 2010 randomized controlled trial of n-3 LCPUFA and high-dose vitamin D supplementation during pregnancy demonstrated a reduced risk of croup in early childhood.

Lactase persistence, milk intake, and mortality in the Danish general population: a Mendelian randomization study.

Meta-analyses have suggested no association between milk intake and mortality. Since only few studies have been conducted, we investigated the association between the lactase persistent genetic variant LCT-13910 C/T (rs4988235), a proxy for long-term low and high intake of milk, and mortality. We used two Danish population-based studies with self-reported intake of milk and genotyping for LCT-13910 C/T. We obtained information on all-cause and cause-specific mortality (cardiovascular and cancer) from the national Danish registries. We used multivariable adjusted Cox regression to assess the association between milk intake and mortality in 74,241 individuals, and both logistic and Cox-regression to assess the association between genetic lactase persistence and mortality in 82,964 individuals using a Mendelian randomization design. We applied per T-allele, co-dominant and dominant models. During a mean follow-up of 7years, 9759 individuals died, 2166 from cardiovascular disease, and 2822 from cancer. Observationally, there was no association between intake of skimmed milk and all-cause or cardiovascular mortality, and we did not find any associations between intake of semi-skimmed or whole milk with all-cause or cause-specific mortality. Intake of skimmed milk was associated with lower cancer mortality with a hazard ratio of 0.97 (95% CI 0.96-1.00) per doubling in milk intake. Per T-allele, milk intake increased with 0.58 (0.50-0.68) glasses/week. Genetically, we found no associations between the lactase persistent LCT-13910 C/T genotype and all-cause or cause-specific mortality; per T-allele OR (95% CI) for all-cause mortality was 1.02 (0.97-1.06). Our study did not provide strong evidence of observational or genetic associations between milk intake and all-cause or cause-specific mortality.

Sexual inactivity and occurrence of STIs in relation to weight status in women: Two large population-based studies

ABSTRACTThe aim of this study was to examine sexual inactivity and occurrence of selected sexually transmitted infections in relation to body mass index. We used data from two large Danish population-based cross-sectional studies conducted in 1991–1995 (HPV study: 6869 women, aged 22–32 years) and in 2004–2005 (Liva study: 19,484 women, aged 18–45 years). Data were collected using a structured interview and measured weight, height, high-risk human papillomavirus DNA, Chlamydia DNA for the HPV study and a structured questionnaire for the Liva study. Overweight and obese women were more likely to have had no lifetime sexual partner or no sexual partner in the last year, e.g., obese women had a threefold (95 percent CI: 1.95–5.04) odds ratio of having had no sexual partner in the last year compared to normal weight women. Additionally, overweight and obese women had a lower likelihood of genital warts and high-risk human papillomavirus infection. A similar tendency was found for self-reported Chlamydia, but not with presence of Chlamydia DNA. If higher likelihood of no lifetime or recent sexual partners among overweight and obese women reflects unmet sexual needs, it could give rise to concern because quality of sexual life is associated with general quality of life.

Comparison of three competitive immunoassays for measurement of TSH receptor antibodies in patients with Graves’ disease

Thyrotropin (TSH) receptor antibodies (TRAb) mediate the hyperthyroidism of Graves’ disease (GD). The aim of the study was to compare the diagnostic performance and assay agreement between three immunoassays for the measurement of TRAb in patients with newly diagnosed GD. TRAb was measured with three different assays [H-TRAb (BRAHMS Diagnostica), M22-Man (RSR Limited) and M22-Aut (Roche Diagnostics)] in 387 participants who were recruited from two Danish population-based studies and diagnosed with GD (n = 101), multinodular toxic goitre (n = 88), primary autoimmune hypothyroidism (n = 100) or included as controls (n = 98). Coefficient of variation for duplicate measurements with each of the three assays were H-TRAb: 3.6%, M22-Man: 9.4%, M22-Aut: 7.7%. Frequency of TRAb positivity in patients with GD were H-TRAb: 95%, M22-Man: 94%, M22-Aut: 96%. Receiver operating characteristic analysis revealed a high sensitivity (H-TRAb: 95%, M22-Man: 93%, M22-Aut: 95%) and specificity (H-TRAb: 99%, M22-Man: 99%, M22-Aut: 97%) for the diagnosis of GD with all assays. Comparison of TRAb levels showed inter-assay variability and values were considerably lower with the M22-Man assay. All TRAb assays showed a high diagnostic performance for GD, but a high inter-assay variability was observed limiting the use of different assays in clinical monitoring of patients with GD.

