Hypertension presents major risk factors for cardiovascular and renal disease. High salt and high fructose (HSHF) consumption contribute to hypertension via salt retention and obesity. Sex differences in blood pressure regulation are well known. Some studies have shown protection for females from angiotensin II (AngII)‐induced and dietary‐induced increase in blood pressure. Our results indicate that HSHF consumption increases blood pressure in male and female mice. Also, AngII administration increased blood pressure in male and female mice while consuming normal diet with water, but no sex differences were noted (Rouch, A. FASEB J. 32(1) A904.6, 2018). The objective of this study was to determine the effects of AngII on blood pressure, sodium excretion, and urine flow rate in male and female CD‐1 mice while consuming a HSHF diet. Four groups of mice included male‐vehicle, male‐AngII, female‐vehicle, and female‐AngII (n=6/group). Mice at four weeks of age were placed in metabolic cages for a 5‐day baseline period followed by a ten‐day AngII period where AngII was administered via an Alzet® osmotic minipump containing either saline (vehicle) or AngII to yield 1mg/kg/min. All mice consumed a diet of 4% salt with fluid containing 1% NaCl and 20% fructose ad libitum. Systolic blood pressure was measured daily via the tail‐cuff method (CODA, Kent Scientific). Excessive fluid retention evidenced by a significant increase in body weight of 4–5 g occurred in the AngII‐treated mice of both sexes in the first 5 days of the AngII period. One mouse of each AngII‐treated group died before the end of the AngII period while the other mice recovered to their normal body weight by the end of the ten‐day period. AngII increased systolic blood pressure (mmHg) in females from 108.0 ± 3.4 to 130.0 ± 6.1 (p<0.0001) and in males from 101.1 ± 1.3 to 127.5 ± 3.2 (p<0.0001). In both AngII‐treated groups, daily urine flow rate and sodium excretion demonstrated biphasic patterns of significant decreases in the first 5 days of the AngII period followed by increased levels to achieve fluid and sodium balance. We conclude that AngII‐infusion during HSHF consumption in mice presents with potentially fatal salt and water retention. No sex differences in the AngII‐induced increase in SBP or renal handling of sodium were measured. Support or Funding Information OK‐INBRE SURP
Background Transcriptome-wide association studies (TWAS) improve to detect functionally relevant loci by leveraging expression quantitative trait loci (eQTLs) from reference panels in relevant tissues. Herein, we developed machine learning-based prediction models using a novel Korean TWAS model for early progression to stricturing or penetrating phenotypes in Korean patients with Crohn’s disease (CD). Methods A total of 431 patients diagnosed with CD were retrospectively enrolled from 15 referral hospitals in Korea. Single-nucleotide polymorphism genotype was analyzed using the Korea Biobank Array. Using the GTEx genotype and Korean chip genotype database from the terminal ileum, a novel Korean TWAS model was developed and compared with a European TWAS model. Predictive models for early progression were trained and cross-validated using logistic regression models and leave-one-out cross validation. Early progression was defined as transition to stricturing or penetrating phenotypes within 2 years from the diagnosis of CD. Results Among the study population, early progression to stricturing and penetrating phenotype was detected in 60 (13.9%) and 73 patients (16.9%), respectively. Combined clinical-gene expression prediction models predicted early progression to stricturing (AUROC, 0.816) and penetrating phenotypes (AUROC, 0.801) more accurately than the models using clinical parameters alone. The following gene expression was significantly associated with early progression: CCDC154, FAM189A2, TAS2R19, FCSK, SP1, and KCNIP1 for stricturing phenotype and PUS7, CCDC146, MLXIP, LRGUK, UROS, and TAFA1 for penetrating phenotype. Conclusion The clinical-genetic machine learning models predicted progression to stricturing or penetrating phenotypes in the early stage of CD. Use of the comprehensive prediction models might enable clinicians to select patients requiring early aggressive therapeutic strategy to prevent disease-related complications.
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