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1.
Eur Respir J ; 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744833

RESUMO

Pulmonary arterial hypertension (PAH) is a rare disease that leads to premature death from right heart failure. It is strongly associated with elevated red cell distribution width (RDW), a correlate of several iron status biomarkers. High RDW values can signal early stage iron deficiency or iron deficiency anaemia. This study investigated if elevated RDW is causally associated with PAH.A two-sample Mendelian randomisation (MR) approach was applied to investigate whether genetic predisposition to higher levels of RDW increases the odds of developing PAH. Primary and secondary MR analyses were performed using all available genome-wide significant RDW variants (n=179) and five genome-wide significant RDW variants that act via systemic iron status, respectively.We confirmed the observed association between RDW and PAH (OR=1.90, 95% CI=1.80-2.01) in a multi-centre case-control study (N cases=642, N disease controls=15 889). The primary MR analysis was adequately powered to detect a causal effect (OR) from between 1.25 and 1.52 or greater based on estimates reported in the RDW GWAS or from our own data. There was no evidence for a causal association between RDW and PAH in either the primary (ORcausal=1.07, 95% CI=0.92-1.24) or the secondary (ORcausal=1.09, 95% CI=0.77-1.54) MR analysis.The results suggest that at least some of the observed association of RDW with PAH is secondary to disease progression. Results of iron therapeutic trials in PAH should be interpreted with caution as any improvements observed may not be mechanistically linked to the development of PAH.

2.
Nat Genet ; 51(11): 1574-1579, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31676865

RESUMO

Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.

3.
J Thromb Haemost ; 17(11): 1808-1814, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31271701

RESUMO

BACKGROUND: Factor V (FV) is a circulating protein primarily synthesized in the liver, and mainly present in plasma. It is a major component of the coagulation process. OBJECTIVE: To detect novel genetic loci participating to the regulation of FV plasma levels. METHODS: We conducted the first Genome Wide Association Study on FV plasma levels in a sample of 510 individuals and replicated the main findings in an independent sample of 1156 individuals. RESULTS: In addition to genetic variations at the F5 locus, we identified novel associations at the PLXDC2 locus, with the lead PLXDC2 rs927826 polymorphism explaining ~3.7% (P = 7.5 × 10-15 in the combined discovery and replication samples) of the variability of FV plasma levels. In silico transcriptomic analyses in various cell types confirmed that PLXDC2 expression is positively correlated to F5 expression. SiRNA experiments in human hepatocellular carcinoma cell line confirmed the role of PLXDC2 in modulating factor F5 gene expression, and revealed further influences on F2 and F10 expressions. CONCLUSION: Our study identified PLXDC2 as a new molecular player of the coagulation process.

4.
J Am Heart Assoc ; 8(15): e012994, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31310728

RESUMO

Background Systemic iron status has been implicated in atherosclerosis and thrombosis. The aim of this study was to investigate the effect of genetically determined iron status on carotid intima-media thickness, carotid plaque, and venous thromboembolism using Mendelian randomization. Methods and Results Genetic instrumental variables for iron status were selected from a genome-wide meta-analysis of 48 972 subjects. Genetic association estimates for carotid intima-media thickness and carotid plaque were obtained using data from 71 128 and 48 434 participants, respectively, and estimates for venous thromboembolism were obtained using data from a study incorporating 7507 cases and 52 632 controls. Conventional 2-sample summary data Mendelian randomization was performed for the main analysis. Higher genetically determined iron status was associated with increased risk of venous thromboembolism. Odds ratios per SD increase in biomarker levels were 1.37 (95% CI 1.14-1.66) for serum iron, 1.25 (1.09-1.43) for transferrin saturation, 1.92 (1.28-2.88) for ferritin, and 0.76 (0.63-0.92) for serum transferrin (with higher transferrin levels representing lower iron status). In contrast, higher iron status was associated with lower risk of carotid plaque. Corresponding odds ratios were 0.85 (0.73-0.99) for serum iron and 0.89 (0.80-1.00) for transferrin saturation, with concordant trends for serum transferrin and ferritin that did not reach statistical significance. There was no Mendelian randomization evidence of an effect of iron status on carotid intima-media thickness. Conclusions These findings support previous work to suggest that higher genetically determined iron status is protective against some forms of atherosclerotic disease but increases the risk of thrombosis related to stasis of blood.

5.
RNA ; 25(6): 657-668, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30819774

RESUMO

Next-generation sequencing is an increasingly popular and efficient approach to characterize the full set of microRNAs (miRNAs) present in human biosamples. MiRNAs' detection and quantification still remain a challenge as they can undergo different posttranscriptional modifications and might harbor genetic variations (polymiRs) that may impact on the alignment step. We present a novel algorithm, OPTIMIR, that incorporates biological knowledge on miRNA editing and genome-wide genotype data available in the processed samples to improve alignment accuracy. OPTIMIR was applied to 391 human plasma samples that had been typed with genome-wide genotyping arrays. OPTIMIR was able to detect genotyping errors, suggested the existence of novel miRNAs and highlighted the allelic imbalance expression of polymiRs in heterozygous carriers. OPTIMIR is written in python, and freely available on the GENMED website (http://www.genmed.fr/index.php/fr/) and on Github (github.com/FlorianThibord/OptimiR).


Assuntos
Algoritmos , Genoma Humano , MicroRNAs/genética , Alinhamento de Sequência/métodos , Trombose Venosa/genética , Sequência de Bases , Biologia Computacional/métodos , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Genótipo , Heterozigoto , Humanos , MicroRNAs/sangue , MicroRNAs/classificação , Análise de Sequência com Séries de Oligonucleotídeos , Software , Trombose Venosa/sangue , Trombose Venosa/patologia
6.
Diabetologia ; 62(2): 292-305, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30547231

RESUMO

AIMS/HYPOTHESIS: Identifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants. METHODS: We performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included. RESULTS: We identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, ß = 0.27, p = 1.3 × 10-11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10-4, ß with diabetes = 0.69, ß without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10-6). CONCLUSIONS/INTERPRETATION: The current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.


Assuntos
Albuminúria/genética , Diabetes Mellitus/genética , Nefropatias Diabéticas/genética , Receptores de Superfície Celular/genética , Alelos , Grupo com Ancestrais do Continente Europeu , Frequência do Gene , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único
7.
Clin Genet ; 2018 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-30471092

RESUMO

Left ventricular non-compaction (LVNC) is a cardiomyopathy that may be of genetic origin, however few data are available about the yield of mutation, the spectrum of genes and allelic variations. The aim of this study was to better characterize the genetic spectrum of isolated LVNC in a prospective cohort of 95 unrelated adult patients through the molecular investigation of 107 genes involved in cardiomyopathies and arrhythmias. Fifty-two pathogenic or probably pathogenic variants were identified in 40 patients (42%) including 31 patients (32.5%) with single variant and 9 patients with complex genotypes (9.5%). Mutated patients tended to have younger age at diagnosis than patients with no identified mutation. The most prevalent genes were TTN, then HCN4, MYH7, and RYR2. The distribution includes 13 genes previously reported in LVNC and 10 additional candidate genes. Our results show that LVNC is basically a genetic disease and support genetic counseling and cardiac screening in relatives. There is a large genetic heterogeneity, with predominant TTN null mutations and frequent complex genotypes. The gene spectrum is close to the one observed in dilated cardiomyopathy but with specific genes such as HCN4. We also identified new candidate genes that could be involved in this sub-phenotype of cardiomyopathy. This article is protected by copyright. All rights reserved.

8.
Diabetes ; 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30487263

RESUMO

To identify genetic variants associated with diabetic retinopathy (DR), we performed a large, multiethnic genome-wide association study (GWAS). Discovery included eight European cohorts (n = 3,246) and seven African American cohorts (n = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a P value < 1 X 10-5 were investigated in replication cohorts that included 18,545 Europeans, 16,453 Asians and 2,710 Hispanics. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (NVL) was associated with DR in European discovery cohorts (P = 2.1 x 10-9), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR (PDR) was found to have significant connectivity (P=0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in NVL, as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.

9.
Diabetes Care ; 2018 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-30455333

RESUMO

OBJECTIVE: Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts. RESEARCH DESIGN AND METHODS: In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1-3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3-18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD. RESULTS: During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA1c, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, P = 0.003) and lowest in Steno (HR 0.54, P < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, P = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes. CONCLUSIONS: Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.