Association studies of genetic scores of serum vitamin B12 and folate levels with symptoms of depression and anxiety in two danish population studies.

Observational studies have suggested low serum levels of vitamin B12 or folate to be risk factors of depression and anxiety. However, these results may be biased by confounding and reverse causation. Mendelian randomization studies are not subject to these limitations. The aim was to examine the association of genetic scores of vitamin B12 and folate-associated alleles with depression and anxiety. The study included 4126 participants from two Danish population-based studies. Serum vitamin B12 and folate were measured. Weighed allele scores were calculated as the sum of weights (genetic effect sizes) for 12 and two variants increasing circulating levels of vitamin B12 and folate, respectively. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety. An increased weighed allele score for serum vitamin B12 was associated with decreased odds of a SCL-90-R score above the 90th percentile (OR 0.540 (95%CI 0.302-0.967)) in Health2006 but not in Inter99, in the pooled analysis (OR 0.817 (95%CI 0.331-2.018)) or with other outcomes. The weighed allele score for serum folate was not associated with any of the measured outcome variables: SCL-90-R scores of depression (pooled OR 0.603 (95%CI 0.101-3.602)), anxiety (pooled OR 0.619 (95%CI 0.110-3.495)), combined score or history of doctor-diagnosed depression or anxiety. Our results do not provide evidence for a causal effect of circulating folate or vitamin B12 on the risk of depression or anxiety. However, we cannot rule out small to moderate effects, and thus large scale studies are needed.

Drinking water nitrate estimation at household-level in Danish population-based long-term epidemiologic studies

This study presents an approach making drinking water quality data from the Danish national geodatabase Jupiter available for epidemiological studies on long-term health effects of drinking water quality. Drinking water quality was assigned to all Danish households using spatial methods, and the related uncertainty due to sampling density was identified. Nitrate was used as an example contaminant. From 1978, 98% of all Danish households were geocoded with their precise location, yielding a total of 69 million evaluated household-years. Households supplied by a private well (4% of all household-years) were identified; the remaining majority was supplied by public waterworks. Water supply areas were connected to the Jupiter geodatabase to estimate drinking water quality at publicly supplied households. For privately supplied households, the exposure estimate had a substantially higher uncertainty, with 52% of household-years never being sampled, compared with 1% of publicly supplied household-years. For the 18% of all household-years with no nitrate samples, concentrations were estimated by interpolation and an uncertainty score based on the closest nitrate measurement was introduced. While nitrate was used as an example contaminant, the proposed approach is generic and can be used for all monitored drinking water parameters, after preprocessing and validation of the specific data and assumptions.

Genetic determinants of serum vitamin B12 and their relation to body mass index

Lower serum vitamin B12 levels have been related to adverse metabolic health profiles, including adiposity. We used a Mendelian randomization design to test whether this relation might be causal. We included two Danish population-based studies (ntotal = 9311). Linear regression was used to test for associations between (1) serum vitamin B12 levels and body mass index (BMI), (2) genetic variants and serum vitamin B12 levels, and (3) genetic variants and BMI. The effect of a genetically determined decrease in serum vitamin B12 on BMI was estimated by instrumental variable regression. Decreased serum vitamin B12 associated with increased BMI (P < 1 × 10−4). A genetic risk score based on eight vitamin B12 associated variants associated strongly with serum vitamin B12 (P < 2 × 10−43), but not with BMI (P = 0.91). Instrumental variable regression showed that a 20% decrease in serum vitamin B12 was associated with a 0.09 kg/m2 (95% CI 0.05; 0.13) increase in BMI (P = 3 × 10−5), whereas a genetically induced 20% decrease in serum vitamin B12 had no effect on BMI [−0.03 (95% CI −0.22; 0.16) kg/m2] (P = 0.74). Nevertheless, the strongest serum vitamin B12 variant, FUT2 rs602662, which was excluded from the B12 genetic risk score due to potential pleiotropic effects, showed a per allele effect of 0.15 kg/m2 (95% CI 0.01; 0.32) on BMI (P = 0.03). This association was accentuated including two German cohorts (ntotal = 5050), with a combined effect of 0.19 kg/m2 (95% CI 0.08; 0.30) (P = 4 × 10−4). We found no support for a causal role of decreased serum vitamin B12 levels in obesity. However, our study suggests that FUT2, through its regulation of the cross-talk between gut microbes and the human host, might explain a part of the observational association between serum vitamin B12 and BMI.

