Small-RNA sequencing reveals potential serum biomarkers for gallbladder cancer: Results from a three-stage collaborative study of large European prospective cohorts.

Gallbladder cancer (GBC) is an aggressive disease with limited treatment options but high prevention potential. GBC tumours take 10-20 years to develop, a timeframe that holds potential for early detection. MicroRNAs (miRNAs) play a central role in abnormal cell processes, and circulating miRNAs may constitute valuable biomarkers of early disease.

Identification and characterisation of pathogenic and non-pathogenic FGF14 repeat expansions.

Repeat expansions in FGF14 cause autosomal dominant late-onset cerebellar ataxia (SCA27B) with estimated pathogenic thresholds of 250 (incomplete penetrance) and 300 AAG repeats (full penetrance), but the sequence of pathogenic and non-pathogenic expansions remains unexplored. Here, we demonstrate that STRling and ExpansionHunter accurately detect FGF14 expansions from short-read genome data using outlier approaches. By combining long-range PCR and nanopore sequencing in 169 patients with cerebellar ataxia and 802 controls, we compare FGF14 expansion alleles, including interruptions and flanking regions.

Genetic polymorphisms affecting telomere length and their association with cardiovascular disease in the Heinz-Nixdorf-Recall study.

Short telomeres are associated with cardiovascular disease (CVD). We aimed to investigate, if genetically determined telomere-length effects CVD-risk in the Heinz-Nixdorf-Recall study (HNRS) population. We selected 14 single-nucleotide polymorphisms (SNPs) associated with telomere-length (p<10-8) from the literature and after exclusion 9 SNPs were included in the analyses.

Continuous Rather Than Solely Early Farm Exposure Protects From Hay Fever Development.

Background: An important window of opportunity for early-life exposures has been proposed for the development of atopic eczema and asthma.

Objective: However, it is unknown whether hay fever with a peak incidence around late school age to adolescence is similarly determined very early in life.

Methods: In the Protection against Allergy-Study in Rural Environments (PASTURE) birth cohort potentially relevant exposures such as farm milk consumption and exposure to animal sheds were assessed at multiple time points from infancy to age 10.

Klotho KL-VS haplotype does not improve cognition in a population-based sample of adults age 55-87 years.

The heterozygous human Klotho KL-VS haplotype has been associated with improved cognitive performance but results are inconsistent. Here we assessed Klotho KL-VS haplotype and cognition using data from the third examination of the population-based Heinz Nixdorf Recall Study. We analyzed cognition tests (immediate and delayed word list, Trail-Making Test [TMT] part A and B, Maze test, interference condition of the Stroop color-word test, verbal fluency) and their associations with Klotho KL-VS haplotype.

Effect of Farming on Asthma.

In this review, we discuss an immunobiology model of farm exposure towards the protective effect of asthma. Unraveling the protective effect of farming exposure could help develop novel strategies to prevent asthma. Asthma is a chronic airway inflammation that causes coughing, wheezing, chest tightness or shortness of breath.

Hypoxia-inducible factor-2α is crucial for proper brain development.

Sufficient tissue oxygenation is required for regular brain function; thus oxygen supply must be tightly regulated to avoid hypoxia and irreversible cell damage. If hypoxia occurs the transcription factor complex hypoxia-inducible factor (HIF) will accumulate and coordinate adaptation of cells to hypoxia. However, even under atmospheric O conditions stabilized HIF-2α protein was found in brains of adult mice.

Risk prediction for coronary heart disease by a genetic risk score - results from the Heinz Nixdorf Recall study.

Background: A Genetic risk score for coronary artery disease (CAD) improves the ability of predicting coronary heart disease (CHD). It is unclear whether i) the use of a CAD genetic risk score is superior to the measurement of coronary artery calcification (CAC) for CHD risk assessment and ii) the CHD risk assessment using a CAD genetic risk score differs between men and women.

Methods: We included 4041 participants (age-range: 45-76 years, 1919 men) of the Heinz Nixdorf Recall study without CHD or stroke at baseline.

Genetic risk scores for coronary artery disease and its traditional risk factors: Their role in the progression of coronary artery calcification-Results of the Heinz Nixdorf Recall study.

Background: Atherosclerosis is the primary cause of coronary artery disease (CAD). Several observational studies have examined the association of traditional CAD risk factors with the progression of coronary artery calcification (CAC). In our study we investigated the effect of 11 different genetic risk scores associated with CAD and CAD risk factors on the progression of CAC.

Association between lipoprotein(a) (Lp(a)) levels and Lp(a) genetic variants with coronary artery calcification.

Background: To examine the association between lipoprotein(a) (Lp(a)) levels, LPA (rs10455872 and rs3798220) and IL1F9 (rs13415097) single nucleotide polymorphisms (SNPs) with coronary artery calcification (CAC), an important predictor for coronary artery disease (CAD).

Methods: We used data from 3799 (mean age ± SD: 59.0 ± 7.

Male-pattern baldness and incident coronary heart disease and risk factors in the Heinz Nixdorf Recall Study.

Male-pattern baldness (MPB) is characterized by a progressive hair loss from the frontal and vertex scalp that affects about 80% of men at the age of 80 years. Epidemiological studies show positive associations between MPB and coronary heart disease (CHD) and CHD related risk factors such as blood pressure (BP), diabetes mellitus (DM) or elevated blood lipid levels. The results however vary with regard to the pattern of hair loss (i.

HDAC9 is implicated in atherosclerotic aortic calcification and affects vascular smooth muscle cell phenotype.

Aortic calcification is an important independent predictor of future cardiovascular events. We performed a genome-wide association meta-analysis to determine SNPs associated with the extent of abdominal aortic calcification (n = 9,417) or descending thoracic aortic calcification (n = 8,422). Two genetic loci, HDAC9 and RAP1GAP, were associated with abdominal aortic calcification at a genome-wide level (P < 5.

Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance: a genome-wide genetic interaction study.

Background: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways.

An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci ( < 5 × 10), including variants near the , , and genes.

Socioeconomic Status Interacts with the Genetic Effect of a Chromosome 9p21.3 Common Variant to Influence Coronary Artery Calcification and Incident Coronary Events in the Heinz Nixdorf Recall Study (Risk Factors, Evaluation of Coronary Calcium, and Lifestyle).

Background: Genetic variants of a locus within the chromosome 9p21.3 region are consistently associated with coronary artery disease and coronary artery calcification (CAC). The aim of this study was to examine whether a 9p21.

A statistical model for the analysis of beta values in DNA methylation studies.

Background: The analysis of DNA methylation is a key component in the development of personalized treatment approaches. A common way to measure DNA methylation is the calculation of beta values, which are bounded variables of the form M/(M+U) that are generated by Illumina's 450k BeadChip array. The statistical analysis of beta values is considered to be challenging, as traditional methods for the analysis of bounded variables, such as M-value regression and beta regression, are based on regularity assumptions that are often too strong to adequately describe the distribution of beta values.

Anthropometric markers and their association with incident type 2 diabetes mellitus: which marker is best for prediction? Pooled analysis of four German population-based cohort studies and comparison with a nationwide cohort study.

Objective: To compare the association between different anthropometric measurements and incident type 2 diabetes mellitus (T2DM) and to assess their predictive ability in different regions of Germany.

Methods: Data of 10,258 participants from 4 prospective population-based cohorts were pooled to assess the association of body weight, body mass index (BMI), waist circumference (WC), waist-to-hip-ratio (WHR) and waist-to-height-ratio (WHtR) with incident T2DM by calculating HRs of the crude, adjusted and standardised markers, as well as providing receiver operator characteristic (ROC) curves. Differences between HRs and ROCs for the different anthropometric markers were calculated to compare their predictive ability.

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation.

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)).

Serum lipid levels, body mass index, and their role in coronary artery calcification: a polygenic analysis.

Background: Coronary artery calcification (CAC) is widely regarded as a cumulative lifetime measure of atherosclerosis, but it remains unclear what is the relationship between calcification and traditional risk factors for coronary artery disease (CAD) and myocardial infarction (MI). This study characterizes the genetic architecture of CAC by evaluating the overall impact of common alleles associated with CAD/MI and its traditional risk factors.

Methods And Results: On the basis of summary-association results from the CARDIoGRAMplusC4D study of CAD/MI, we calculated polygenic risk scores in 2599 participants of the Dutch and Belgian Lung Cancer Screening (NELSON) trial, in whom quantitative CAC levels (Agatston scores) were determined from chest computerized tomographic imaging data.

Defining the role of common variation in the genomic and biological architecture of adult human height.

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability.