Blood DNA methylation signature of diet quality, and association with cardiometabolic traits

BACKGROUND: Diet quality might influence cardiometabolic health through epigenetic changes, but this has been little investigated in adults. Our aim was to identify Cytosine-phosphate-Guanine (CpG) dinucleotides associated with diet quality by conducting an epigenome-wide association study (EWAS) based on blood DNA methylation (DNAm), and to assess how diet-related CpGs associate with inherited susceptibility to cardiometabolic traits: body mass index (BMI), systolic blood pressure (SBP), triglycerides, type 2 diabetes (T2D) and coronary heart disease (CHD). METHODS: Meta-EWAS including 5,274 participants in four cohorts from Spain, the US and the UK. We derived three dietary scores (exposures) to measure adherence to a Mediterranean diet (MMDS), to a healthy plant-based diet (HPDI) and to the Dietary Approaches to Stop Hypertension (DASH). Blood DNAm (outcome) was assessed with the Infinium arrays Human Methylation 450 K BeadChip and MethylationEPIC BeadChip. For each diet score, we performed linear EWAS adjusted for age, sex, blood cells, smoking and technical variables, and BMI in a second set of models. We also conducted Mendelian randomization analyses to assess the potential causal relationship between diet-related CpGs and cardiometabolic traits. RESULTS: We found 18 differentially methylated CpGs associated with dietary scores (p-value < 1.08 × 10-7; Bonferroni correction), of which 12 were previously associated with cardiometabolic traits. Enrichment analysis revealed overrepresentation of diet-associated genes in pathways involved in inflammation and cardiovascular disease. Mendelian randomization analyses suggested that genetically determined methylation levels corresponding to lower diet quality at cg02079413 (SNORA54), cg02107842 (MAST4), and cg23761815 (SLC29A3) were causally associated with higher BMI, and at cg05399785 (WDR8) with greater SBP; and methylation levels associated with higher diet quality at cg00711496 (PRMT1) with lower BMI, T2D risk and CHD risk, and at cg0557921 (AHRR) with lower CHD risk. CONCLUSIONS: Diet quality in adults was related to differential methylation in blood at 18 CpGs, some of which related to cardiometabolic health.Availability: The R code for the analysis is available in the following Github repository: https://github.com/jorgedb98/B64_DIAMETR.git

Impact of FLT3–ITD Mutation Status and Its Ratio in a Cohort of 2901 Patients Undergoing Upfront Intensive Chemotherapy: A PETHEMA Registry Study

FLT3–ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3–ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3–ITD mutations. In multivariate analyses, patients with an FLT3–ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p 0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3–ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3–ITD status in all patients, and we found that the group of FLT3–ITD-positive patients with AR 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3–ITD mutations.Depto. de MedicinaFac. de MedicinaTRUEInstituto de Salud Carlos IIIFundación CRIS Contra el CáncerInstituto de Investigación Hospital 12 de OctubreUnión Europeapu

Impact of FLT3–ITD Mutation Status and Its Ratio in a Cohort of 2901 Patients Undergoing Upfront Intensive Chemotherapy: A PETHEMA Registry Study

FLT3–ITD results in a poor prognosis in terms of overall survival (OS) and relapse-free survival (RFS) in acute myeloid leukemia (AML). However, the prognostic usefulness of the allelic ratio (AR) to select post-remission therapy remains controversial. Our study focuses on the prognostic impact of FLT3–ITD and its ratio in a series of 2901 adult patients treated intensively in the pre-FLT3 inhibitor era and reported in the PETHEMA registry. A total of 579 of these patients (20%) harbored FLT3–ITD mutations. In multivariate analyses, patients with an FLT3–ITD allele ratio (AR) of >0.5 showed a lower complete remission (CR rate) and OS (HR 1.47, p = 0.009), while AR > 0.8 was associated with poorer RFS (HR 2.1; p 0.5). Using the maximally selected log-rank statistics, we established an optimal cutoff of FLT3–ITD AR of 0.44 for OS, and 0.8 for RFS. We analyzed the OS and RFS according to FLT3–ITD status in all patients, and we found that the group of FLT3–ITD-positive patients with AR 0.44, allo-HSCT was superior to auto-HSCT in terms of OS and RFS. This study provides more evidence for a better characterization of patients with AML harboring FLT3–ITD mutations.This study was fundedby Instituto de Salud Carlos III (ISCIII) through the project PI19/01518 and PI19/00730 and co- funded by the European Union, the CRIS Against Cancer Foundation, grant 2018/001, and by the Instituto de Investigación Hospital 12 de Octubre (IMAS12). APeer reviewe

