Summary Background Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction when information is available for other risk factors. We studied ...the separate and combined associations of body-mass index (BMI), waist circumference, and waist-to-hip ratio with risk of first-onset cardiovascular disease. Methods We used individual records from 58 cohorts to calculate hazard ratios (HRs) per 1 SD higher baseline values (4·56 kg/m2 higher BMI, 12·6 cm higher waist circumference, and 0·083 higher waist-to-hip ratio) and measures of risk discrimination and reclassification. Serial adiposity assessments were used to calculate regression dilution ratios. Results Individual records were available for 221 934 people in 17 countries (14 297 incident cardiovascular disease outcomes; 1·87 million person-years at risk). Serial adiposity assessments were made in up to 63 821 people (mean interval 5·7 years SD 3·9). In people with BMI of 20 kg/m2 or higher, HRs for cardiovascular disease were 1·23 (95% CI 1·17–1·29) with BMI, 1·27 (1·20–1·33) with waist circumference, and 1·25 (1·19–1·31) with waist-to-hip ratio, after adjustment for age, sex, and smoking status. After further adjustment for baseline systolic blood pressure, history of diabetes, and total and HDL cholesterol, corresponding HRs were 1·07 (1·03–1·11) with BMI, 1·10 (1·05–1·14) with waist circumference, and 1·12 (1·08–1·15) with waist-to-hip ratio. Addition of information on BMI, waist circumference, or waist-to-hip ratio to a cardiovascular disease risk prediction model containing conventional risk factors did not importantly improve risk discrimination (C-index changes of −0·0001, −0·0001, and 0·0008, respectively), nor classification of participants to categories of predicted 10-year risk (net reclassification improvement −0·19%, −0·05%, and −0·05%, respectively). Findings were similar when adiposity measures were considered in combination. Reproducibility was greater for BMI (regression dilution ratio 0·95, 95% CI 0·93–0·97) than for waist circumference (0·86, 0·83–0·89) or waist-to-hip ratio (0·63, 0·57–0·70). Interpretation BMI, waist circumference, and waist-to-hip ratio, whether assessed singly or in combination, do not importantly improve cardiovascular disease risk prediction in people in developed countries when additional information is available for systolic blood pressure, history of diabetes, and lipids. Funding British Heart Foundation and UK Medical Research Council.
Abstract
Background/Introduction
A quarter of all strokes are caused by cerebral small vessel disease (CSVD), which is also the most common pathology underlying vascular dementia. 1 White matter ...hyperintensities (WMH), a radiological marker detectable on magnetic resonance imaging (MRI), can serve as a proxy for CSVD. WMH is associated with stroke, increased risk of dementia and functional decline in older age. 2,3
Purpose
We aimed at investigating the genetic architecture of WMH using cerebral MRI data.
Methods
We used imaging data ∼40,000 individuals from the UK Biobank, a large population-based, prospective cohort study. We selected individuals with available total volume of WMH from T1 and T2_FLAIR images.
We performed a genome-wide association study (GWAS) on autosomal genetic variants assuming an additive model based on genotype dosages with BOLT-LMM treating WMH as outcome.
We applied LD score regression (LDSC software) to estimate the genetic correlation between WMH traits and traits selected based on availability and relevance for cardiovascular disease.
Results
We included a total of 36,577 individuals with available quality controlled cerebral MRI data.
Genome-wide analysis identified 20 loci of statistical significance, six of which are not previously reported (Fig. 1). Within these novel loci, the following genes are located in proximity to lead variants: EHBP1, OTX1, WDPCP, VCAN, WNT16, FAM3C, ERI1, PRAG1, CACNB2, MTHFSD, FOXL1, FOXC2. Using BOLT, we found the heritability of WMH to be 37%.
We investigated genetic correlation between WMH and multiple phenotypes (Fig. 2). We observed the highest correlation with small vessel stroke (rg=0.56, P=3.9x10–4) Interestingly, WMH was genetically correlated with left atrial volume (rg=0.24, P=2.8x10–3).
Conclusion
In a GWAS on WMH acquired from cerebral MRI, we identified 20 significant loci, of which six are novel. This genetic study provides insights on the biological understanding and epidemiology of CSVD.
Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): John and Birthe Meyer FoundationThe Hallas-Møller Emerging Investigator Novo Nordisk
•It is acceptable to screen with nonfasting lipids.•It is recommended to follow up abnormal results with fasting levels.•Non-HDL cholesterol levels can effectively guide ASCVD prevention.•Advanced ...lipoprotein tests may guide therapeutic decisions in select patients.•Better harmonization of advanced lipid measurement methods is needed.•Recommendations for lipids in clinical care.
