Circulating mitochondrial long non-coding 7S RNA in primary health care patients with depression/anxiety.

BACKGROUND: The significant role of long non-coding 7S RNA in controlling mitochondrial transcription highlights its importance in mitochondrial function. Considering the suggested connection between mitochondrial dysfunction and the onset of mental disorders, this study aimed to explore the potential involvement of 7S RNA in the context of depression/anxiety. RESULTS: A total of 181 patients in primary health care (age 20-64 years) with depression/anxiety and 59 healthy controls were included in the study. 7S RNA was measured using quantitative real-time PCR in plasma samples collected before (baseline) and after 8 weeks of treatment (mindfulness or cognitive-based behavioral therapy). Upon adjustment for age and sex, the baseline plasma levels of 7S RNA were significantly higher in patients than in healthy controls (p < 0.001). Notably, post-treatment, there was a significant reduction in 7S RNA levels (p = 0.03). These changes in 7S RNA were related to the treatment response, as indicated by HADS-D (Hospital Anxiety and Depression Scale) scores (ß = -0.04, p = 0.04), even after accounting for baseline scores and other cofounders. CONCLUSION: The findings of this study indicate an association between plasma 7S RNA levels and depression/anxiety, as well as treatment response. While further confirmatory analyses are necessary, plasma 7S RNA holds promise as a potential predictive biomarker for both depression/anxiety and the treatment response within these disorders.

Mitochondrial heteroplasmic shifts reveal a positive selection of breast cancer.

BACKGROUND: Breast cancer is, despite screening, not always detected early enough and is together with other tumor types known to shed genetic information in circulation. Unlike single-copy nuclear DNA, mitochondrial DNA (mtDNA) copies range from 100s to 10,000s per cell, thus providing a potentially alternative to identify potential missing cancer information in circulation at an early stage. METHODS: To characterize mitochondrial mutation landscapes in breast cancer, whole mtDNA sequencing and bioinformatics analyses were performed on 86 breast cancer biopsies and 50 available matched baseline cancer-free whole blood samples from the same individuals, selected from a cohort of middle-aged women in Sweden. To determine whether the mutations can be detected in blood plasma prior to cancer diagnosis, we further designed a nested case-control study (n = 663) and validated the shortlisted mutations using droplet digital PCR. RESULTS: We detected different mutation landscapes between biopsies and matched whole blood samples. Compared to whole blood samples, mtDNA from biopsies had higher heteroplasmic mutations in the D-loop region (P = 0.02), RNR2 (P = 0.005), COX1 (P = 0.037) and CYTB (P = 0.006). Furthermore, the germline mtDNA mutations had higher heteroplasmy level than the lost (P = 0.002) and de novo mutations (P = 0.04). The nonsynonymous to synonymous substitution ratio (dN/dS) was higher for the heteroplasmic mutations (P = 7.25 × 10-12) than that for the homoplasmic mutations, but the de novo (P = 0.06) and lost mutations (P = 0.03) had lower dN/dS than the germline mutations. Interestingly, we found that the critical regions for mitochondrial transcription: MT-HSP1 (odds ratio [OR]: 21.41), MT-TFH (OR: 7.70) and MT-TAS2 (OR: 3.62), had significantly higher heteroplasmic mutations than the rest of the D-loop sub-regions. Finally, we found that the presence of mt.16093T > C mutation increases 67% risk of developing breast cancer. CONCLUSIONS: Our findings show that mitochondrial genetic landscape changes during cancer pathogenesis and positive selection of mtDNA heteroplasmic mutations in breast cancer. Most importantly, the mitochondrial mutations identified in biopsies can be traced back in matched plasma samples and could potentially be used as early breast cancer diagnostic biomarkers.

Association of Circulating Long Noncoding 7S RNA with Deep Vein Thrombosis.

Mitochondrial dysfunction is a recognized factor in the pathogenesis of deep vein thrombosis (DVT). The role of 7S RNA, a long noncoding RNA that plays an important role in mitochondrial function, in DVT remains unclear. In this study, we aimed to investigate the potential use of 7S RNA as a biomarker in DVT. Plasma samples were obtained from 237 patients (aged 16-95 years) with suspected DVT recruited in a prospective multicenter management study (SCORE) where 53 patients were objectively confirmed with a diagnosis of DVT and the rest were diagnosed as non-DVT. 7S RNA was measured using quantitative real-time polymerase chain reaction in plasma samples. The plasma expression of 7S RNA was significantly lower in DVT compared with non-DVT (0.50 vs. 0.95, p = 0.043). With the linear regression analysis, we showed that the association between the plasma expression of 7S RNA and DVT (ß = -0.72, p = 0.007) was independent of potential confounders. Receiver-operating characteristic curve analysis showed the area under the curve values of 0.60 for 7S RNA. The findings of the present study showed a notable association between 7S RNA and DVT. However, further investigations are needed to fully elucidate the exact role of 7S RNA in the pathophysiology of DVT and its diagnostic value.

Role of multiple risk factors in mental disorders diagnosed in middle-aged women: A population-based follow-up study.

The aims of the study were 1). to investigate the association between the potential risk factors including socio-demographic, lifestyle and DNA methylation and mental disorders in middle-aged women from a large population-based follow-up study, and 2). to estimate the risk score by combining the potential risk factors to examine the mental disorder's incidence. A total of 6461 women, aged 50-65 years, were included in the study. After a median follow-up of 17 years, 2026 (31%) women were diagnosed with mental disorders. The association between these factors and the risk of mental disorders was analyzed using Cox regression models. Harrell's concordance index (C-index) was used to quantify models' predictive performance for future mental disorders. Blood-based global DNA methylation was assessed by an enzyme-linked immunosorbent assay. We found that smoking (HR = 1.38, 95% CI: 1.24-1.54), less physical activity (HR = 1.33, 95% CI: 1.10-1.60), being single (HR = 1.16, 95% CI: 1.04-1.29) and unemployment (HR = 1.50, 95% CI: 1.33-1.70) were independently associated with an increased risk of overall mental disorders. Risk score models combining all these observed factors showed an increased risk, but the prediction ability was low, except for the risk of alcohol use disorders (AUD) and drug use disorders (DUD) (C-index = 0.8). Finally, women who developed MDD/anxiety during follow-up had significantly higher global DNA methylation at baseline than women who did not develop MDD/anxiety (p = 0.005). In conclusion, our results indicate that the studied risk factors were associated with mental disorders in a type-specific manner. The predictive model showed that smoking, alcohol consumption, education and physical activity may predict future AUD/DUD. Global DNA methylation may be a potential risk factor for MDD/anxiety incidence.

The association of mitochondrial DNA copy number with incident mental disorders in women: A population-based follow-up study.

BACKGROUND: Available evidence suggests that mitochondrial DNA copy number (mtDNA-CN) may differ among patients with mental disorders compared to the general population. However, whether mtDNA-CN is independently associated with the subsequent incidence of mental disorders remains unclear. MATERIAL AND METHODS: We used droplet digital PCR to measure the absolute mtDNA-CN in DNA samples obtained from a population-based follow-up study, which included a total of 2354 middle-aged women (52-63 years) who were free of mental disorders at baseline. After 17 years (median) of follow-up, 727 participants were diagnosed with mental disorders. RESULTS: In the univariate Cox regression, lower baseline mtDNA-CN (mtDNA-CN < 117) was associated with a higher risk of mental disorders (HR = 1.16, p = 0.047). In addition, smoking, marital status and sleeping quality were associated with both mtDNA-CN and mental disorders. After adjusting for these variables, the association between mtDNA-CN and mental disorders decreased and became non-significant (HR = 1.07, p = 0.36). Stratification of data according to the subtype of mental disorders, showed that low mtDNA-CN was associated with a higher risk of alcohol or drug use disorders (HR = 1.82, p = 0.045 after adjusting). CONCLUSION: In the present study, we could not find any independent association between mtDNA-CN blood and the most common mental disorders in a population-based follow-up study of Swedish women, except for alcohol and drug use disorders. The use of blood mtDNA-CN as a biomarker of mental disorders, in addition to other risk factors, needs to be further examined in future studies.

The association of zonulin-related proteins with prevalent and incident inflammatory bowel disease.

BACKGROUND: Current evidence regarding the association of serum zonulin-related proteins (ZRP) levels with prevalent inflammatory bowel disease (IBD) is contradictory. Moreover, the association with the subsequent risk of incident IBD is still unexplored. This study aimed to investigate the association of serum ZRP levels with both prevalent and incident IBD. METHOD: The study included a total of 130 women (51-61 years) from the Women's Health in Lund Area (WHILA) study, which included 18 prevalent IBD (diagnosed before baseline) and 47 incident IBD diagnosed during the 17 years (median) follow-up and age- and sampling time-matched controls. Serum ZRP was tested in all participants by ELISA. RESULTS: The serum ZRP levels were significantly higher in prevalent IBD compared to their matched controls (63.2 ng/ml vs 57.0 ng/ml, p = 0.02), however, no evidence of a difference in ZRP levels was found between the women who developed IBD during the follow-up period and their matched controls (61.2 ng/ml vs 59.7 ng/ml, p = 0.34). Using linear mixed models, we found that the association between serum ZRP levels and prevalent IBD (ß = 6.2, p = 0.01), remained after adjusting for potential confounders. Conditional logistic regression models showed no evidence of an association between ZRP level and incident IBD (OR 1.03, p = 0.34). CONCLUSION: Higher serum ZRP levels were associated with prevalent IBD, but not with incident IBD in our study samples.

Association of circulating let-7b-5p with major depressive disorder: a nested case-control study.

BACKGROUND: Major depressive disorder (MDD) is one of the most common psychiatric disorders and is a great disease burden. However, its underlying pathophysiology and aetiology remain poorly understood. Available evidence suggests that circulating microRNAs (miRNAs) are associated with MDD, but it is still unknown whether miRNAs can predict subsequent incident MDD. METHODS: In this nested case-control study, a total of 104 individuals, who were free of MDD at baseline, from the Women's Health in Lund Area (WHILA) cohort were included. Among them, 52 individuals developed MDD (cases) during the 5 years follow-up and 52 individuals did not develop MDD (controls). Plasma expression levels of miR-17-5p, miR-134-5p, miR-144-5p, let-7b-5p and let-7c-5p at baseline were assessed using qRT-PCR. Logistic regression was used to estimate the odds of developing MDD among individuals with different levels of miRNA expression. RESULTS: Plasma expression levels of let-7b-5p were significantly lower (p = 0.02) at baseline in cases compared to controls. After adjustment for age and BMI, let-7b-5p was negatively associated with odds for developing MDD (OR = 0.33, p = 0.03, 95% CI = 0.12-0.91). Moreover, let-7b-5p expression levels showed a trend over time with larger differences between cases and controls for the earlier cases (MDD diagnosis <2 years from baseline) than MDD cases developed later (MDD diagnosis 2-5 years from baseline). CONCLUSIONS: These findings show that lower plasma levels of let-7b-5p are associated with a higher future risk of MDD. Results need to be validated in a large cohort to examine its potential as a peripheral biomarker for MDD.

Association of Mitochondrial DNA Copy Number and Telomere Length with Prevalent and Incident Cancer and Cancer Mortality in Women: A Prospective Swedish Population-Based Study.

Changes in mitochondrial DNA copy number (mtDNA-CN) and telomere length have, separately, been proposed as risk factors for various cancer types. However, those results are conflicting. Here, mtDNA-CN and relative telomere length were measured in 3225 middle-aged women included in a large population-based prospective cohort. The baseline mtDNA-CN in patients with prevalent breast cancer was significantly higher (12.39 copies/µL) than cancer-free individuals. During an average of 15.2 years of follow-up, 520 patients were diagnosed with cancer. Lower mtDNA-CN was associated with decreased risk of genital organ cancer (hazard ratio (HR), 0.84), and shorter telomere length was associated with increased risk of urinary system cancer (HR, 1.79). Furthermore, mtDNA-CN was inversely associated with all-cause (HR, 1.20) and cancer-specific mortality (HR, 1.21) when considering all cancer types. Surprisingly, shorter telomere length was associated with decreased risk of cancer-specific mortality when considering all cancer types (HR, 0.85). Finally, lower mtDNA-CN and shorter telomere length were associated with increased risk of both all-cause and cancer-specific mortality in genital organ cancer patients. In this study population, we found that mtDNA-CN and telomere length were significantly associated with prevalent and incident cancer and cancer mortality. However, these associations were cancer type specific and need further investigation.

Association of mitochondrial DNA copy number with prevalent and incident type 2 diabetes in women: A population-based follow-up study.

Mitochondrial dysfunction is an important factor of the aging process and may play a key role in various diseases. Mitochondrial DNA copy number (mtDNA-CN) is an indirect measure of mitochondrial dysfunction and is associated with type 2 diabetes mellitus (T2DM); however, whether mtDNA-CN can predict the risk of developing T2DM is not well-known. We quantified absolute mtDNA-CN in both prevalent and incident T2DM by well-optimized droplet digital PCR (ddPCR) method in a population-based follow-up study of middle aged (50-59 years) Swedish women (n = 2387). The median follow-up period was 17 years. Compared to those who were free of T2DM, mtDNA-CN was significantly lower in both prevalent T2DM and in women who developed T2DM during the follow-up period. Mitochondrial DNA-copy number was also associated with glucose intolerance, systolic blood pressure, smoking status and education. In multivariable Cox regression analysis, lower baseline mtDNA-CN was prospectively associated with a higher risk of T2DM, independent of age, BMI, education, smoking status and physical activity. Moreover, interaction term analysis showed that smoking increased the effect of low mtDNA-CN at baseline on the risk of incident T2DM. Mitochondrial DNA-copy number may be a risk factor of T2DM in women. The clinical usefulness of mtDNA-CN to predict the future risk of T2DM warrants further investigation.

Diagnostic potential of circulating cell-free nuclear and mitochondrial DNA for several cancer types and nonmalignant diseases: A study on suspected cancer patients.

Circulating cell-free nuclear DNA (nDNA) has been implicated in individual cancer types with a diagnostic value; however, the role of cell-free mitochondrial DNA (mtDNA) in cancers is controversial. We aimed to investigate and compare the diagnostic potential of both nDNA and mtDNA for multiple cancers and to investigate their ability to distinguish multiple cancers from healthy controls and from nonmalignant diseases. We also investigated the prognostic value of both nDNA and mtDNA. The absolute copy number of circulating DNAs in suspected cancer patients (n = 286) referred to a cancer diagnostic center and healthy controls (n = 109) was quantified by droplet digital polymerase chain reaction. Among the suspected cancer patients, 66 (23%) were diagnosed with various cancers, 193 (67%) with nonmalignant diseases, and 27 (10%) with no active disease. Levels of nDNA were significantly higher in cancers (copies/µl; mean ± SD, 21.0 ± 14.2) as compared with nonmalignant diseases (15.2 ± 10.0) and controls (9.3 ± 4.1). In contrast, levels of mtDNA were significantly lower in cancers (copies/µl; mean ± SD, 68,557 ± 66,663) and nonmalignant diseases (60,174 ± 55,831) as compared with controls (98,714 ± 77,789). Receiver operating curve analysis showed that nDNA not only could distinguish multiple cancers from controls (area under curve [AUC] = 0.78; 95% confidence interval [CI] = 0.70-0.86) but also from nonmalignant diseases (AUC = 0.68; 95% CI = 0.59-0.76). However, mtDNA could only differentiate cancers from controls (AUC = 0.65; 95% CI = 0.56-0.73). Higher levels of nDNA were also associated with increased mortality in the cancer patients (hazard ratio = 2.3; 95% CI = 1.1-4.7). Circulating cell-free nDNA, but not the mtDNA, could distinguish multiple cancers from nonmalignant diseases and was associated with poor survival of cancer patients.

Macrophage Migration Inhibitory Factor and microRNA-451a in Response to Mindfulness-based Therapy or Treatment as Usual in Patients with Depression, Anxiety, or Stress and Adjustment Disorders.

Background: Macrophage migration inhibitory factor is a proinflammatory cytokine that has been associated with various psychiatric disorders. MicroRNA-451a can directly target macrophage migration inhibitory factor and downregulate its expression in cells. However, the role of macrophage migration inhibitory factor and microRNA-451a in psychiatric patients treated with psychotherapeutic interventions is unknown. In this study, our aim was to investigate levels of macrophage migration inhibitory factor and its regulating microRNA-451a in patients with depression, anxiety, or stress and adjustment disorders who underwent mindfulness-based therapy or treatment as usual. Methods: A total of 168 patients with psychiatric disorders were included from a randomized controlled trial that compared mindfulness-based therapy with treatment as usual. Plasma levels of macrophage migration inhibitory factor and microRNA-451a were measured at baseline and after the 8-week follow-up using Luminex assay and qPCR. Results: Macrophage migration inhibitory factor levels decreased significantly in patients posttreatment, whereas microRNA-451a levels showed a nonsignificant change. Macrophage migration inhibitory factor levels were inversely associated with microRNA-451a expression levels at baseline (ß=-0.04, P=.008). The change in macrophage migration inhibitory factor levels (follow-up levels minus baseline levels) was associated with the change in microRNA-451a (follow-up levels minus baseline levels) (ß=-0.06, P < .0001). The change in either macrophage migration inhibitory factor or microRNA-451a was not associated with improvement in psychiatric symptoms. Conclusion: We demonstrate that the levels of macrophage migration inhibitory factor decreased after psychotherapeutic interventions in patients with psychiatric disorders. However, this reduction was not associated with an improvement in psychiatric symptoms in response to the treatment. We also found an association between macrophage migration inhibitory factor and its regulating microRNA. However, this association needs to be further examined in future studies.

Quantification of mitochondrial DNA copy number in suspected cancer patients by a well optimized ddPCR method.

Changes in mitochondrial DNA (mtDNA) content is a useful clinical biomarker for various diseases, however results are controversial as several analytical factors can affect measurement of mtDNA. MtDNA is often quantified by taking ratio between a target mitochondrial gene and a reference nuclear gene (mtDNA/nDNA) using quantitative real time PCR often on two separate experiments. It measures relative levels by using external calibrator which may not be comparable across laboratories. We have developed and optimized a droplet digital PCR (ddPCR) based method for quantification of absolute copy number of both mtDNA and nDNA gene in whole blood. Finally, the role of mtDNA in suspected cancer patients referred to a cancer diagnostic center was investigated. Analytical factors which can result in false quantification of mtDNA have been optimized and both target and reference have been quantified simultaneously with intra- and inter-assay coefficient variances as 3.1% and 4.2% respectively. Quantification of mtDNA show that compared to controls, solid tumors (but not hematologic malignancies) and other diseases had significantly lower copy number of mtDNA. Higher mtDNA (highest quartile) was associated with a significantly lower risk of both solid tumors and other diseases, independent of age and sex. Receiver operating curve demonstrated that mtDNA levels could differentiate controls from patients with solid tumors and other diseases. Quantification of mtDNA by a well optimized ddPCR method showed that its depletion may be a hallmark of general illness and can be used to stratify healthy individuals from patients diagnosed with cancer and other chronic diseases.

Role of IL-8, CRP and epidermal growth factor in depression and anxiety patients treated with mindfulness-based therapy or cognitive behavioral therapy in primary health care.

Epidermal growth factor (EGF) and inflammatory markers have been associated with various neuro-psychiatric disorders. However, their role in mild to moderate depression and anxiety patients treated with mindfulness-based group therapy (mindfulness) or cognitive behavioral therapy (CBT) is not known. In this study we analyzed plasma levels of interleukin (IL)-6, IL-8, high sensitivity C-reactive protein (hsCRP) and EGF before (baseline) and after treatment (8 weeks) and investigated their role in response to both arms of the treatment. To cover variety of mental symptoms, treatment response was analyzed by four scales, the Montgomery-Åsberg depression rating scale (MADRS), Hospital anxiety and depression scale- Depression (HADS-D) and anxiety (HADS-A) and patients health questionnaire-9. EGF levels were significantly decreased after both mindfulness and CBT and were associated with treatment response on all scales independent of the use of tranquilizers and antidepressant treatment. Moreover, baseline EGF levels were significantly associated only with baseline scores of anxiety scale. Levels of inflammatory markers analyzed in this study, were not significantly associated with treatment response on any scale. Our findings suggest that improvement in symptoms of depression and anxiety after both mindfulness and CBT is associated with changes in EGF levels but not with the inflammatory markers.

Leukocyte telomere length and depression, anxiety and stress and adjustment disorders in primary health care patients.

BACKGROUND: The primary aim was to examine possible differences in telomere length between primary health care patients, with depression, anxiety or stress and adjustment disorders, and healthy controls. The second aim was to examine the association between telomere length and baseline characteristics in the patients. The third aim was to examine the potential effects of the 8-week treatments (mindfulness-based group therapy or treatment as usual, i.e. mostly cognitive-based therapy) on telomere length, and to examine whether there was a difference in the potential effect on telomere length between the two groups. METHODS: A total of 501 individuals including 181 patients (aged 20-64 years), with depression, anxiety and stress and adjustment disorders, and 320 healthy controls (aged 19-70 years) were recruited in the study. Patient data were collected from a randomized controlled trial comparing mindfulness-based group therapy with treatment as usual. We isolated genomic DNA from blood samples, collected at baseline and after the 8-week follow-up. Telomere length was measured by quantitative real-time (qRT)-PCR. RESULTS: Telomere length was significantly shorter in the patients (mean = 0.77 ± 0.12,), compared to the controls (mean = 0.81 ± 0.14) (p = 0.006). The difference in telomere length remained significant after controlling for age and sex. Old age, male sex and being overweight were associated with shorter telomere length. There was no significant difference in telomere length between baseline and at the 8-week follow-up in any of the treatment groups and no difference between the two groups. CONCLUSION: Our findings confirm that telomere length, as compared with healthy controls, is shortened in patients with depression, anxiety and stress and adjustment disorders. In both groups (mindfulness-based group therapy or treatment as usual), the telomere length remained unchanged after the 8-week treatment/follow-up and there was no difference between the two groups. TRIAL REGISTRATION: (ClinicalTrials.gov ID: NCT01476371 ) Registered November 11, 2011.

Diagnostic potential of plasma microRNA signatures in patients with deep-vein thrombosis.

For excluding deep-vein thrombosis (DVT), a negative D-dimer and low clinical probability are used to rule out DVT. Circulating microRNAs (miRNAs) are stably present in the plasma, serum and other body fluids. Their diagnostic function has been investigated in many diseases but not in DVT. The aims of present study were to assess the diagnostic ability of plasma miRNAs in DVT and to examine their correlation with known markers of hypercoagulability, such as D-dimer and APC-PCI complex. Plasma samples were obtained from 238 patients (aged 16-95 years) with suspected DVT included in a prospective multicentre management study (SCORE). We first performed miRNA screening of plasma samples from three plasma pools containing plasma from 12 patients with DVT and three plasma pools containing plasma from 12 patients without DVT using a microRNA Ready-to-use PCR Panel comprising 742 miRNA primer sets. Thirteen miRNAs that differentially expressed were further investigated by quantitative real-time (qRT)-PCR in the entire cohort. The plasma level of miR-424-5p (p=0.01) were significantly higher, whereas the levels of miR-136-5p (p=0.03) were significantly lower in DVT patients compared to patients without DVT. Receiver-operating characteristic curve analysis showed the area under the curve (AUC) values of 0.63 for miR-424-5p and 0.60 for miR-136-5p. The plasma level of miR-424-5p was associated with both D-dimer and APC-PCI complex levels (p<0.0001 and p=0.001, respectively). In conclusions, these findings indicate that certain miRNAs are associated with DVT and markers of hypercoagulability, though their diagnostic abilities are probably too low.

Plasminogen activator inhibitor-1 4G/5G polymorphism, factor V Leiden, prothrombin mutations and the risk of VTE recurrence.

Plasminogen-activator inhibitor (PAI)-1 is an important inhibitor of the plasminogen/plasmin system. PAI-1 levels are influenced by the 4G/5G polymorphism in the PAI-1 promoter. We investigated the relationship between the PAI-1 polymorphism and VTE recurrence, and its possible modification by factor V Leiden (FVL) and prothrombin (PTM) mutations. Patients (n=1,069) from the Malmö Thrombophilia Study were followed from discontinuation of anticoagulant treatment until diagnosis of VTE recurrence or the end of the study (maximum follow-up 9.8 years). One hundred twenty-seven patients (11.9 %) had VTE recurrence. PAI-1 was genotyped by TaqMan PCR. Cox regression analysis adjusted for age, sex and acquired risk factors of VTE showed no evidence of an association between PAI-1 genotype and risk of VTE recurrence in the study population as a whole. However, by including an interaction term in the analysis we showed that FVL but not PTM modified the effect of PAI-1 genotype: patients with the 4G allele plus FVL had a higher risk of VTE recurrence [hazard ratio (HR) =2.3, 95 % confidence interval (CI) =1.5-3.3] compared to patients with the 4G allele but no FVL (reference group) or FVL irrespective of PAI-1 genotype (HR=1.8, 95 % CI=1.3-2.5). Compared to reference group, 5G allele irrespective of FVL was associated with lower risk of VTE recurrence only when compared with 4G allele together with FVL. In conclusion, FVL has a modifying effect on PAI-1 polymorphism in relation to risk of VTE recurrence. The role of PAI-1 polymorphism as a risk factor of recurrent VTE may be FVL dependent.

Circulating microRNA-144-5p is associated with depressive disorders.

BACKGROUND: Depressive/anxiety disorders are the most common types of mental illnesses in the world. The present study was the first to explore the association between plasma microRNAs (miRNAs) and depression/anxiety in primary care patients. RESULTS: In total, 169 patients (aged 20-64 years) from 16 primary health centers were enrolled in the present study. The healthy controls were consisted of 52 individuals. We first performed miRNA screening of plasma samples from 11 patients using a Serum/Plasma Focus microRNA Panel comprising 179 miRNA primer sets. Six miRNAs were differentially expressed and were then validated by quantitative real-time (qRT)-PCR in the entire study cohort. The mean plasma miR-144-5p level in the depression/anxiety patients increased significantly compared to baseline (p < 0.0001) after the 8-week follow-up. No significant associations were found between the differentially expressed miRNAs and a change in the Montgomery-Åsberg Depression Rating Scale (MADRS-S) score after the follow-up. In linear regression analysis, the plasma miR-144-5p expression level was inversely related to the depression score (MADRS-S) (ß = -0.02, p < 0.01), after adjustment for sex and age, at baseline. In addition, plasma miR-144-5p levels at baseline in the depression/anxiety patients were significantly lower compared with the healthy controls (p < 0.001). CONCLUSIONS: Our findings show that plasma miR-144-5p levels are associated with depressive symptoms. Although confirmatory analyses are required, plasma miRNA-144-5p is a potential peripheral biomarker for pathologic processes related to depression.