10.
Stroke ; 49(9): 2220-2223, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30354977

RESUMO

Background and Purpose- Arterial vasospasm is a well-known delayed complication of aneurysmal subarachnoid hemorrhage (aSAH). However, no validated biomarker exists to help clinicians discriminating patients with aSAH who will develop vasospasm (VSP+) and identifying those who then deserve aggressive preventive therapy. We hypothesized that whole-blood miRNAs could be a source of candidate biomarkers for vasospasm. Methods- Using a next-generation sequencing approach, we performed whole-blood miRNA profiling between VSP+patients with aSAH and patients who did not develop vasospasm (VSP-) in a prospective cohort of 32 patients. Profiling was performed on the admission day and 3 days before vasospasm. Results- Four hundred forty-two miRNAs were highly expressed in whole blood of patients with aSAH. Among them, hsa-miR-3177-3p demonstrated significant ( P=5.9×10-5; PBonferroni corrected=0.03) lower levels in VSP- compared with VSP+ patients. Looking for whole-blood mRNA correlates of hsa-miR-3177-3p, we observed some evidence that the decrease in hsa-miR-3177-3p levels after aSAH was associated with an increase in LDHA mRNA levels in VSP- ( P<10-3) but not in VSP+ ( P=0.66) patients. Conclusions- Whole-blood miRNA levels of hsa-miR-3177-3p could serve as a biomarker for vasospasm. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01779713.

11.
Sci Rep ; 8(1): 14668, 2018 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-30279450

RESUMO

The intermediate filament protein nestin is expressed during embryonic development, but considered largely restricted to areas of regeneration in the adult. Here, we perform a body-wide transcriptome and protein-profiling analysis to reveal that nestin is constitutively, and highly-selectively, expressed in adult human endothelial cells (EC), independent of proliferative status. Correspondingly, we demonstrate that it is not a marker for tumour EC in multiple malignancy types. Imaging of EC from different vascular beds reveals nestin subcellular distribution is shear-modulated. siRNA inhibition of nestin increases EC proliferation, and nestin expression is reduced in atherosclerotic plaque neovessels. eQTL analysis reveals an association between SNPs linked to cardiovascular disease and reduced aortic EC nestin mRNA expression. Our study challenges the dogma that nestin is a marker of proliferation, and provides insight into its regulation and function in EC. Furthermore, our systems-based approach can be applied to investigate body-wide expression profiles of any candidate protein.

12.
Sci Transl Med ; 10(457)2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30185651

RESUMO

The thymus is the primary lymphoid organ where naïve T cells are generated; however, with the exception of age, the parameters that govern its function in healthy humans remain unknown. We characterized the variability of thymic function among 1000 age- and sex-stratified healthy adults of the Milieu Intérieur cohort, using quantification of T cell receptor excision circles (TRECs) in peripheral blood T cells as a surrogate marker of thymopoiesis. Age and sex were the only nonheritable factors identified that affect thymic function. TREC amounts decreased with age and were higher in women compared to men. In addition, a genome-wide association study revealed a common variant (rs2204985) within the T cell receptor TCRA-TCRD locus, between the DD2 and DD3 gene segments, which associated with TREC amounts. Strikingly, transplantation of human hematopoietic stem cells with the rs2204985 GG genotype into immunodeficient mice led to thymopoiesis with higher TRECs, increased thymocyte counts, and a higher TCR repertoire diversity. Our population immunology approach revealed a genetic locus that influences thymopoiesis in healthy adults, with potentially broad implications in precision medicine.

13.
JAMA Cardiol ; 3(9): 877-882, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30073300

RESUMO

Importance: Women are at higher risk of drug-induced torsade de pointes (TdP) than men. Androgens are protective. Influence of oral contraception on drug-induced TdP and QT prolongation is controversial. Objective: To determine if the extent of sotalol-induced corrected QT (QTc) prolongation and specific T-wave morphological changes, which are biomarkers for the risk of drug-induced TdP, differ in patients according to the androgenic activity of the type of oral contraceptive (OCs) they take compared with patients who took no pills. Design, Setting, and Participants: A cohort of 498 healthy, nonmenopausal women received 80 mg of oral sotalol, a drug with known risk of drug-induced TdP, during this study in a clinical investigation center. The participants also took either no oral contraception or received OCs with different types of progestin: levonorgestrel (which has high androgenic potency), desogestrel or gestodene (which has intermediate androgenic potency), or drospirenone (which has antiandrogenic properties). Women were enrolled from February 2008 to February 2012, and data analysis took place from September 2014 to May 2018. Main Outcomes and Measures: Electrocardiographic changes 3 hours after sotalol administration. Results: A total of 137 women received levonorgestrel, 41 received desogestrel, 51 received gestodene, and 62 received drospirenone; another 207 received no OCs. Baseline QTc duration, plasma sotalol levels, and potassium levels did not significantly differ among groups. However, 3 hours after sotalol exposure, QTc prolongation was greater in women taking drospirenone (mean [SD] increase, 31.2 [12.6] milliseconds from baseline) than in women taking no OCs (mean [SD] increase, 24.6 [12.5] milliseconds; P = .005) or those taking levonorgestrel (mean [SD] increase, 24.2 [13.7] milliseconds; P = .005). The frequency of sotalol-induced T-wave alteration was higher in women taking drospirenone (n = 13 of 61 [21.0%]) than those taking levonorgestrel (n = 20 of 137 [14.6%]) or women taking no OCs (n = 24 of 207 [11.6%]; P = .01). Disproportionality analysis using the European pharmacovigilance database showed a higher reporting rate of OC-induced prolonged QT and ventricular arrhythmias in women taking drospirenone than levonorgestrel (drug-induced long QT syndrome: reporting odds ratio [ROR], 6.2 [95% CI, 1.3-30.8]; P = .01; ventricular arrhythmia: ROR, 3.3 [95% CI, 1.7-6.3]; P < .001). Conclusions and Relevance: Contraceptive pills are associated with variable drug-induced alterations of ventricular repolarization in healthy nonmenopausal women. Drospirenone, an antiandrogenic pill, was associated with increased sotalol-induced QTc prolongation, although absolute QTc prolongation was modest. This finding was supported by the European pharmacovigilance database, which showed a higher reporting rate of suspected OC-induced ventricular arrhythmias on drospirenone compared with levonorgestrel. More data are required on whether antiandrogenic OCs lead to clinically significant adverse events in patients taking QTc-prolonging drugs.

14.
Blood ; 132(17): 1842-1850, 2018 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-30042098

RESUMO

Many hemostatic factors are associated with age and age-related diseases; however, much remains unknown about the biological mechanisms linking aging and hemostatic factors. DNA methylation is a novel means by which to assess epigenetic aging, which is a measure of age and the aging processes as determined by altered epigenetic states. We used a meta-analysis approach to examine the association between measures of epigenetic aging and hemostatic factors, as well as a clotting time measure. For fibrinogen, we performed European and African ancestry-specific meta-analyses which were then combined via a random effects meta-analysis. For all other measures we could not estimate ancestry-specific effects and used a single fixed effects meta-analysis. We found that 1-year higher extrinsic epigenetic age as compared with chronological age was associated with higher fibrinogen (0.004 g/L/y; 95% confidence interval, 0.001-0.007; P = .01) and plasminogen activator inhibitor 1 (PAI-1; 0.13 U/mL/y; 95% confidence interval, 0.07-0.20; P = 6.6 × 10-5) concentrations, as well as lower activated partial thromboplastin time, a measure of clotting time. We replicated PAI-1 associations using an independent cohort. To further elucidate potential functional mechanisms, we associated epigenetic aging with expression levels of the PAI-1 protein encoding gene (SERPINE1) and the 3 fibrinogen subunit-encoding genes (FGA, FGG, and FGB) in both peripheral blood and aorta intima-media samples. We observed associations between accelerated epigenetic aging and transcription of FGG in both tissues. Collectively, our results indicate that accelerated epigenetic aging is associated with a procoagulation hemostatic profile, and that epigenetic aging may regulate hemostasis in part via gene transcription.

15.
Bioinformatics ; 34(19): 3396-3398, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-29726922

RESUMO

Summary: Predicted deleteriousness of coding variants is a frequently used criterion to filter out variants detected in next-generation sequencing projects and to select candidates impacting on the risk of human diseases. Most available dedicated tools implement a base-to-base annotation approach that could be biased in presence of several variants in the same genetic codon. We here proposed the MACARON program that, from a standard VCF file, identifies, re-annotates and predicts the amino acid change resulting from multiple single nucleotide variants (SNVs) within the same genetic codon. Applied to the whole exome dataset of 573 individuals, MACARON identifies 114 situations where multiple SNVs within a genetic codon induce an amino acid change that is different from those predicted by standard single SNV annotation tool. Such events are not uncommon and deserve to be studied in sequencing projects with inconclusive findings. Availability and implementation: MACARON is written in python with codes available on the GENMED website (www.genmed.fr). Supplementary information: Supplementary data are available at Bioinformatics online.

16.
Cardiovasc Diabetol ; 17(1): 61, 2018 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-29695241

RESUMO

BACKGROUND: Patients with type 1 diabetes are more at risk of coronary artery disease than the general population. Although evidence points to a genetic risk there have been no study investigating genetic risk factors of coronary artery disease specific to individuals with type 1 diabetes. To identify low frequency and common genetic variations associated with coronary artery disease in populations of individuals with type 1 diabetes. METHODS: A two-stage genome wide association study was conducted. The discovery phase involved the meta-analysis of three genome-wide association cohorts totaling 434 patients with type 1 diabetes and coronary artery disease (cases) and 3123 T1D individuals with no evidence of coronary artery disease (controls). Replication of the top association signals (p < 10-5) was performed in five additional independent cohorts totaling 585 cases and 2612 controls. RESULTS: One locus (rs115829748, located upstream of the MAP1B gene) reached the statistical threshold of 5 × 10-8 for genome-wide significance but did not replicate. Nevertheless, three single nucleotide polymorphisms provided suggestive evidence for association with coronary artery disease in the combined studies: CDK18 rs138760780 (OR = 2.60 95% confidence interval [1.75-3.85], p = 2.02 × 10-6), FAM189A2 rs12344245 (OR = 1.85 [1.41-2.43], p = 8.52 × 10-6) and PKD1 rs116092985 (OR = 1.53 [1.27-1.85], p = 1.01 × 10-5). In addition, our analyses suggested that genetic variations at the ANKS1A, COL4A2 and APOE loci previously found associated with coronary artery disease in the general population could have stronger effects in patients with type 1 diabetes. CONCLUSIONS: This study suggests three novel candidate genes for coronary artery disease in the subgroup of patients affected with type 1 diabetes. The detected associations deserve to be definitively validated in additional epidemiological studies.

17.
Nephrol Dial Transplant ; 33(12): 2201-2207, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29361146

RESUMO

Background: MicroRNAs (miRNAs) are small non-coding RNAs participating in post-transcriptional regulation of genes. Their key role in modulating the susceptibility to human diseases is now widely recognized, in particular in the context of cardiometabolic disorders. The aim of the present study was to identify miRNAs associated with diabetic nephropathy (DN) in patients with type 2 diabetes (T2D). Methods: A next-generation sequencing-based miRNA profiling was performed in a case-control study for DN in plasma samples of 23 T2D patients with DN (cases) and 23 T2D without (controls). The main associations were confirmed using quantitative reverse transcription-polymerase chain reaction and tested for replication in an independent case-control collection of 100 T2D patients, 50 with DN and 50 without. Results: From the 381 known mature miRNAs that were found highly expressed in the discovery samples, we observed and replicated an association between increased plasma levels of hsa-miR-152-3p and DN (P = 4.03 × 10-4 in the combined samples). Hsa-miR-152-3p plasma levels were further found to be positively correlated (P = 0.003) to plasma osmolarity, a surrogate marker for solute carrier net activity, whose regulation is controlled by several genes including SLC5A3, one of the predicted targets of hsa-miR-152-3p. Conclusions: We observed strong evidence for the association of hsa-miR-152-3p plasma levels and DN in patients with T2D, confirming an association previously observed in patients with type 1 diabetes.

18.
Br J Haematol ; 180(3): 335-345, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29082522

RESUMO

Venous thromboembolism (VTE) has a strong genetic component. This review summarizes what is known at the seventeen genes that are now well established to harbour VTE-associated genetic variants. In addition, it discusses additional candidate genes that deserve further validation before being claimed as VTE associated genes. Finally, several research strategies are briefly described to identify other molecular determinants of the disease.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Tromboembolia Venosa/genética , Alelos , Animais , Loci Gênicos , Variação Genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos
19.
PLoS One ; 12(10): e0182472, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29084233

RESUMO

BACKGROUND: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. METHODS: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. RESULTS: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. CONCLUSIONS: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes.


Assuntos
Metilação de DNA , Homocisteína/metabolismo , Leucócitos/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Cromossomos Humanos Par 6 , Estudos de Coortes , Ilhas de CpG , Humanos , Polimorfismo de Nucleotídeo Único
20.
Epigenomics ; 9(11): 1403-1422, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28990796

RESUMO

AIM: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes. METHODS: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis. RESULTS: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methylated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6. CONCLUSION: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.


Assuntos
Metilação de DNA , Epigênese Genética , Homocisteína/sangue , Leucócitos/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Humanos , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/genética , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Masculino , Tenascina/genética , Tenascina/metabolismo
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