Neonatal vitamin D status is not associated with later risk of type 1 diabetes: results from two large Danish population-based studies.

The aim of this work was to assess whether neonatal levels of 25-hydroxyvitamin D (25(OH)D) are associated with risk of developing type 1 diabetes before the age of 18years. Two large-scale studies with different designs-a case-cohort and a case-control-were conducted using Danish national register data and biobank material. Weighted Cox regression and conditional logistic regression were used to calculate HRs and ORs, respectively. The concentration of 25(OH)D was assessed from neonatal dried blood spots using highly sensitive liquid chromatography-tandem mass spectrometry. Quintiles of 25(OH)D3 were used in the main analyses. The case-cohort study included 912 type 1 diabetes cases and 2866 individuals without type 1 diabetes born in Denmark between 1981 and 2002 and followed up until the end of 2012. The case-control study included 527 matched case-control pairs born between 1981 and 1999 and followed up until May 2004. Both studies found no association between 25(OH)D3 levels and later risk of developing type 1 diabetes. The neonatal total 25(OH)D levels in the studies were low: 46% (case-cohort study) and 51% (case-control study) of individuals had 25(OH)D levels <25nmol/l. Our two large-scale national studies showed that 25(OH)D3 levels around the time of birth were not associated with later type 1 diabetes risk. Whether higher levels of 25(OH)D3 during pregnancy, acquired by higher doses of supplementation than are recommended today in most countries, could protect the offspring against type 1 diabetes cannot be ruled out by the present studies.

Mendelian randomisation study of the associations of vitamin B12 and folate genetic risk scores with blood pressure and fasting serum lipid levels in three Danish population-based studies.

The aim was to examine the association of genetic risk scores (GRSs) of vitamin B12 and folate-associated variants with blood pressure and lipids. The study included 12 532 adults from three population-based studies (Inter99, Health2006 and Dan-MONICA10) conducted in Denmark. GRSs were calculated by summarising the number of vitamin B12 and folate increasing alleles. Weighted GRSs were calculated as the sum of weights for each allele corresponding to genetic effects sizes. GRSs for serum vitamin B12 and folate were associated with serum vitamin B12 and folate, respectively. The β coefficients (95% confidence interval (CI), P-value) for regression of log-transformed serum B12/folate on the weighted GRSs were 0.57 (0.54, 0.61), P<0.001 and 0.85 (0.70, 1.01), P<0.01. No associations were observed between the vitamin B12 GRSs and any of the blood pressure and lipid-related outcomes in the combined analyses. Increasing number of folate increasing alleles was associated with increased high-density lipoprotein (HDL) cholesterol concentrations (β coefficient (95% CI, P-value) for regression of log-transformed HDL on the weighted GRSs, 0.081 (0.015, 0.148), P=0.017), but not with blood pressure, triglyceride, and low-density lipoprotein and total cholesterol levels. GRSs were not associated with blood pressure and lipid levels, except for an association between the GRS for folate and HDL cholesterol. Further studies are needed to determine whether a causal association between folate and HDL cholesterol exists.

Lifestyle-Related Factors and Atopy in Seven Danish Population-Based Studies from Different Time Periods.

BackgroundThe prevalence of allergic respiratory disease tends to increase in populations that adopt the so-called Westernized lifestyle. We investigated the association between atopy and several possible lifestyle-related factors in seven Danish population-based studies.MethodsA total of 20048 persons participated in the seven studies. We used logistic regression to analyse the associations between possible determinants and atopy defined as serum specific IgE or skin prick test positivity against inhalant allergens. Associations were expressed as odds ratios (ORs) with 95% confidence intervals (95% CIs). In addition, individual participant data meta-analyses were performed.ResultsAtopy was significantly associated with younger age (OR per 1 year increase in age: 0.97; 95% CI: 0.97, 0.98); male sex (OR for males versus females: 1.34; 95% CI: 1.24, 1.45), heavy drinking (OR for heavy drinkers versus light drinkers: 1.15; 95% CI: 1.04, 1.27), never smoking (OR for current versus never smokers: 0.73; 95% CI: 0.67, 0.80), and higher educational level (OR for educated versus uneducated: 1.27; 95% CI: 1.15, 1.41). Atopy was not associated with blood pressure, serum total cholesterol, physical activity or body mass except in women only, where we found a positive association (OR for obese vs. normal weight: 1.18; 95% CI: 1.00, 1.39) with ptrend = 0.032.ConclusionsOf interest for preventive purposes, we found that atopy was associated with some of the reversible lifestyle-related factors that characterize a Westernized lifestyle.

Serum 25-hydroxyvitamin D and self-reported mental health status in adult Danes.

Vitamin D receptors and vitamin D-metabolising enzymes are present in the brain and in the central nervous system at sites responsible for the regulation of emotions and behaviour. This raises the hypothesis that low vitamin D is related to poor mental health. Our aim was to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and the self-reported symptoms and diagnosis of depression and anxiety in the adult general population. Serum 25(OH)D was measured in three Danish population-based studies, including 5308 adults aged 18-64 years. After 5 years, 2004 participants were re-examined. Symptoms of depression and anxiety were assessed by the Symptom Check List (SCL)-90-R, and self-reported doctor-diagnosed depression and anxiety was recorded by using a questionnaire. Serum 25(OH)D was not associated with SCL average scores for depression and anxiety when analysed by quantile median regression adjusted for sex, age and other potential confounders. The β-coefficient and 95% confidence interval (CI) per 10 nmol/l serum 25(OH)D were 0.00 (-0.00 to 0.01) and P=0.23 for depression and -0.00 (-0.01 to 0.00) and P=0.19 for anxiety. Furthermore, no evidence of an association was observed with longitudinal changes (combining depression and anxiety score: β (95% CI)=0.00 (-0.00 to 0.00), P=0.90), with scores >90 percentiles (odds ratio (OR) (95% CI)=1.02 (0.98-1.07), P=0.32), or with self-reported history (OR (95% CI)=1.02 (0.97-1.07), P=0.47) or incidence (OR (95% CI)=1.02 (0.92-1.12), P=0.77) of doctor-diagnosed depression and/or anxiety. Our results suggest that low serum 25(OH)D is not associated with self-reported symptoms/diagnosis of depression and anxiety.

Atopy and Development of Cancer: A Population-Based Prospective Study

Atopy is the familial or personal propensity to develop IgE antibodies against environmental allergens. Atopy, theoretically, could both prevent and promote the development of cancer. However, evidence from epidemiologic studies has been inconclusive. We investigated the longitudinal association between atopy and the incidence of total and specific types of cancers of 5 Danish population-based studies. Atopy was defined as serum specific IgE positivity against inhalant allergens. A total of 14,849 persons were followed up prospectively by linkage to the Danish Cancer Registry. We used Cox regression analysis, and risk was expressed as hazard ratios (HR) (95% CIs) for persons with atopy versus those without atopy. There were 1919 incident cancers (median follow-up, 11.8 years). There were no statistically significant associations between atopy and risk of any cancer (HR 1.00 [95% CI, 0.89-1.12]), any cancer excluding nonmelanoma skin cancer (HR 0.93 [95% CI, 0.82-1.07]), head and neck cancer (HR 1.74 [95% CI, 0.98-3.09]), colorectal cancer (HR 0.92 [95% CI, 0.64-1.32]), cancer of the bronchus and lung (HR 0.78 [95% CI, 0.54-1.13]), breast cancer (HR 1.00 [95% CI, 0.73-1.37]), cancer of the uterus (HR 0.90 [95% CI, 0.43- 1.88]), prostate cancer (HR 0.79 [95% CI, 0.53-1.18]), urinary cancer (HR 1.08 [95% CI, 0.60-1.96]), malignant melanoma (HR 0.95 [95% CI, 0.54-1.66]), and nonmelanoma skin cancer (HR 1.20 [95% CI, 0.98-1.47]). Our data did not support the hypothesis that atopy is associated with an altered risk of total cancer development, although effects of atopy on specific types of cancer cannot be excluded.