Aspectos reproductivos de Grapsus grapsus (Decapoda: Grapsidae) en islas del sureste del Golfo de California

Objetive. The sex ratio, ovigerous females, first sexual maturity lengths and fecundity of Grapsus grapsus crab in the Lobos, Venados and Pajaros islands (southeastern Gulf of California) were analyzed. Materials and methods. Sampling was monthly between March 2011 and February 2012, collections were nocturnal at low tide, 30 crabs were collected in a quadrant (25 m2) for island and&nbsp;sampling. AN (mm) and PT (g) were determined. The proportion of sexes and size of first sexual maturity (AN50%) was estimated, in ovigerous females, embryonic stages and fecundity (gravimetric method). Results. The sex ratio of M:H was 1:1.3. The average maturity was AN50% 34.9 mm. It is evident the presence of ovigerous females (71.3%) and all the embryonic phases, 48% of ovigerous was red-orange phase. Eggs diameter from 1.1 to 5 µm, with an averange diameter of 2.05 µm. The mean fecundity was 24339.3 eggs. The maximum and minimum weight per female egg was 69.9 and 15.2 g. Conclusions. Based on the biological characteristics of the sex ratio, ovigerous females, first sexual maturity lengths and fecundity of G. grapsus, represent a favorable effect on its subsequent administration and management of this resource in this area.Objetivo. Se analizó la proporción de sexos, hembras ovígeras, talla de primera madurez sexual y fecundidad del cangrejo roca Grapsus grapsus en islas Lobos, Venados y Pájaros (sureste del Golfo de California). Material y métodos. Los muestreos fueron mensuales entre marzo 2011 y febrero 2012, las colectas fueron nocturnas durante la bajamar, se obtuvieron en un cuadrante (25 m2) por isla 30 organismos al azar, se les determinó el AN (mm) y PT (g). Se estimó la proporción de sexos y talla de primera madurez sexual (AN50%), se analizaron en hembras grávidas, las fases embrionarias y la fecundidad (método gravimétrico). Resultados. La proporción de M:H fue 1:1.3. La talla media de primera madurez fue AN50% 34.9 mm. Es evidente la presencia de hembras ovígeras (71.3%) y todas las fases embrionarias, la fase rojo-naranja fue la mayor representada en 48%. La variación del diámetro del huevo fue 1.1 a 5 µm y el promedio de 3.05 µm. La fecundidad media fue 24339.3 cigotos. El máximo y mínimo peso de hembras ovígeras fue 69.9 y 15.2 g, respectivamente. Conclusiones. Con base a las características biológicas del recurso tales como la proporción de sexos, hembras ovígeras, talla de primera madurez sexual y fecundidad en la población de G. grapsus, representa un efecto favorable en su posterior administración y manejo de este recurso en esta zona

An integrated precision medicine approach in major depressive disorder: a study protocol to create a new algorithm for the prediction of treatment response

Major depressive disorder (MDD) is the most common psychiatric disease worldwide with a huge socio-economic impact. Pharmacotherapy represents the most common option among the first-line treatment choice; however, only about one third of patients respond to the first trial and about 30% are classified as treatment-resistant depression (TRD). TRD is associated with specific clinical features and genetic/gene expression signatures. To date, single sets of markers have shown limited power in response prediction. Here we describe the methodology of the PROMPT project that aims at the development of a precision medicine algorithm that would help early detection of non-responder patients, who might be more prone to later develop TRD. To address this, the project will be organized in 2 phases. Phase 1 will involve 300 patients with MDD already recruited, comprising 150 TRD and 150 responders, considered as extremes phenotypes of response. A deep clinical stratification will be performed for all patients; moreover, a genomic, transcriptomic and miRNomic profiling will be conducted. The data generated will be exploited to develop an innovative algorithm integrating clinical, omics and sex-related data, in order to predict treatment response and TRD development. In phase 2, a new naturalistic cohort of 300 MDD patients will be recruited to assess, under real-world conditions, the capability of the algorithm to correctly predict the treatment outcomes. Moreover, in this phase we will investigate shared decision making (SDM) in the context of pharmacogenetic testing and evaluate various needs and perspectives of different stakeholders toward the use of predictive tools for MDD treatment to foster active participation and patients' empowerment. This project represents a proof-of-concept study. The obtained results will provide information about the feasibility and usefulness of the proposed approach, with the perspective of designing future clinical trials in which algorithms could be tested as a predictive tool to drive decision making by clinicians, enabling a better prevention and management of MDD resistance

Blood DNA methylation signature of diet quality and association with cardiometabolic traits

