Let-7a induces metabolic reprogramming in breast cancer cells via targeting mitochondrial encoded ND4.

BACKGROUND AND OBJECTIVES: MicroRNA (miRNA) that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNA (mitomiR). Albeit mitomiRs have been shown to modulate gene expression, their functional impact within mitochondria is unknown. The main objective of this study is to investigate whether the mitochondrial genome is regulated by miR present inside the mitochondria. METHODS AND RESULTS: Here, we report mitomiR let-7a regulates mitochondrial transcription in breast cancer cells and reprogram the metabolism accordingly. These effects were mediated through the interaction of let-7a with mtDNA, as studied by RNA pull-down assays, altering the activity of Complex I in a cell line-specific manner. Our study, for the first time, identifies the role of mitomiR (let-7a) in regulating the mitochondrial genome by transcriptional repression and its contribution to regulating mitochondrial metabolism of breast cancer cells. CONCLUSION: These findings uncover a novel mechanism by which mitomiR regulates mitochondrial transcription.

Carotid-Femoral Pulse Wave Velocity as a Risk Marker for Development of Complications in Type 1 Diabetes Mellitus.

Background The value of carotid-femoral pulse wave velocity (cfPWV) as risk factor for development of complications in type 1 diabetes mellitus remains to be determined. We investigated associations between cfPWV and renal outcomes, cardiovascular events, and all-cause mortality in people with type 1 diabetes mellitus. Methods and Results cfPWV was measured with SphygmoCor in 633 people with type 1 diabetes mellitus. Median (interquartile range) follow-up was 6.2 (5.8-6.7) years. End points included progression in albuminuria group, decline in estimated glomerular filtration rate (eGFR) ≥30%, end-stage kidney disease, cardiovascular event, mortality, and a composite renal end point. Hazard ratios (HRs) were calculated per 1-SD increase in cfPWV. Adjustments included age, sex, hemoglobin A1c, mean arterial pressure, body mass index, low-density lipoprotein cholesterol, smoking, urine albumin excretion rate, and eGFR. The cohort included 45% women, mean (SD) age was 54 (13) years, mean (SD) eGFR was 83.2 (27.9) mL/min per 1.73 m2, and mean (SD) cfPWV was 10.4 (3.3) m/s. Median (interquartile range) albumin excretion rate was 17 (17-63) mg/24 h. After adjustment, higher cfPWV was associated with increased hazard of progression in albuminuria (HR, 1.59; 95% CI, 1.10-2.32); decline in eGFR ≥30% (HR, 1.38; 95% CI, 1.06-1.79); cardiovascular event (HR, 1.31; 95% CI, 1.01-1.70); mortality (HR, 1.36; 95% CI, 1.00-1.85); and the composite renal end point (HR, 1.30; 95% CI, 1.04-1.63), but not with end-stage kidney disease (HR, 1.18; 95% CI, 0.62-2.26). Higher cfPWV was associated with steeper yearly increase in albumin excretion and steeper yearly decline in eGFR after adjustment (P=0.002 and P=0.01, respectively). Conclusions cfPWV was associated with increased hazard of renal outcomes, cardiovascular event, and mortality. cfPWV may be suited for risk stratification in type 1 diabetes mellitus.

Carriers of a VEGFA enhancer polymorphism selectively binding CHOP/DDIT3 are predisposed to increased circulating levels of thyroid-stimulating hormone.

BACKGROUND: Levels of serum thyroid-stimulating hormone (TSH) indicate thyroid function, because thyroid hormone negatively controls TSH release. Genetic variants in the vascular endothelial growth factor A (VEGFA) gene are associated with TSH levels. The aim of this study was to characterise the association of VEGFA variants with TSH in a Danish cohort and to identify and characterise functional variants. METHODS: We performed an association study of the VEGFA locus for circulating TSH levels in 8445 Danish individuals. Lead variants were tested for allele-specific effects in vitro using luciferase reporter and gel-shift assays. RESULTS: Four SNPs in VEGFA were associated with circulating TSH (rs9472138, rs881858, rs943080 and rs4711751). For rs881858, the presence of each G-allele was associated with a corresponding decrease in TSH levels of 2.3% (p=8.4×10-9) and an increase in circulating free T4 levels (p=0.0014). The SNP rs881858 is located in a binding site for CHOP (C/EBP homology protein) and c/EBPß (ccaat enhancer binding protein ß). Reporter-gene analysis showed increased basal enhancer activity of the rs881858 A-allele versus the G-allele (34.5±9.9% (average±SEM), p=0.0012), while co-expression of CHOP effectively suppressed the rs881858 A-allele activity. The A-allele showed stronger binding to CHOP in gel-shift assays. CONCLUSIONS: VEGF is an important angiogenic signal required for tissue expansion. We show that VEGFA variation giving allele-specific response to transcription factors with overlapping binding sites associate closely with circulating TSH levels. Because CHOP is induced by several types of intracellular stress, this indicates that cellular stress could be involved in the normal or pathophysiological response of the thyroid to TSH. TRIAL REGISTRATION NUMBER: NCT00289237, NCT00316667; Results.

Investigating the possible causal association of smoking with depression and anxiety using Mendelian randomisation meta-analysis: the CARTA consortium.

OBJECTIVES: To investigate whether associations of smoking with depression and anxiety are likely to be causal, using a Mendelian randomisation approach. DESIGN: Mendelian randomisation meta-analyses using a genetic variant (rs16969968/rs1051730) as a proxy for smoking heaviness, and observational meta-analyses of the associations of smoking status and smoking heaviness with depression, anxiety and psychological distress. PARTICIPANTS: Current, former and never smokers of European ancestry aged ≥16 years from 25 studies in the Consortium for Causal Analysis Research in Tobacco and Alcohol (CARTA). PRIMARY OUTCOME MEASURES: Binary definitions of depression, anxiety and psychological distress assessed by clinical interview, symptom scales or self-reported recall of clinician diagnosis. RESULTS: The analytic sample included up to 58 176 never smokers, 37 428 former smokers and 32 028 current smokers (total N=127 632). In observational analyses, current smokers had 1.85 times greater odds of depression (95% CI 1.65 to 2.07), 1.71 times greater odds of anxiety (95% CI 1.54 to 1.90) and 1.69 times greater odds of psychological distress (95% CI 1.56 to 1.83) than never smokers. Former smokers also had greater odds of depression, anxiety and psychological distress than never smokers. There was evidence for positive associations of smoking heaviness with depression, anxiety and psychological distress (ORs per cigarette per day: 1.03 (95% CI 1.02 to 1.04), 1.03 (95% CI 1.02 to 1.04) and 1.02 (95% CI 1.02 to 1.03) respectively). In Mendelian randomisation analyses, there was no strong evidence that the minor allele of rs16969968/rs1051730 was associated with depression (OR=1.00, 95% CI 0.95 to 1.05), anxiety (OR=1.02, 95% CI 0.97 to 1.07) or psychological distress (OR=1.02, 95% CI 0.98 to 1.06) in current smokers. Results were similar for former smokers. CONCLUSIONS: Findings from Mendelian randomisation analyses do not support a causal role of smoking heaviness in the development of depression and anxiety.

Dietary ascorbic acid and subsequent change in body weight and waist circumference: associations may depend on genetic predisposition to obesity--a prospective study of three independent cohorts.

BACKGROUND: Cross-sectional data suggests that a low level of plasma ascorbic acid positively associates with both Body Mass Index (BMI) and Waist Circumference (WC). This leads to questions about a possible relationship between dietary intake of ascorbic acid and subsequent changes in anthropometry, and whether such associations may depend on genetic predisposition to obesity. Hence, we examined whether dietary ascorbic acid, possibly in interaction with the genetic predisposition to a high BMI, WC or waist-hip ratio adjusted for BMI (WHR), associates with subsequent annual changes in weight (∆BW) and waist circumference (∆WC). METHODS: A total of 7,569 participants' from MONICA, the Diet Cancer and Health study and the INTER99 study were included in the study. We combined 50 obesity associated single nucleotide polymorphisms (SNPs) in four genetic scores: a score of all SNPs and a score for each of the traits (BMI, WC and WHR) with which the SNPs associate. Linear regression was used to examine the association between ascorbic acid intake and ΔBW or ΔWC. SNP-score × ascorbic acid interactions were examined by adding product terms to the models. RESULTS: We found no significant associations between dietary ascorbic acid and ∆BW or ∆WC. Regarding SNP-score × ascorbic acid interactions, each additional risk allele of the 14 WHR associated SNPs associated with a ∆WC of 0.039 cm/year (P = 0.02, 95% CI: 0.005 to 0.073) per 100 mg/day higher ascorbic acid intake. However, the association to ∆WC only remained borderline significant after adjustment for ∆BW. CONCLUSION: In general, our study does not support an association between dietary ascorbic acid and ∆BW or ∆WC, but a diet with a high content of ascorbic acid may be weakly associated to higher WC gain among people who are genetically predisposed to a high WHR. However, given the quite limited association any public health relevance is questionable.

Interaction between genetic predisposition to obesity and dietary calcium in relation to subsequent change in body weight and waist circumference.

BACKGROUND: Studies indicate an effect of dietary calcium on change in body weight (BW) and waist circumference (WC), but the results are inconsistent. Furthermore, a relation could depend on genetic predisposition to obesity. OBJECTIVE: The objective was to examine whether genetic predisposition to higher body mass index (BMI), WC, or waist-hip ratio (WHR) interacts with dietary calcium in relation to subsequent annual change in BW (ΔBW) and WC (ΔWC). DESIGN: The study was based on 7569 individuals from the MONItoring trends and determinants of CArdiovascular disease Study, a sample from the Danish Diet, Cancer and Health Study and the INTER99 study, with information on diet; 54 single-nucleotide polymorphisms (SNPs) associated with BMI, WC, or WHR adjusted for BMI; and potential confounders. The SNPs were combined in 4 scores as indicators of genetic predisposition; all SNPs in a general score and a score for each of 3 phenotypes: BMI, WC, and WHR. Linear regression was used to examine the association between calcium intake and ΔBW or ΔWC adjusted for concurrent ΔBW. SNP score × calcium interactions were examined by adding product terms to the models. RESULTS: We found a significant ΔBW of -0.076 kg (P = 0.021; 95% CI: -0.140, -0.012) per 1000 mg Ca. No significant association was observed between dietary calcium and ΔWC. In the analyses with ΔBW as outcome, we found no significant interactions between the developed predisposition scores and calcium. However, we found a significant interaction between a score of 6 WC-associated SNPs and calcium in relation to ΔWC. Each risk allele was associated with a ΔWC of -0.043 cm (P = 0.038; 95% CI: -0.083, -0.002) per 1000 mg Ca. CONCLUSIONS: Our study suggests that dietary calcium relates weakly to BW loss. We found no evidence of a general association between calcium and ΔWC, but calcium may reduce WC among people genetically predisposed to a high WC. However, further replication of this finding is needed.

ACE I/D polymorphism in Indian patients with hypertrophic cardiomyopathy and dilated cardiomyopathy.

AIM: The study was carried to determine the association of angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism with the risk of hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and restrictive cardiomyopathy (RCM). METHODS AND RESULTS: A total of 174 patients diagnosed with cardiomyopathy (118 with HCM, 51 with DCM, and 5 with RCM) and 164 ethnically, age- and gender-matched controls were included in the study. ACE I/D genotyping was performed by PCR. In total, 25.86% of the patients were in New York Heart Association (NYHA) class III and IV at presentation. A total of 67.24% patients had dyspnea, 56.89% had angina pectoris, and 25.28% of the patients had at least one event of syncope. Frequency of occurrence of the disease was more in male patients compared to female patients (P < 0.05). After adjustment for age, sex, body mass index (BMI), and smoking habit, the prevalence of ACE DD genotype, and ACE 'D' allele was significantly higher in patients as compared to controls and was associated with increased risk (DD: OR 2.11, 95% CI 1.27-3.52, P < 0.05; 'D': OR 1.91, 95% CI 1.08-3.35, P < 0.05). The mean septal thickness was higher for DD and ID genotypes (20.40 +/- 3.73 mm and 21.82 +/- 5.35 mm, respectively) when compared with II genotype (18.63 +/- 6.69 mm) in HCM patients, however, the differences were not significant statistically (P > 0.05). The DCM patients with ID genotype showed significantly decreased left ventricular ejection fraction (LVEF) at enrolment (26.50 +/- 8.04%) (P = 0.04). CONCLUSION: Our results suggest that D allele of ACE I/D polymorphism significantly influences the HCM and DCM phenotypes.