Lipoprotein measurements are pivotal in the management of patients at risk for atherosclerotic coronary heart disease (CHD) with myocardial infarction and coronary death as the main outcomes, and for atherosclerotic cardiovascular disease (ASCVD), which includes CHD and stroke. Recent developments and changes in guidelines affect optimization of using lipid measures as cardiovascular biomarkers. This scientific statement reviews the pre-analytical, analytical, post-analytical, and clinical aspects of lipoprotein measurements. Highlights include the following: i) It is acceptable to screen with nonfasting lipids. ii) non-high-density lipoprotein HDL-cholesterol (non-HDL-C) is measured reliably in either the fasting or the nonfasting state and can effectively guide ASCVD prevention. iii) low density lipoprotein cholesterol (LDL-C) can be estimated from total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglyceride (TG) measurements. For patients with LDL-C>100 mg/dL and TG ≤150 mg/dL it is reasonable to use the Friedewald formula. However, for those with TG 150-400 mg/dL the Friedewald formula for LDL-C estimation is less accurate. The Martin/Hopkins method is recommended for LDL-C estimation throughout the range of LDL-C levels and up to TG levels of 399 mg/dL. For TG levels ≥400 mg/dL LDL-C estimating equations are currently not recommended and newer methods are being evaluated. iv) When LDL-C or TG screening results are abnormal the clinician should consider obtaining fasting lipids. v) Advanced lipoprotein tests using apolipoprotein B (apoB), LDL Particle Number (LDL-P) or remnant cholesterol may help to guide therapeutic decisions in select patients, but data are limited for patients already on lipid lowering therapy with low LDL-C levels. Better harmonization of advanced lipid measurement methods is needed. Lipid measurements are recommended 4-12 weeks after a change in lipid treatment. Lipid laboratory reports should denote desirable values and specifically identify extremely elevated LDL-C levels (≥190 mg/dL at any age or ≥160 mg/dL in children) as severe hypercholesterolemia. Potentially actionable abnormal lipid test results, including fasting triglycerides (TG) ≥500 mg/dL, should be reported as hypertriglyceridemia. Appropriate use and reporting of lipid tests should improve their utility in the management of persons at high risk for ASCVD events.
Abstract
Background/Introduction
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally, and treatment of well-established lifestyle risk factors are cornerstones in ...CVD prevention. An atherogenic lipid profile with high concentrations of low-density lipoprotein (LDL) cholesterol and other apolipoprotein B containing lipoproteins is a driving force in the pathogenesis of atherosclerotic CVD (ASCVD). The lifelong atherosclerotic process is proportional to concentrations of apolipoprotein B-containing lipoproteins, hence risk of developing ASCVD is cumulative over time. The higher the baseline concentrations, the sooner the threshold for increased risk of ASCVD will be reached. It is therefore crucial to implement changes as early as possible and prevent risk factors in occurring – so-called primordial prevention. Childhood has been described as a "window of opportunity" for preventing risk factors in occurring and thus avoiding ASCVD. Whether concentrations of atherogenic lipoproteins at birth can predict future concentrations in early childhood and thus may indicate increased risk of dyslipidemia later in life remains unknown.
Purpose
The aim of the present study was to investigate atherogenic lipid traits during the first year of life, to identify influential factors for lipid concentrations, and to determine whether concentrations at birth can predict future lipid concentrations in early childhood.
Methods
For this purpose, we used the Copenhagen Baby Heart Study comprising more than 13,000 umbilical cord blood samples and parallel venous blood samples from children and parents at birth (n=444), at two months (n=363), and at 14-16 months (n=158). Lipid traits were determined in all samples.
Results
Concentrations of low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (HDL) cholesterol, and apolipoprotein B increased during the first year of life. Girls had higher concentrations at birth and at two months compared with boys. Children born preterm had higher cord blood concentrations than children born at term. A linear mixed model showed that high concentrations of LDL cholesterol, non-HDL cholesterol and apolipoprotein B at birth predicted high concentrations at two months and at 14-16 months. Multivariable adjusted odds ratios (95% CI) for having high concentrations at two months when children had high concentrations at birth were 1.95 (1.01-3.79) for LDL cholesterol, 1.36 (0.69-2.67) for non-HDL cholesterol and 1.90 (1.02-3.53) for apolipoprotein B.
Conclusion
The lipid profile change during the first year of life and sex and gestational age influence concentrations. Children with high concentrations of LDL cholesterol, non-HDL cholesterol and apolipoprotein B at birth had higher levels at two and at 14-16 months. Concentrations at birth may thus be used to identify children at risk of dyslipidemia in later life.
. Haase CL, Frikke‐Schmidt R, Nordestgaard BG, Kateifides AK, Kardassis D, Nielsen LB, Andersen CB, Køber L, Johnsen AH, Grande P, Zannis VI, Tybjærg‐Hansen A (Copenhagen University Hospitals and ...Faculty of Health Sciences, University of Copenhagen, Denmark; University of Crete Medical School, Heraklion, Greece; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA). Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels. J Intern Med 2011; 270: 136–146.
Objectives. To determine whether mutations in APOA1 affect levels of high‐density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) and total mortality in the general population.
Background. Epidemiologically, risk of IHD is inversely related to HDL cholesterol levels. Mutations in apolipoprotein (apo) A‐I, the major protein constituent of HDL, might be associated with low HDL cholesterol and predispose to IHD and early death.
Design. We resequenced APOA1 in 190 individuals and examined the effect of mutations on HDL cholesterol, risk of IHD, myocardial infarction (MI) and mortality in 10 440 individuals in the prospective Copenhagen City Heart Study followed for 31 years. Results were validated in an independent case–control study (n = 16 035). Additionally, we determined plasma ratios of mutant to wildtype (WT) apoA‐I in human heterozygotes and functional effects of mutations in adenovirus‐transfected mice.
Results. We identified a new mutation, A164S (1 : 500 in the general population), which predicted hazard ratios for IHD, MI and total mortality of 3.2 95% confidence interval (CI): 1.6–6.5, 5.5 (95% CI: 2.6–11.7) and 2.5 (95% CI: 1.3–4.8), respectively, in heterozygotes compared with noncarriers. Mean reduction in survival time in heterozygotes was 10 years (P < 0.0001). Results for IHD and MI were confirmed in the case–control study. Furthermore, the ratio of mutant S164 to WT A164 apoA‐I in plasma of heterozygotes was reduced. In addition, A164S heterozygotes had normal plasma lipid and lipoprotein levels, including HDL cholesterol and apoA‐I, and this finding was confirmed in adenovirus‐transfected mice.
Conclusions. A164S is the first mutation in APOA1 to be described that predicts an increased risk of IHD, MI and total mortality without low HDL cholesterol levels.
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