Polymorphisms in the WNK1 gene are asociated with blood pressure variation and urinary potassium excretion

WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p = 0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p = 0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p = 0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p = 0.02 and p = 0.01 respectively). The major allele (A) of rs765250, located in intron 1, demonstrated the strongest evidence for association with SBP, effect size 3.14 mmHg (95%CI:1.23–4.9), DBP 1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n = 14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p = 7×10−3, combined with BRIGHT data-set p = 2×10−4, n = 17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p10 mmHg reduction) and risk for hypertension (OR<0.60). Our data indicates that multiple rare and common WNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH

HYPEST study: profile of hypertensive patients in Estonia

<p>Abstract</p> <p>Background</p> <p>More than one third of adult population in Estonia has problems with elevated blood pressure (BP). The <it>Hypertension in Estonia </it>(HYPEST) study represents the country's first hypertension-targeted sample collection aiming to examine the epidemiological and genetic determinants for hypertension (HTN) and related cardiovascular diseases (CVD) in Estonian population. The HYPEST subjects (n = 1,966) were recruited across Estonia between 2004-2007 including clinically diagnosed HTN cases and population-based controls. The present report is focused on the clinical and epidemiological profile of HYPEST cases, and gender-specific effects on the pathophysiology of hypertension.</p> <p>Methods</p> <p>Current analysis was performed on 1,007 clinically diagnosed HTN patients (617 women and 390 men) aged 18-85 years. The hypertensives were recruited to the study by BP specialists at the North Estonia Medical Center, Centre of Cardiology, Tallinn or at the Cardiology Clinic, Tartu University Hospital, Estonia. Longitudinal BP data was extracted retrospectively from clinical records. Current and retrospective data of patient's medical history, medication intake and lifestyle habits were derived from self-administrated questionnaire and each variable was examined separately for men and women. Eleven biochemical parameters were measured from fasting serum samples of 756 patients.</p> <p>Results</p> <p>The distribution of recruited men and women was 39% and 61% respectively. Majority of Estonian HTN patients (85%) were overweight (BMI ≥ 25 kg/m²) and a total of 79% of patients had additional complications with cardiovascular system. In men, the hypertension started almost 5 years earlier than in women (40.5 ± 14.5 vs 46.1 ± 12.7 years), which led to earlier age of first myocardial infarction (MI) and overall higher incidence rate of MI among male patients (men 21.2%, women 8.9%, <it>P </it>< 0.0001). Heart arrhythmia, thyroid diseases, renal tubulo-intestinal diseases and hyperlipidemia were more prevalent in hypertensive women compared to men (<it>P </it>< 0.0001). An earlier age of HTN onset was significantly associated with smoking (<it>P </it>= 0.00007), obesity (BMI ≥ 30 kg/m²; <it>P </it>= 0.0003), increased stress (<it>P </it>= 0.0003) and alcohol consumption (<it>P </it>= 0.004).</p> <p>Conclusion</p> <p>Understanding the clinical profile of HTN patients contributes to CVD management. Estonian hypertension patients exhibited different disease and risk profiles of male and female patients. This well-characterized sample set provides a good resource for studying hypertension and other cardiovascular phenotypes.</p

Hypervariable intronic region in NCX1 is enriched in short insertion-deletion polymorphisms and showed association with cardiovascular traits

<p>Abstract</p> <p>Background</p> <p>Conserved non-coding regions (CNR) have been shown to harbor gene expression regulatory elements. Genetic variations in these regions may potentially contribute to complex disease susceptibility.</p> <p>Methods</p> <p>We targeted CNRs of cardiovascular disease (CVD) candidate gene, <it>Na(+)-Ca(2+) exchanger (NCX1) </it>with polymorphism screening among CVD patients (n = 46) using DHPLC technology. The flanking region (348 bp) of the 14 bp indel in intron 2 was further genotyped by DGGE assay in two Eastern-European CVD samples: essential hypertension (HYPEST; 470 cases, 652 controls) and coronary artery disease, CAD (CADCZ; 257 cases, controls 413). Genotype-phenotype associations were tested by regression analysis implemented in PLINK. Alignments of primate sequences were performed by ClustalW2.</p> <p>Results</p> <p>Nine of the identified <it>NCX1 </it>variants were either singletons or targeted by commercial platforms. The 14 bp intronic indel (rs11274804) was represented with substantial frequency in HYPEST (6.82%) and CADCZ (14.58%). Genotyping in Eastern-Europeans (n = 1792) revealed hypervariable nature of this locus, represented by seven alternative alleles. The alignments of human-chimpanzee-macaque sequences showed that the major human variant (allele frequency 90.45%) was actually a human-specific deletion compared to other primates. In humans, this deletion was surrounded by other short (5-43 bp) deletion variants and a duplication (40 bp) polymorphism possessing overlapping breakpoints. This indicates a potential indel hotspot, triggered by the initial deletion in human lineage. An association was detected between the carrier status of 14 bp indel ancestral allele and CAD (<it>P </it>= 0.0016, OR = 2.02; Bonferroni significance level alpha = 0.0045), but not with hypertension. The risk for the CAD development was even higher among the patients additionally diagnosed with metabolic syndrome (<it>P </it>= 0.0014, OR = 2.34). Consistent with the effect on metabolic processes, suggestive evidence for the association with heart rate, serum triglyceride and LDL levels was detected (<it>P </it>= 0.04).</p> <p>Conclusions</p> <p>Compared to SNPs targeted by large number of locus-specific and genome-wide assays, considerably less attention has been paid to short indel variants in the human genome. The data of genome dynamics, mutation rate and population genetics of short indels, as well as their impact on gene expressional profile and human disease susceptibility is limited. The characterization of <it>NCX1 </it>intronic hypervariable non-coding region enriched in human-specific indel variants contributes to this gap of knowledge.</p

Tidying Up International Nucleotide Sequence Databases: Ecological, Geographical and Sequence Quality Annotation of ITS Sequences of Mycorrhizal Fungi

Sequence analysis of the ribosomal RNA operon, particularly the internal transcribed spacer (ITS) region, provides a powerful tool for identification of mycorrhizal fungi. The sequence data deposited in the International Nucleotide Sequence Databases (INSD) are, however, unfiltered for quality and are often poorly annotated with metadata. To detect chimeric and low-quality sequences and assign the ectomycorrhizal fungi to phylogenetic lineages, fungal ITS sequences were downloaded from INSD, aligned within family-level groups, and examined through phylogenetic analyses and BLAST searches. By combining the fungal sequence database UNITE and the annotation and search tool PlutoF, we also added metadata from the literature to these accessions. Altogether 35,632 sequences belonged to mycorrhizal fungi or originated from ericoid and orchid mycorrhizal roots. Of these sequences, 677 were considered chimeric and 2,174 of low read quality. Information detailing country of collection, geographical coordinates, interacting taxon and isolation source were supplemented to cover 78.0%, 33.0%, 41.7% and 96.4% of the sequences, respectively. These annotated sequences are publicly available via UNITE (http://unite.ut.ee/) for downstream biogeographic, ecological and taxonomic analyses. In European Nucleotide Archive (ENA; http://www.ebi.ac.uk/ena/), the annotated sequences have a special link-out to UNITE. We intend to expand the data annotation to additional genes and all taxonomic groups and functional guilds of fungi

A co-registration investigation of inter-word spacing and parafoveal preview: Eye movements and fixation-related potentials

Participants’ eye movements (EMs) and EEG signal were simultaneously recorded to examine foveal and parafoveal processing during sentence reading. All the words in the sentence were manipulated for inter-word spacing (intact spaces vs. spaces replaced by a random letter) and parafoveal preview (identical preview vs. random letter string preview). We observed disruption for unspaced text and invalid preview conditions in both EMs and fixation-related potentials (FRPs). Unspaced and invalid preview conditions received longer reading times than spaced and valid preview conditions. In addition, the FRP data showed that unspaced previews disrupted reading in earlier time windows of analysis, compared to string preview conditions. Moreover, the effect of parafoveal preview was greater for spaced relative to unspaced conditions, in both EMs and FRPs. These findings replicate well-established preview effects, provide novel insight into the neural correlates of reading with and without inter-word spacing and suggest that spatial selection precedes lexical processing

High-level classification of the Fungi and a tool for evolutionary ecological analyses

High-throughput sequencing studies generate vast amounts of taxonomic data. Evolutionary ecological hypotheses of the recovered taxa and Species Hypotheses are difficult to test due to problems with alignments and the lack of a phylogenetic backbone. We propose an updated phylum-and class-level fungal classification accounting for monophyly and divergence time so that the main taxonomic ranks are more informative. Based on phylogenies and divergence time estimates, we adopt phylum rank to Aphelidiomycota, Basidiobolomycota, Calcarisporiellomycota, Glomeromycota, Entomophthoromycota, Entorrhizomycota, Kickxellomycota, Monoblepharomycota, Mortierellomycota and Olpidiomycota. We accept nine subkingdoms to accommodate these 18 phyla. We consider the kingdom Nucleariae (phyla Nuclearida and Fonticulida) as a sister group to the Fungi. We also introduce a perl script and a newick-formatted classification backbone for assigning Species Hypotheses into a hierarchical taxonomic framework, using this or any other classification system. We provide an example of testing evolutionary ecological hypotheses based on a global soil fungal data set.Peer reviewe