Owing to the dynamic nature of the transcriptome, gene expression profiling is a promising tool for discovery of disease-related genes and biological pathways. In the present study, we examined gene ...expression in whole blood of 12 patients with CAD (coronary artery disease) and 12 healthy control subjects. Furthermore, ten patients with CAD underwent whole-blood gene expression analysis before and after the completion of a cardiac rehabilitation programme following surgical coronary revascularization. mRNA and miRNA (microRNA) were isolated for expression profiling. Gene expression analysis identified 365 differentially expressed genes in patients with CAD compared with healthy controls (175 up- and 190 down-regulated in CAD), and 645 in CAD rehabilitation patients (196 up- and 449 down-regulated post-rehabilitation). Biological pathway analysis identified a number of canonical pathways, including oxidative phosphorylation and mitochondrial function, as being significantly and consistently modulated across the groups. Analysis of miRNA expression revealed a number of differentially expressed miRNAs, including hsa-miR-140-3p (control compared with CAD, P=0.017), hsa-miR-182 (control compared with CAD, P=0.093), hsa-miR-92a and hsa-miR-92b (post- compared with pre-exercise, P<0.01). Global analysis of predicted miRNA targets found significantly reduced expression of genes with target regions compared with those without: hsa-miR-140-3p (P=0.002), hsa-miR-182 (P=0.001), hsa-miR-92a and hsa-miR-92b (P=2.2x10-16). In conclusion, using whole blood as a 'surrogate tissue' in patients with CAD, we have identified differentially expressed miRNAs, differentially regulated genes and modulated pathways which warrant further investigation in the setting of cardiovascular function. This approach may represent a novel non-invasive strategy to unravel potentially modifiable pathways and possible therapeutic targets in cardiovascular disease.
Precision medicine envisages the integration of an individual's clinical and biological features obtained from laboratory tests, imaging, high-throughput omics and health records, to drive a ...personalised approach to diagnosis and treatment with a higher chance of success. As only up to half of patients respond to medication prescribed following the current one-size-fits-all treatment strategy, the need for a more personalised approach is evident. One of the routes to transforming healthcare through precision medicine is pharmacogenomics (PGx). Around 95% of the population is estimated to carry one or more actionable pharmacogenetic variants and over 75% of adults over 50 years old are on a prescription with a known PGx association. Whilst there are compelling examples of pharmacogenomic implementation in clinical practice, the case for cardiovascular PGx is still evolving. In this review, we shall summarise the current status of PGx in cardiovascular diseases and look at the key enablers and barriers to PGx implementation in clinical practice.
Transforming growth factor (TGF)-β is one of the main fibrogenic cytokines that drives the pathophysiology of progressive renal scarring. MicroRNAs (miRNAs) are endogenous non-coding RNAs that ...post-transcriptionally regulate gene expression. We examined the role of TGF-β–induced expression of miR-21, miRNAs in cell culture models and miRNA expression in relevant models of renal disease. In vitro , TGF-β changed expression of miR-21, miR-214, and miR-145 in rat mesangial cells (CRL-2753) and miR-214, miR-21, miR-30c, miR-200b, and miR-200c during induction of epithelial-mesenchymal transition in rat tubular epithelial cells (NRK52E). miR-214 expression was robustly modulated in both cell types, whereas in tubular epithelial cells miR-21 was increased and miR-200b and miR-200c were decreased by 58% and 48%, respectively, in response to TGF-β. TGF-β receptor-1 was found to be a target of miR-200b/c and was down-regulated after overexpression of miR-200c. To assess the differential expression of these miRNAs in vivo , we used the anti-Thy1.1 mesangial glomerulonephritis model and the unilateral ureteral obstruction model in which TGF-β plays a role and also a genetic model of hypertension, the stroke-prone spontaneously hypertensive rat with and without salt loading. The expressions of miR-214 and miR-21 were significantly increased in all in vivo models, showing a possible miRNA signature of renal damage despite differing causes.
TREX1 acts in concert with the SET complex in granzyme A-mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic ...frameshift or missense mutations and one 3′ UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 × 10−7). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE.
A Turner Syndrome (TS) Transition clinic, Royal Hospital for Children Glasgow (RHCG), with paediatric and adult endocrinology/gynaecology teams was established in 1998 with an aim of improving health ...outcomes in TS throughout the lifespan.
To evaluate the success of our TS transition service, focussing on evaluating established follow-up after transfer to adult services.
Girls attending the TS Transition clinic at Royal Hospital for Children Glasgow, 1998-2017, were identified. Attendance data were obtained from patient records and an electronic appointment system. We assessed good and late early attendance in our cohort of TS patients as well as established endocrine follow-up, defined as those still attending adult endocrine services 3 years after transfer. Success of TS transition was determined by the proportion of girls in established endocrine follow-up.
Forty-six girls (median age 18.3 yrs) were identified. Thirty-six, 36/46 girls transferred prior to 2015 and 26 of those (72%) were in established follow-up at 3 years, 22/36 girls had met with an Adult specialist prior to transfer and 14/36 had not met with an adult specialist prior to transfer. Twenty-one (80.7%) were good early attenders (p = 0.10). In the early attenders' cohort, there was no significant difference between those that had and had not met an adult specialist prior to transfer.
A significant proportion of girls with TS are currently lost to endocrine follow-up following transfer to adult clinics. Early attendance at an adult clinic appears to predict established long-term follow-up. Strategies to improve early attendance and long-term endocrine follow-up are needed to ensure lifelong health needs are addressed.
The diagnosis of stable angina involves the use of probability estimates based on clinical presentation, age, gender and cardiovascular risk factors. In view of the link between the cardiac and ...systemic vasculature we tested whether non-invasive measures of systemic micro- and macrovascular structure and function differentiate between individuals with flow-limiting coronary artery disease (CAD) and those with normal coronary arteries (NCA).
We recruited 84 patients undergoing elective coronary angiography for investigation of symptoms of stable angina. Patients were selected for either having significant CAD or NCA (n = 43/41; age, 56±7 vs 57±7 years, P = 0.309). Only microvascular endothelial function, measured using the Endo-PAT2000 device to determine reactive hyperaemia index (CAD vs. NCA; 1.9 1.5; 2.3 vs. 2.1 1.8; 2.4, P = 0.03) and sonographic carotid plaque score (CAD vs. NCA; 3.0 1.5; 4.5 vs. 1.2 0; 2.55, P<0.001) were significantly different between patients with CAD and NCA. No significant differences were detected in reflection magnitude (CAD vs. NCA; 1.7 1.5; 1.8 % vs 1.7 1.5; 1.9 %, P = 0.342), pulse wave velocity (CAD vs. NCA; 7.8±1.4 m/sec vs. 8.3±1.5 m/sec, P = 0.186), carotid intima-media thickness (CAD vs. NCA; 0.73±0.10 mm vs. 0.75±0.10 mm, P = 0.518) or carotid distensibility (CAD vs. NCA; 3.8±1.2 10-3/kPa vs. 3.4±0.9 10-3/kPa, P = 0.092). Also, the c-statistic of the pre-test probability based on history and traditional risk factors (c = 0.665; 95% CI, 0.540-0.789) was improved by the addition of the inverse RHI (c = 0.720; 95% CI, 0.605-0.836), carotid plaque score (c = 0.770, 95% CI, 0.659-0.881), and of both markers in combination (c = 0.801; 95% CI, 0.701-0.900).
There are distinct differences in the systemic vasculature between patients with CAD and NCA that may have the potential to guide diagnostic and therapeutic decisions. Carotid artery plaque burden and microvascular function appear to be most promising in this context.
Chloride (Cl-) is the major extracellular anion in the body, accompanying sodium (Na+), and is primarily derived from dietary sources. Data suggest that increased dietary Cl- intake increases blood ...pressure, yet paradoxically, higher serum Cl- appears associated with lower mortality and cardiovascular risk. This implies that serum Cl- also reflects risk pathways independent of blood pressure, serum Na+, and bicarbonate (HCO3-). We analyzed 12,968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl- was an independent predictor of mortality. To distinguish the effect of Cl- from Na+ and HCO3-, we adjusted for these electrolytes and also performed the analysis stratified by Na+ /HCO3- and Cl- levels. Generalized estimating equation was used to determine the effect of baseline Cl- on follow-up blood pressure. The total time at risk was 19,7101 person-years. The lowest quintile of serum Cl- (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl- was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na+, K+ , and HCO3- levels. The group with Na+ > 135 and Cl- > 100 had the best survival, and compared with this group, the Na+ >135 and Cl- <100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl- and risk.
Abstract Objective There remains controversy over how women with abnormal thyroid function tests in pregnancy should be classified. In this study we assessed the proportion of women with thyroid ...stimulating hormone (TSH) ≥ 2.5 mU/l in a large obstetric cohort, and examined how many have gone on to develop thyroid disease in the years since their pregnancy. Study Design 4643 women were recruited and samples taken in early pregnancy between 2007 and 2010. Thyroid function tests were analysed in 2014; in women with raised TSH computerised health records and prescription databases were used to identify thyroid disease detected since pregnancy. Results 58 women (1.5%) had a TSH over 5 mU/l and 396 women (10.3%) had TSH between 2.5 and 5 mU/l. Women with TSH > 5mU/l delivered infants of lower birthweight than those with TSH < 2.5 mU/l; there were no other differences in obstetric outcomes between the groups. Of those who have had thyroid tests since their pregnancy, 78% of those with TSH > 5 mU/l and 19% of those with TSH between 2.5 and 5 mU/l have gone on to be diagnosed with thyroid disease. Conclusions Using a TSH cut-off of 2.5 mU/l in keeping with European and US guidelines means that over 12% of women in this cohort would be classified as having subclinical hypothyroidism. Treatment and monitoring of these women would have major implications for planning of obstetric services.
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