Application of statistical and functional methodologies for the investigation of genetic determinants of coronary heart disease biomarkers: lipoprotein lipase genotype and plasma triglycerides as an exemplar

Genome-wide association studies have proved very successful in identifying novel single-nucleotide polymorphisms (SNPs) associated with disease or traits, but the related, functional SNP is usually unknown. In this paper, we describe a methodology to locate and validate candidate functional SNPs using lipoprotein lipase (LPL), a gene previously associated with triglyceride levels, as an exemplar. Two thousand seven hundred and eighty-six healthy middle-aged men from the NPHSII UK prospective study (with up to six measures of plasma lipid levels) were genotyped for 20 LPL tagging (t)SNPs using Illumina Bead technology. Using model-selection procedures and haplotypes, we identified eight SNPs that consistently maximized the fit of the model to the phenotype. Fifteen SNPs in high linkage disequilibrium with these were identified, and functional assays were carried out on all 23 SNPs. Electrophoretic mobility shift assay (EMSA) was used to identify SNPs that had the potential to alter DNA–protein interactions, reducing the number to eight possible candidate SNPs. These were examined for ability to alter expression using a luciferase reporter assay, and two regulatory SNPs, showing genotype differences, rs327 and rs3289, were identified. Finally, multiplexed-competitor-EMSA (MC-EMSA) and supershift EMSA identified FOXA2 to rs327T, and CREB-binding protein (CBP) and CCAAT displacement protein (CDP) to rs3289C as the factors responsible for transcription binding. We have identified two novel candidate functional SNPs in LPL and presented a procedure aimed to efficiently detect SNPs potentially causal to genetic association. We believe that this methodology could be successfully applied to future re-sequencing data

Increased Risk of Diabetes and Polychlorinated Biphenyls and Dioxins: A 24-year follow-up study of the Yucheng cohort

OBJECTIVE—Polychlorinated biphenyls (PCBs) and polychlorinated dibenzofurans (PCDFs) are important and persistent organic pollutants (POPs) in humans. Recent cross-sectional studies have detected increased concentrations of serum POPs in diabetic patients. We aimed to examine the association between previous high exposures to PCBs and PCDFs and the cumulative incidence of type 2 diabetes and hypertension

Metabolic Syndrome and Risk for Incident Alzheimer's Disease or Vascular Dementia: The Three-City Study

OBJECTIVE—Associations between metabolic syndrome and its individual components with risk of incident dementia and its different subtypes are inconsistent

Genetic analysis of a major international collection of cultivated apple varieties reveals previously unknown historic heteroploid and inbred relationships

Domesticated apple (Malus x domestica Borkh.) is a major global crop and the genetic diversity held within the pool of cultivated varieties is important for the development of future cultivars. The aim of this study was to investigate the diversity held within the domesticated form, through the analysis of a major international germplasm collection of cultivated varieties, the UK National Fruit Collection, consisting of over 2,000 selections of named cultivars and seedling varieties. We utilised Diversity Array Technology (DArT) markers to assess the genetic diversity within the collection. Clustering attempts, using the software STRUCTURE revealed that the accessions formed a complex and historically admixed group for which clear clustering was challenging. Comparison of accessions using the Jaccard similarity coefficient allowed us to identify clonal and duplicate material as well as revealing pairs and groups that appeared more closely related than a standard parent-offspring or full-sibling relations. From further investigation, we were able to propose a number of new pedigrees, which revealed that some historically important cultivars were more closely related than previously documented and that some of them were partially inbred. We were also able to elucidate a number of parent-offspring relationships that had resulted in a number of important polyploid cultivars. This included reuniting polyploid cultivars that in some cases dated as far back as the 18th century, with diploid parents that potentially date back as far as the 13th century

Dose-Dependent Effect of Rosuvastatin on VLDL–Apolipoprotein C-III Kinetics in the Metabolic Syndrome

OBJECTIVE—Dysregulated apolipoprotein (apo)C-III metabolism may account for hypertriglyceridemia and increased cardiovascular risk in the metabolic syndrome. This study investigated the dose-dependent effect of rosuvastatin on VLDL apoC-III transport in men with the metabolic syndrome

Nonlinear modeling of venous leg ulcer healing rates

<p>Abstract</p> <p>Background</p> <p>The purpose of this manuscript was to determine whether the change in wound surface area over time could be described through nonlinear mathematics.</p> <p>Methods</p> <p>We studied 3,588 serial wound tracings of 338 venous leg ulcers (VLUs) that had been followed during a controlled, prospective, randomized trial of two topical wound treatments.</p> <p>Results</p> <p>A majority (72%) of VLUs exhibited surface area reduction via an exponential decay model, particularly during the early stages of healing. These results were consistent with the mechanics of wound contraction and epithelial cell proliferation, supported by the higher frequency at which exponential surface area reduction associated with full wound closure (35% of wounds that fit the exponential model healed vs. 21% of wounds that did not fit the exponential model completely healed during the study period, p = 0.018). Goodness-of-fit statistics suggested that much of the individual variation in healing could be described as nonlinear variation from the exponential model.</p> <p>Conclusion</p> <p>We believe that parameter estimates from a mathematical model may provide a more accurate quantification of wound healing rates, and that similar models may someday reach routine use in comparing the efficacy of various treatments in routine practice and in product registration trials.</p

Bronchoarterial ratio in never‐smokers adults: Implications for bronchial dilation definition

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135610/1/resp12875_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135610/2/resp12875.pd