Sandra Wilde

A Genome-wide Association Study Identifies LIPA as a Susceptibility Gene for Coronary Artery Disease

Background— eQTL analyses are important to improve the understanding of genetic association results. We performed a genome-wide association and global gene expression study to identify functionally relevant variants affecting the risk of coronary artery disease (CAD). Methods and Results— In a genome-wide association analysis of 2078 CAD cases and 2953 control subjects, we identified 950 single-nucleotide polymorphisms (SNPs) that were associated with CAD at P<10−3. Subsequent in silico and wet-laboratory replication stages and a final meta-analysis of 21 428 CAD cases and 38 361 control subjects revealed a novel association signal at chromosome 10q23.31 within the LIPA (lysosomal acid lipase A) gene (P=3.7×10−8; odds ratio, 1.1; 95% confidence interval, 1.07 to 1.14). The association of this locus with global gene expression was assessed by genome-wide expression analyses in the monocyte transcriptome of 1494 individuals. The results showed a strong association of this locus with expression of the LIPA transcript (P=1.3×10−96). An assessment of LIPA SNPs and transcript with cardiovascular phenotypes revealed an association of LIPA transcript levels with impaired endothelial function (P=4.4×10−3). Conclusions— The use of data on genetic variants and the addition of data on global monocytic gene expression led to the identification of the novel functional CAD susceptibility locus LIPA, located on chromosome 10q23.31. The respective eSNPs associated with CAD strongly affect LIPA gene expression level, which was related to endothelial dysfunction, a precursor of CAD.

Direct evidence for positive selection of skin, hair, and eye pigmentation in Europeans during the last 5,000 y

Significance Eye, hair, and skin pigmentation are highly variable in humans, particularly in western Eurasian populations. This diversity may be explained by population history, the relaxation of selection pressures, or positive selection. To investigate whether positive natural selection is responsible for depigmentation within Europe, we estimated the strength of selection acting on three genes known to have significant effects on human pigmentation. In a direct approach, these estimates were made using ancient DNA from prehistoric Europeans and computer simulations. This allowed us to determine selection coefficients for a precisely bounded period in the deep past. Our results indicate that strong selection has been operating on pigmentation-related genes within western Eurasia for the past 5,000 y. Pigmentation is a polygenic trait encompassing some of the most visible phenotypic variation observed in humans. Here we present direct estimates of selection acting on functional alleles in three key genes known to be involved in human pigmentation pathways—HERC2, SLC45A2, and TYR—using allele frequency estimates from Eneolithic, Bronze Age, and modern Eastern European samples and forward simulations. Neutrality was overwhelmingly rejected for all alleles studied, with point estimates of selection ranging from around 2–10% per generation. Our results provide direct evidence that strong selection favoring lighter skin, hair, and eye pigmentation has been operating in European populations over the last 5,000 y.

Atrial fibrillation: its prevalence and risk factor profile in the German general population.

BACKGROUND Atrial fibrillation (AF) is an increasingly common problem in primary care, but little is known about its prevalence and the distribution of AF risk factors in the general population. METHODS We determined the prevalence of AF and the distribution of known AF risk factors among persons participating in the population-based Gutenberg Health Study. To this end, we used interview data about the medical diagnosis of AF and electrocardiograms (ECGs) that were performed for the study in 5000 persons aged 35 to 74. The response rate was 60.4%. RESULTS There were 5000 persons in the study sample (age 52.2 ± 11 years; 50.6% were women). The prevalence of AF, weighted for the age and sex distribution of the general population, was 2.5%. AF was found to be more common in older persons, with a more pronounced increase in men: whereas its prevalence was 0.7% in 35- to 44-year-old men, the corresponding figure for the age group 65- to 74 was as high as 10.6%. Twenty five participants (15.5% of AF cases) received their initial diagnosis of AF on the basis of the study ECG. Compared to persons without AF, persons with AF were older and more commonly male, and they had a higher burden of cardiovascular risk factors. 14.3% of persons with AF had none of the well-established risk factors for AF (systolic blood pressure, antihypertensive medication, increased body-mass-index, heart failure). 42.7% of persons with AF were not taking either anticoagulants or platelet inhibitors. CONCLUSION These data indicate that the prevalence of AF in the middle-aged general population is 2.5% overall, and higher in the elderly. AF is thus a significant public health problem, and greater awareness of it is needed.

Predictors and outcomes after transcatheter aortic valve implantation using different approaches according to the valve academic research consortium definitions

We report the results of a large single‐center study evaluating predictors and outcomes after transcatheter aortic valve implantation (TAVI) with different devices and access routes according to the Valve Academic Research Consortium (VARC).

Distribution and Categorization of Left Ventricular Measurements in the General Population Results From the Population-Based Gutenberg Heart Study

Background— Echocardiography, the dominant imaging modality for quantification of left ventricular metrics, has undergone continuing development in the past few decades. However, given the lack of population-based data, current guidelines are still based on restricted and small data sets analyzed with methods including expert opinion. This work presents empirically derived reference values from a large-scale, epidemiologic study conducted with state-of-the-art imaging technology and methods. Methods and Results— The distribution of echocardiographic measurements of the left ventricle was analyzed in a population-based sample of 5000 mid-Europeans from the Gutenberg Heart Study in Germany. The randomly selected, noninstitutionalized sample provides data on apparently healthy individuals, as well as on those with prevalent disease. Standardized echocardiograms were recorded in a comprehensive data set at a single site with centralized training and certification of sonographers. Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated, and nomograms were created by quantile regression. Detailed information is given on the association between left ventricular geometry and age. Conclusions— The rapidly evolving echocardiographic technology with persistent improvements in image quality and new measurement conventions require the evaluation of new reference limits for left ventricular metrics. The present investigation formulates reference limits and nomograms from state-of-the-art technology and methods based on a large population-based data set. The distribution of echocardiographic measures of left ventricular geometry presents, in part, nonlinear associations with age, which should be the subject of future investigations.Background—Echocardiography, the dominant imaging modality for quantification of left ventricular metrics, has undergone continuing development in the past few decades. However, given the lack of population-based data, current guidelines are still based on restricted and small data sets analyzed with methods including expert opinion. This work presents empirically derived reference values from a large-scale, epidemiologic study conducted with state-of-the-art imaging technology and methods. Methods and Results—The distribution of echocardiographic measurements of the left ventricle was analyzed in a population-based sample of 5000 mid-Europeans from the Gutenberg Heart Study in Germany. The randomly selected, noninstitutionalized sample provides data on apparently healthy individuals, as well as on those with prevalent disease. Standardized echocardiograms were recorded in a comprehensive data set at a single site with centralized training and certification of sonographers. Sex-specific reference limits and categories indicating the grade of deviation from the reference were calculated, and nomograms were created by quantile regression. Detailed information is given on the association between left ventricular geometry and age. Conclusions—The rapidly evolving echocardiographic technology with persistent improvements in image quality and new measurement conventions require the evaluation of new reference limits for left ventricular metrics. The present investigation formulates reference limits and nomograms from state-of-the-art technology and methods based on a large population-based data set. The distribution of echocardiographic measures of left ventricular geometry presents, in part, nonlinear associations with age, which should be the subject of future investigations.

Sex Differences in Early Carotid Atherosclerosis (from the Community-Based Gutenberg-Heart Study)

The objectives of this study were to describe gender differences in intima-media thickness (IMT) in a community-based population study and to define normal IMT values for healthy men and women. In total, 4,814 participants (aged 35 to 74 years; 2,433 men, 2,381 women) from the Gutenberg-Heart Study (GHS) were included. IMT was measured at both common carotid arteries using an edge detection system. Median IMT was 0.62 mm (25th percentile 0.55, 75th percentile 0.70) in women and 0.65 mm (25th percentile 0.57, 75th percentile 0.75) in men and was significantly associated with age (p <0.0001). On multivariate analysis, advanced age, smoking, and arterial hypertension were positively associated with higher IMT in men and women. A subgroup of 1,025 subjects without cardiovascular risk factors or previous cardiovascular disease was analyzed to define normal IMT values. Nomograms were calculated according to age and gender. For each age group, IMT >95th percentile was defined as abnormal. In this subgroup, gender differences in IMT became nonsignificant at older ages. At the age of 35 years, IMT was 0.71 mm in men and 0.61 mm in women at the 95th percentile. In comparison, at the age of 74 years, IMT at the 95th percentile was 0.90 mm in men and 0.89 mm in women. In conclusion, men had higher carotid IMT than women, but predictors of early carotid atherosclerosis were similar across genders. In young subjects without cardiovascular risk factors, normal values for IMT were lower in women compared with men. In contrast, in older subjects, gender differences in IMT became nonsignificant.

Multiple Endothelial Biomarkers and Noninvasive Vascular Function in the General Population The Gutenberg Health Study

Vascular reactivity is reflected by blood biomarkers and noninvasive vascular function measurement. The relation of biomarkers to flow-mediated dilation and peripheral arterial tonometry in the general population is little understood. In 5000 individuals (mean age, 56±11 years; age range, 35–74 years; 49% women) of the population-based Gutenberg Health Study we simultaneously assessed 6 biomarkers of cardiovascular function (midregional proadrenomedullin [MR-proADM], midregional pro atrial natriuretic peptide [MR-proANP], N-terminal pro B-type natriuretic peptide, copeptin, C-terminal proendothelin 1, and neopterin) in relation to flow-mediated dilation and peripheral arterial tonometry. Strongest partial correlations (adjusted for age and sex) were observed for baseline pulse amplitude with MR-proADM (r=0.13) and MR-proANP (r=−0.13); hyperemic response variables showed the highest correlation for MR-proADM and peripheral arterial tonometry ratio (r=−0.14). In multivariable linear regression models, strongest associations with baseline vascular function were observed for MR-proANP with baseline pulse amplitude (&bgr; per SD increase [99.17%], −0.080 [−0.115 to −0.044]; P<0.0001 after Bonferroni correction for multiple testing) and MR-proADM (−0.044 [−0.070 to −0.017]; P<0.0001), as well as MR-proANP (−0.033 [−0.057 to −0.009]; P=0.0017) and N-terminal pro B-type natriuretic peptide (−0.027 [−0.051 to −0.003]; P=0.015) with brachial artery diameter. For hyperemic response variables, highest associations were seen for peripheral arterial tonometry ratio with MR-proADM (−0.022 [−0.043 to −0.004]; P=0.043), MR-proANP (0.016 [−0.0034 to 0.035]; P=0.18), and C-terminal proendothelin 1 (−0.025 [−0.043 to −0.008]; P=0.00094]. In our large, population-based study, we identified MR-proADM and MR-proANP as circulating biomarkers of vascular function most strongly related to noninvasive measures of conduit artery and peripheral arterial performance. Whether determination of blood biomarkers helps to better understand vascular pathology and may provide prognostic information needs to be investigated in future studies.

Kidney injury and mortality after transcatheter aortic valve implantation in a routine clinical cohort

We aimed at identifying predictors of renal impairment and its impact on long‐term outcome after transcatheter aortic valve implantation (TAVI).

Blood transfusion is associated with impaired outcome after transcatheter aortic valve implantation

We sought to evaluate the relationship of blood transfusion after transcatheter aortic valve implantation (TAVI) and mid‐term outcome to improve patient selection and periprocedural treatment.

Ancestry and demography and descendants of Iron Age nomads of the Eurasian Steppe

During the 1st millennium before the Common Era (BCE), nomadic tribes associated with the Iron Age Scythian culture spread over the Eurasian Steppe, covering a territory of more than 3,500 km in breadth. To understand the demographic processes behind the spread of the Scythian culture, we analysed genomic data from eight individuals and a mitochondrial dataset of 96 individuals originating in eastern and western parts of the Eurasian Steppe. Genomic inference reveals that Scythians in the east and the west of the steppe zone can best be described as a mixture of Yamnaya-related ancestry and an East Asian component. Demographic modelling suggests independent origins for eastern and western groups with ongoing gene-flow between them, plausibly explaining the striking uniformity of their material culture. We also find evidence that significant gene-flow from east to west Eurasia must have occurred early during the Iron Age.