The 2014 Danish references from birth to 20 years for height, weight and body mass index

To construct new Danish growth charts for 0- to 20-year-olds and to compare them with Danish references from 1982 and with World Health Organization (WHO) standards for children aged 0-5 years from 2006, by applying similar inclusion and exclusion criteria. Anthropometric data from three contemporary Danish population-based studies were combined. References for height were based on healthy Caucasian children born at term. A total of 12,671 height measurements (8055 in boys and 4616 in girls) were included. Reference charts were developed using the generalised additive models for location, scale and shape. From prepubertal ages, a secular increase in height was observed for both genders. The differences were most pronounced in puberty, and final heights were increased by 1.4 cm in boys and 2.9 cm in girls compared to 1982 references. In boys, but not girls an upward shift in body mass index (BMI) above median levels was found. Reference curves for height were superimposable with standard curves based on the selective WHO criteria. Danish children were longer/taller and heavier and they had larger head circumferences than those reported in the recent multiethnic WHO standards. We recommend national implementation of these contemporary 2014 Danish references for anthropometric measurements.

Investigating the causal effect of vitamin D on serum adiponectin using a mendelian randomization approach

The aim was to examine the causal effect of vitamin D on serum adiponectin using a multiple instrument Mendelian randomization approach. Serum 25-hydroxy vitamin D (25(OH)D) and serum total or high molecular weight (HMW) adiponectin were measured in two Danish population-based studies: the Inter99 study (6405 adults, 30-60 years) conducted in 1999-2001, and the MONICA10 study (2656 adults, 41-71 years) conducted in 1993-1994. In the Inter99 study, serum 25(OH)D was positively associated with total adiponectin (the effect estimate in % per doubling of 25(OH)D was 4.78, 95% CI: 1.96, 7.68, P<0.001). Using variations in the vitamin D-binding protein gene and the filaggrin gene as instrumental variables, the causal effect in % was estimated to 61.46, 95% CI: 17.51, 120.28, P=0.003 higher adiponectin per doubling of 25(OH)D. In the MONICA10 cohort, no significant association was observed between the serum concentrations of 25(OH)D and HMW adiponectin (the effect estimate in % per doubling of 25(OH)D was -1.51, 95% CI: -5.80, 2.98, P=0.50), although the instrumental variables analysis to some extent supported a positive causal association (the effect estimate in % per doubling of 25(OH)D was 37.13, 95% CI: -3.67, 95.20, P=0.080). The results indicate a possible causal association between serum 25(OH)D and total adiponectin. However, the association was not replicated for HMW adiponectin. Thus, further studies are needed to confirm a causal relationship.

Mechanisms of Lipoprotein(a) Pathogenicity

High quality, large prospective population-based studies are like well-tended orchards: they take many years to bear fruit, but when they do, they yield a bounty. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology , fruit is on offer from 2 important Danish population-based studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, which previously provided key evidence that genetically based levels of C-reactive protein were not related to vascular disease,1 and from 3 case-control studies conducted in Copenhagen. In the present study,2 Kamstrup et al3 use a Mendelian randomization study similar to that described in 2009 to probe the relationship between plasma-derived and genetically determined levels of lipoprotein(a) (Lp[a]), and the development of venous thromboembolism (VTE; thrombotic events), vascular stenosis (atherosclerotic events), and myocardial infarction (which they called combined atherosclerotic and thrombotic events). See accompanying article on page 1732 The ultimate goal of the study was to further our understanding of the mechanism of Lp(a) action in vascular disease, which has been controversial. Results over the years from both in vitro and in vivo studies have reflected the duality of Lp(a) structure: in this regard, both proatherosclerotic (low-density lipoprotein–like) and prothrombotic (plasminogen-like) functions have been reported (Figure).4 By comparing the contribution of genetically elevated Lp(a) to arterial stenosis, thrombotic events secondary to atherosclerosis, and pure thrombotic events in …