Aims: Diet quality might influence cardiometabolic health through epigenetic changes, but this has been little investigated in adults. Our aims were to identify cytosine-phosphate-guanine (CpG) dinucleotides associated with diet quality by conducting an epigenome-wide association study (EWAS) based on blood DNA methylation (DNAm) and to assess how diet-related CpGs associate with inherited susceptibility to cardiometabolic traits: body mass index (BMI), systolic blood pressure (SBP), triglycerides, type 2 diabetes (T2D), and coronary heart disease (CHD). Methods and results: Meta-EWAS including 5274 participants in four cohorts from Spain, the USA, and the UK. We derived three dietary scores (exposures) to measure adherence to a Mediterranean diet, to a healthy plant-based diet, and to the Dietary Approaches to Stop Hypertension. Blood DNAm (outcome) was assessed with the Infinium arrays Human Methylation 450K BeadChip and MethylationEPIC BeadChip. For each diet score, we performed linear EWAS adjusted for age, sex, blood cells, smoking and technical variables, and BMI in a second set of models. We also conducted Mendelian randomization analyses to assess the potential causal relationship between diet-related CpGs and cardiometabolic traits. We found 18 differentially methylated CpGs associated with dietary scores (P < 1.08 × 10-7; Bonferroni correction), of which 12 were previously associated with cardiometabolic traits. Enrichment analysis revealed overrepresentation of diet-associated genes in pathways involved in inflammation and cardiovascular disease. Mendelian randomization analyses suggested that genetically determined methylation levels corresponding to lower diet quality at cg02079413 (SNORA54), cg02107842 (MAST4), and cg23761815 (SLC29A3) were causally associated with higher BMI and at cg05399785 (WDR8) with greater SBP, and methylation levels associated with higher diet quality at cg00711496 (PRMT1) with lower BMI, T2D risk, and CHD risk and at cg0557921 (AHRR) with lower CHD risk. Conclusion: Diet quality in adults was related to differential methylation in blood at 18 CpGs, some of which related to cardiometabolic health.C.L. was supported by a fellowship from "la Caixa" Foundation (ID 100010434) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement no. 847 648. The fellowship code is LCF/BQ/PR21/11840003. The REGICOR study was funded by the Carlos III Health Institute and European Regional Development Fund (FIS PI12/00232; FIS PI15/00051, CIBERCV, CIBERESP) and the Government of Catalonia through the Agency for Management of University and Research Grants (AGAUR: PERIS SLT002/16/00088, 2017SGR222). A.F.-S. was supported by the British Heart Foundation (AA/18/1/34219) and the Medical Research Council (UK MRC) (MC_UU_00011/6). O.R. was supported by a UKRI Future Leaders Fellowship (MR/S03532X/1). The Framingham Heart Study (FHS) is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract no. N01-HC-25195 and HHSN268201500001I). The Women’s Health Initiative (WHI) programme is funded by the NHLBI (contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221). This manuscript was not prepared in collaboration with investigators of the FHS/WHI, has not been reviewed and/or approved by the FHS/WHI, and does not necessarily reflect the opinions or views of the FHS and WHI investigators or the NHLBI. The funding bodies had no role in the study design, collection, analysis, and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication

Characteristics and Outcomes of Adult Patients in the PETHEMA Registry with Relapsed or Refractory FLT3-ITD Mutation-Positive Acute Myeloid Leukemia

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1-and 5-year OS rates were 25% and 7%. OS was significantly (p <0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant

Characteristics and Outcomes of Adult Patients in the PETHEMA Registry with Relapsed or Refractory FLT3-ITD Mutation-Positive Acute Myeloid Leukemia

This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p &lt; 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p &lt; 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant

Characteristics and outcomes of adult patients in the PETHEMA registry with relapsed or refractory FLT3-ITD mutation-positive acute myeloid leukemia

Simple Summary Most adult patients with acute myeloid leukemia (AML) relapse after achieving complete remission with chemotherapy; however, there is no standard second-line (salvage) treatment. We retrospectively investigated 404 patients aged >= 18 years with relapsed/refractory (R/R) AML with an FMS-like tyrosine kinase 3 (FLT3) mutation, treated at a PETHEMA (NCT02607059) site between 1998 and 2018. Patients received salvage treatment with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care (n = 80). Complete remission was achieved by 48% of patients who received intensive therapy vs. 19% with non-intensive therapy. Intensive/non-intensive therapy prolonged overall survival significantly compared with supportive therapy. Of evaluable patients, 22% received an allogeneic stem-cell transplant after complete remission. The majority of patients with FLT3-mutated R/R AML received intensive salvage therapy, with the best outcomes being obtained when intensive salvage treatment was combined with stem-cell transplant. This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant