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Sökning: WFRF:(Mwinyi Jessica)

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  • Bostrom, Adrian E., et al. (författare)
  • Hypermethylation-associated downregulation of microRNA-4456 in hypersexual disorder with putative influence on oxytocin signalling : A DNA methylation analysis of miRNA genes
  • 2020
  • Ingår i: Epigenetics. - : Taylor & Francis. - 1559-2294 .- 1559-2308. ; 15:1-2, s. 145-160
  • Tidskriftsartikel (refereegranskat)abstract
    • Hypersexual disorder (HD) was proposed as a diagnosis in the DSM-5 and the classification ‘Compulsive Sexual Behavior Disorder’ is now presented as an impulse-control disorder in ICD-11. HD incorporates several pathophysiological mechanisms; including impulsivity, compulsivity, sexual desire dysregulation and sexual addiction. No previous study investigated HD in a methylation analysis limited to microRNA (miRNA) associated CpG-sites. The genome wide methylation pattern was measured in whole blood from 60 subjects with HD and 33 healthy volunteers using the Illumina EPIC BeadChip. 8,852 miRNA associated CpG-sites were investigated in multiple linear regression analyses of methylation M-values to a binary independent variable of disease state (HD or healthy volunteer), adjusting for optimally determined covariates. Expression levels of candidate miRNAs were investigated in the same individuals for differential expression analysis. Candidate methylation loci were further studied for an association with alcohol dependence in an independent cohort of 107 subjects. Two CpG-sites were borderline significant in HD – cg18222192 (MIR708)(p < 10E-05,pFDR = 5.81E-02) and cg01299774 (MIR4456)(p < 10E-06, pFDR = 5.81E-02). MIR4456 was significantly lower expressed in HD in both univariate (p < 0.0001) and multivariate (p < 0.05) analyses. Cg01299774 methylation levels were inversely correlated with expression levels of MIR4456 (p < 0.01) and were also differentially methylated in alcohol dependence (p = 0.026). Gene target prediction and pathway analysis revealed that MIR4456 putatively targets genes preferentially expressed in brain and that are involved in major neuronal molecular mechanisms thought to be relevant for HD, e.g., the oxytocin signalling pathway. In summary, our study implicates a potential contribution of MIR4456 in the pathophysiology of HD by putatively influencing oxytocin signalling.
  • Ciuculete, Diana-Maria, et al. (författare)
  • A genetic risk score is significantly associated with statin therapy response in the elderly population
  • 2017
  • Ingår i: Clinical Genetics. - 0009-9163 .- 1399-0004. ; 91:3, s. 379-385
  • Tidskriftsartikel (refereegranskat)abstract
    • The ability of statins to strongly reduce low-density lipoprotein cholesterol (LDL-C) varies interindividually and is partially influenced by genetic variants. Based on a comprehensive analysis of 23 single nucleotide polymorphisms (SNPs) known to be associated with pharmacokinetics and dynamics of statins, we developed a genetic risk score to study its impact on the therapy outcome in elderly individuals under at least 5 years statin therapy. The study was performed in a population-based cohort of 1016 elderly individuals, which comprised 168 statin users investigated at age 75 and 80. Using random forest models, the major variants influencing LDL-C levels were summarized in a weighted GRS (wGRS). The wGRS was tested with lipid and glucose outcomes and validated in an independent population-based cohort including 221 statin users. Four SNPs within the APOE cluster (rs7412, rs4420638), ABCC2 (rs2002042) and CELSR/SORT1/PSRC1 (rs646776), displayed a major impact on statin efficacy. The wGRS was significantly associated with lower LDL-C at age 75 and 80. This association was replicated displaying similar results. GRS analysis is a powerful tool to evaluate the additive effects of genetic variants on statin response and to estimate the magnitude of LDL-C reduction to a considerable extent in the older population.
  • Ciuculete, Diana-Maria, et al. (författare)
  • Changes in methylation within the STK32B promoter are associated with an increased risk for generalized anxiety disorder in adolescents
  • 2018
  • Ingår i: Journal of Psychiatric Research. - 0022-3956 .- 1879-1379. ; 102, s. 44-51
  • Tidskriftsartikel (refereegranskat)abstract
    • Generalized anxiety disorder (GAD) is highly prevalent among adolescents. An early detection of individuals at risk may prevent later psychiatric condition. Genome-wide studies investigating single nucleotide polymorphisms (SNPs) concluded that a focus on epigenetic mechanisms, which mediate the impact of environmental factors, could more efficiently help the understanding of GAD pathogenesis. We investigated the relationship between epigenetic shifts in blood and the risk to develop GAD, evaluated by the Development and Well-Being Assessment (DAWBA) score, in 221 otherwise healthy adolescents. Our analysis focused specifically on methylation sites showing high inter-individual variation but low tissue-specific variation, in order to infer a potential correlation between results obtained in blood and brain. Two statistical methods were applied, 1) a linear model with limma and 2) a likelihood test followed by Bonferroni correction. Methylation findings were validated in a cohort of 160 adults applying logistic models against the outcome variable "anxiety treatment obtained in the past" and studied in a third cohort with regards to associated expression changes measured in monocytes. One CpG site showed 1% increased methylation in adolescents at high risk of GAD (cg16333992, P-adj. = 0.028, estimate = 3.22), as confirmed in the second cohort (p = 0.031, estimate = 1.32). The identified and validated CpG site is located within the STK32B promoter region and its methylation level was positively associated with gene expression. Gene ontology analysis revealed that STK32B is involved in stress response and defense response. Our results provide evidence that shifts in DNA methylation are associated with a modulated risk profile for GAD in adolescence.
  • Ciuculete, Diana Maria, et al. (författare)
  • Longitudinal DNA methylation changes at MET may alter HGF/c-MET signalling in adolescents at risk for depression
  • 2020
  • Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 15:6-7, s. 646-663
  • Tidskriftsartikel (refereegranskat)abstract
    • Unrecognized depression during adolescence can result in adult suicidal behaviour. The aim of this study was to identify, replicate and characterize DNA methylation (DNAm) shifts in depression aetiology, using a longitudinal, multi-tissue (blood and brain) and multi-layered (genetics, epigenetics, transcriptomics) approach. We measured genome-wide blood DNAm data at baseline and one-year follow-up, and imputed genetic variants, in 59 healthy adolescents comprising the discovery cohort. Depression and suicidal symptoms were determined using the Development and Well-Being Assessment (DAWBA) depression band, Montgomery-Åsberg Depression Rating Scale-Self (MADRS-S) and SUicide Assessment Scale (SUAS). DNAm levels at follow-up were regressed against depression scores, adjusting for sex, age and the DNAm residuals at baseline. Higher methylation levels of 5% and 13% at cg24627299 within the MET gene were associated with higher depression scores (praw<1e-4) and susceptibility for suicidal symptoms (padj.<0.005). The nearby rs39748 was discovered to be a methylation and expression quantitative trait locus in blood cells. mRNA levels of hepatocyte growth factor (HGF) expression, known to strongly interact with MET, were inversely associated with methylation levels at cg24627299, in an independent cohort of 1180 CD14+ samples. In an open-access dataset of brain tissue, lower methylation at cg24627299 was found in 45 adults diagnosed with major depressive disorder compared with matched controls (padj.<0.05). Furthermore, lower MET expression was identified in the hippocampus of depressed individuals compared with controls in a fourth, independent cohort. Our findings reveal methylation changes at MET in the pathology of depression, possibly involved in downregulation of HGF/c-MET signalling the hippocampal region.
  • Ciuculete, Diana-Maria, et al. (författare)
  • meQTL and ncRNA functional analyses of 102 GWAS-SNPs associated with depression implicate HACE1 and SHANK2 genes
  • 2020
  • Ingår i: Clinical Epigenetics. - : BMC. - 1868-7083. ; 12:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Little is known about how genetics and epigenetics interplay in depression. Evidence suggests that genetic variants may change vulnerability to depression by modulating DNA methylation (DNAm) and non-coding RNA (ncRNA) levels. Therefore, the aim of the study was to investigate the effect of the genetic variation, previously identified in the largest genome-wide association study for depression, on proximal DNAm and ncRNA levels. Results We performed DNAm quantitative trait locus (meQTL) analysis in two independent cohorts (totaln= 435 healthy individuals), testing associations between 102 single-nucleotide polymorphisms (SNPs) and DNAm levels in whole blood. We identified and replicated 64 SNP-CpG pairs (p(adj.)< 0.05) with meQTL effect. Lower DNAm at cg02098413 located in theHACE1promoter conferred by the risk allele (C allele) at rs1933802 was associated with higher risk for depression (p(raw)= 0.014, DNAm = 2.3%). In 1202 CD14+ cells sorted from blood, DNAm at cg02088412 positively correlated withHACE1mRNA expression. Investigation in postmortem brain tissue of adults diagnosed with major depressive disorder (MDD) indicated 1% higher DNAm at cg02098413 in neurons and lowerHACE1mRNA expression in CA1 hippocampus of MDD patients compared with healthy controls (p= 0.008 and 0.012, respectively). Expression QTL analysis in blood of 74 adolescent revealed that hsa-miR-3664-5p was associated with rs7117514 (SHANK2) (p(adj.)= 0.015, mRNA difference = 5.2%). Gene ontology analysis of the miRNA target genes highlighted implication in neuronal processes. Conclusions Collectively, our findings from a multi-tissue (blood and brain) and multi-layered (genetic, epigenetic, transcriptomic) approach suggest that genetic factors may influence depression by modulating DNAm and miRNA levels. Alterations atHACE1andSHANK2loci imply potential mechanisms, such as oxidative stress in the brain, underlying depression. Our results deepened the knowledge of molecular mechanisms in depression and suggest new epigenetic targets that should be further evaluated.
  • Skuladottir, Gudrun Valgerdur, et al. (författare)
  • Plasma stearoyl-CoA desaturase activity indices and bile acid concentrations after a low-fat meal : association with a genetic variant in the FTO gene
  • 2018
  • Ingår i: Diabetes, Metabolic Syndrome and Obesity. - 1178-7007 .- 1178-7007. ; 11, s. 611-618
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: Dietary macronutrient composition, stearoyl-CoA desaturase (SCD) activity indices, and primary bile acid (BA) concentrations are among the factors that have been associated with lipid metabolism and contributed to obesity. We investigated the association between the polymorphic expression of the fat mass and obesity-associated (FTO) gene and its relationship with SCD activity indices and primary BA concentrations after a low-fat meal. Subjects and methods: Blood plasma samples were collected from 56 young (20-36 years) healthy subjects with different rs9939609 FTO genotypes. Fasting and post-meal (2 hours after a low-fat breakfast) blood samples were collected on the subsequent morning for the analysis of DNA methylation, SCD activity indices (product-to-precursor fatty acid ratios; 16:1n-7/16:0 and 18: 1n-9/18:0), and chenodeoxycholic acid (CDCA) and cholic acid (CA) concentrations. Expression of lipogenic genes was investigated post-meal to assess the relationship between the CDCA and CA concentrations and mRNA levels of lipogenic genes. Results: The FTO AA (obesity risk) genotype group (n = 18) had higher (P<0.05) post-meal SCD-16 activity index than the FTO TT (wild type) genotype group (n=26). In both the FTO TT (n=16) and AA (n=8) genotype groups, the post-meal concentrations of CDCA and CA were lower (P<0.05) compared with the fasted state. No difference in BA concentrations between the FTO TT and AA genotype groups in both meal states was observed. After adjusting for the body mass index, the highest 50% post-meal concentrations of CA were inversely (P=0.010) correlated with the level of mRNA SCD expression. Conclusion: FTO AA carriers may be at a higher risk for obesity through higher SCD activity in a low-fat diet environment. This effect may be partly pronounced by very low CA concentrations.
  • Bandstein, Marcus, 1988-, et al. (författare)
  • A genetic risk score is associated with weight loss following Roux-Y gastric bypass surgery
  • 2016
  • Ingår i: Obesity Surgery. - 0960-8923 .- 1708-0428. ; 26:9, s. 2183-2189
  • Tidskriftsartikel (refereegranskat)abstract
    • Currently, Roux-en Y gastric bypass (RYGB) is the most efficient therapy for severe obesity. Weight loss after surgery is, however, highly variable and genetically influenced. Genome-wide association studies have identified several single nucleotide polymorphisms (SNP) associated with body mass index (BMI) and waist-hip ratio (WHR). We aimed to identify two genetic risk scores (GRS) composed of weighted BMI and WHR-associated SNPs to estimate their impact on excess BMI loss (EBMIL) after RYGB surgery. Two hundred and thirty-eight obese patients (BMI 45.1 +/- 6.2 kg/m(2), 74 % women), who underwent RYGB, were genotyped for 35 BMI and WHR-associated SNPs and were followed up after 2 years. SNPs with high impact on post-surgical weight loss were filtered out using a random forest model. The filtered SNPs were combined into a GRS and analyzed in a linear regression model. An up to 11 % lower EBMIL with higher risk score was estimated for two GRS models (P = 0.026 resp. P = 0.021) composed of seven BMI-associated SNPs (closest genes: MC4R, TMEM160, PTBP2, NUDT3, TFAP2B, ZNF608, MAP2K5, GNPDA2, and MTCH2) and of three WHR-associated SNPs (closest genes: HOXC13, LYPLAL1, and DNM3-PIGC). Patients within the lowest GRS quartile had higher EBMIL compared to patients within the other three quartiles in both models. We identified two GRSs composed of BMI and WHR-associated SNPs with significant impact on weight loss after RYGB surgery using random forest analysis as a SNP selection tool. The GRS may be useful to pre-surgically evaluate the risks for patients undergoing RYGB surgery.
  • Bandstein, Marcus, 1988-, et al. (författare)
  • A genetic variant in proximity to the gene LYPLAL1 is associated with lower hunger feelings and increased weight loss following Roux-en Y gastric bypass surgery
  • 2016
  • Ingår i: Scandinavian Journal of Gastroenterology. - 0036-5521 .- 1502-7708. ; 51:9, s. 1050-1055
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Bariatric surgery is the most efficient treatment of severe obesity. We investigated to what extent BMI- or waist-hip ratio (WHR)-related genetic variants are associated with excess BMI loss (EBMIL) two years after Roux-en-Y gastric bypass (RYGB) surgery, and elucidated the affected biological pathways.Methods: Two-hundred fifty-one obese patients (age: 4310.7, preoperative BMI: 45.16.1kg/m(2), 186 women) underwent RYGB surgery and were followed up after two years with regard to BMI. Patients were genotyped for 32 single-nucleotide polymorphisms (SNPs) that were investigated with regard to their impact on response to RYGB and preoperatively measured Three Factor Eating Questionnaire (TFEQ) scores.Results: Homozygous T carriers of the SNP rs4846567 in proximity to the Lysophospholipase-like 1 (LYPLAL1) gene showed a 7% higher EBMIL compared to wild-type and heterozygous carriers (p=0.031). TT-allele carriers showed furthermore lower scores for Hunger (74%, p<0.001), lower Disinhibition (53%, p<0.001), and higher Cognitive restraint (21%, p=0.017) than GG/GT carriers in the TFEQ. Patients within the lowest quartile of Hunger scores had a 32% greater EBMIL compared to patients in the highest quartile (p<0.001).Conclusion: The LYPLAL1 genotype is associated with differences in eating behavior and loss of extensive body weight following RYGB surgery. Genotyping and the use of eating behavior-related questionnaires may help to estimate the RYGB-associated therapy success.
  • Boström, Adrian, et al. (författare)
  • A MIR4646 associated methylation locus is hypomethylated in adolescent depression
  • 2017
  • Ingår i: Journal of Affective Disorders. - 0165-0327 .- 1573-2517. ; 220, s. 117-128
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Studies of epigenetics and transcriptional activity in adolescents may provide knowledge about possible preventive strategies of depression. Methods: We present a methylome-wide association study (MWAS) and cohort validation analysis of depression in adolescents, in two separate cohorts: discovery (n = 93) and validation data set 1 (n = 78). The genome-wide methylation pattern was measured from whole blood using the Illumina 450K array. A second validation cohort, validation data set 2, consists of post-mortem brain biopsies from depressed adults (n = 58). We performed a MWAS by robust multiple linear regressions of methylation to a modified risk-score assessment of depression. Methylation levels of candidate CpG sites were correlated with expression levels of the associated gene in an independent cohort of 11 healthy volunteers. Results: The methylation state of two CpG sites reliably predicted ratings of depression in adolescents (cg13227623 and cg04102384) (p < 10E-06). Cohort validation analysis confirmed cg04102384 - located in the promoter region of microRNA 4646 (MIR4646) - to be hypomethylated in both validation data set 1 and validation data set 2 (p < 0.05). Cg04102384 was inversely correlated to expression levels of MIR4646-3p in healthy controls (p < 0.05). Limitations: MIR4646 was not differentially expressed in a subset of samples with adolescent depression measured by qRT-PCR measurements. Conclusion: We identify a specific MIR4646 associated epigenetic risk site to be associated with depression in adolescents. Cg04102384 putatively regulates gene expression of MIR4646-3p. Target gene prediction and gene set overrepresentation analysis revealed involvement of this miRNA in fatty acid elongation, a process related to omega-3 fatty acids, previously associated with depression.
  • Boström, Adrian E., et al. (författare)
  • Longitudinal genome-wide methylation study of Roux-en-Y gastric bypass patients reveals novel CpG sites associated with essential hypertension
  • 2016
  • Ingår i: BMC Medical Genomics. - 1755-8794 .- 1755-8794. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Essential hypertension is a significant risk factor for cardiovascular diseases. Emerging research suggests a role of DNA methylation in blood pressure physiology. We aimed to investigate epigenetic associations of promoter related CpG sites to essential hypertension in a genome-wide methylation approach. Methods: The genome-wide methylation pattern in whole blood was measured in 11 obese patients before and six months after Roux-en-Y gastric bypass surgery using the Illumina 450 k beadchip. CpG sites located within 1500 bp of the transcriptional start site of adjacent genes were included in our study, resulting in 124 199 probes investigated in the subsequent analysis. Percent changes in methylation states and SBP measured before and six months after surgery were calculated. These parameters were correlated to each other using the Spearman's rank correlation method (Edgeworth series approximation). To further investigate the detected relationship between candidate CpG sites and systolic blood pressure levels, binary logistic regression analyses were performed in a larger and independent cohort of 539 individuals aged 19-101 years to elucidate a relationship between EH and the methylation state in candidate CpG sites. Results: We identified 24 promoter associated CpG sites that correlated with change in SBP after RYGB surgery (p < 10-16). Two of these CpG loci (cg00875989, cg09134341) were significantly hypomethylated in dependency of EH (p < 10-03). These results were independent of age, BMI, ethnicity and sex. Conclusions: The identification of these novel CpG sites may contribute to a further understanding of the epigenetic regulatory mechanisms underlying the development of essential hypertension.
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