Variable phenotype in HNF1B mutations: extrarenal manifestations distinguish affected individuals from the population with congenital anomalies of the kidney and urinary tract

Background: Mutations in hepatocyte nuclear factor 1B (HNF1B) have been associated with congenital anomalies of the kidney and urinary tract (CAKUT) in humans. Diabetes and other less frequent anomalies have also been described. Variable penetrance and intrafamilial variability have been demonstrated including severe prenatal phenotypes. Thus, it is important to differentiate this entity from others with similar clinical features and perform confirmatory molecular diagnosis. Methods: This study reports the results of HNF1B screening in a cohort of 60 patients from 58 unrelated families presenting with renal structural anomalies and/or non-immune glucose metabolism alterations, and other minor features suggesting HNF1B mutations. Results: This study identified a pathogenic variant in 23 patients from 21 families. The most frequent finding was bilateral cystic dysplasia or hyperechogenic kidneys (87% of patients). Sixty percent of them also fulfilled the criteria for impaired glucose metabolism, and these were significantly older than those patients with an HNF1B mutation but without diabetes or prediabetes (14.4 versus 3.3years, P<0.05). Furthermore, patients with HNF1B mutations had higher frequency of pancreatic structural anomalies and hypomagnesaemia than patients without mutations (P<0.001 and P = 0.003, respectively). Hyperuricaemia and increased liver enzymes were detected in some patients as well. Conclusions: Renal anomalies found in patients with HNF1B mutations are frequently unspecific and may resemble those found in other renal pathologies (CAKUT, ciliopathies). Active searching for extrarenal minor features, especially pancreatic structural anomalies or hypomagnesaemia, could support the indication for molecular diagnosis to identify HNF1B mutations

Novel genes and sex differences in COVID-19 severity

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10−8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10−22 and P = 8.1 × 10−12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10−8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10−8) and ARHGAP33 (P = 1.3 × 10−8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10−8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.Instituto de Salud Carlos III (COV20_00622 to A.C., COV20/00792 to M.B., COV20_00181 to C.A., COV20_1144 to M.A.J.S., PI20/00876 to C.F.); European Union (ERDF) ‘A way of making Europe’. Fundación Amancio Ortega, Banco de Santander (to A.C.), Estrella de Levante S.A. and Colabora Mujer Association (to E.G.-N.) and Obra Social La Caixa (to R.B.); Agencia Estatal de Investigación (RTC-2017-6471-1 to C.F.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.)

Celiac Male’s Gluten-Free Diet Profile: Comparison to that of the Control Population and Celiac Women

The aim of the present work was to analyze the body composition and dietary profile of Spanish celiac men and to compare them to control men and celiac women from our previous studies. Forty-two celiac men (31.5 +/- 11.9 years) were recruited and anthropometric measurements were taken. Analysis of energy consumption, macro-and micronutrient intake and food frequency consumption was carried out. Celiac men were more overweight and obese than celiac women, but less than the control population, reporting the same energy intake and macronutrient distribution. Most micronutrient deficiencies in celiac men were not directly related to a gluten free diet; these were also observed for the entire population. The least adherence to Dietary Reference Intakes in women was reported for iron, iodine, potassium and selenium, whereas magnesium intake was higher than in men. Among celiac participants (both genders), cereal, vegetable and legume consumption was poor and meat intake was contrastingly excessive. In conclusion, the dietary profile of celiac men is as unbalanced as that of control men but slightly more than that of celiac women. General nutritional education should be given to both general and celiac populations, and specific advices to celiac men, in order to decrease the risk of celiac disease-related pathologies.Idoia Larretxi is a fellowship of the University of the Basque Country, UPV/EHU (Euskararen eta Etengabeko Prestakuntzaren arloko Errektoreordetza). This research was funded by University of the Basque Country (UPV/EHU) and Basque Government, grant numbers US12/10 and GV2008111042, respectively. We thank the participation of all patients, and the collaboration of "Asociacion de Celiacos de Euskadi (EZE)", specifically that of Mireia Apraiz, Beatriz Zulueta, Nerea Segura, Estibaliz Olabarri Elena Perez-Estevez, Lissette Delgado, Aranzazu Sainz-Espiga, Sagrario Martinez and Lorea Martinez-Indart

Factores asociados a la prevalencia de hipovitaminosis D en mujeres embarazadas y sus recién nacidos

Introducción El hallazgo de hipovitaminosis D en el embarazo ha impulsado el debate acerca de su suplementación. El objetivo del estudio fue medir la prevalencia de hipovitaminosis D en gestantes y recién nacidos. Métodos Se realizó un estudio observacional de un año de duración midiendo los niveles de vitamina D en madres y en sangre de cordón umbilical de recién nacidos. Se registraron variables relacionadas con las características de la madre, el parto y la exposición al sol. Resultados Se encontraron valores menores de 20 ng/ml en el 64,4% de 745 madres y el 41,3% de 560 recién nacidos y menores de 30 ng/ml en el 88,7% y 67,1% respectivamente. Los niveles medios fueron más altos en verano-otoño que en invierno-primavera (21,73 y 13,70 ng/ml en madres y 29,04 y 20,49 ng/ml en cordón) y mayores en el cordón umbilical que en el plasma materno. Los embarazos múltiples (OR: 6,29) y el origen no europeo (OR: 13,09) fueron factores de riesgo de hipovitaminosis materna mientras que la suplementación materna (OR: 0,19), la actividad física (OR: 0,57) y la exposición al sol (OR: 0,46) tuvieron un efecto preventivo. Conclusiones Las altas tasas de hipovitaminosis respaldan la política de dar suplementos dietéticos a los recién nacidos. El alto nivel de hipovitaminosis encontrado apoya la extensión del cribado y suplementación a todas las embarazadas y no solamente a aquellas con factores de riesgo. La mayor diferencia entre madre e hijo en las temporadas de baja exposición solar puede interpretarse como un efecto protector.This project was funded by the Department of Health of the Basque Country (Project number 2011111107)

Fatty Acid Profile of Mature Red Blood Cell Membranes and Dietary Intake as a New Approach to Characterize Children with Overweight and Obesity

Obesity is a chronic metabolic disease of high complexity and of multifactorial origin. Understanding the effects of nutrition on childhood obesity metabolism remains a challenge. The aim of this study was to determine the fatty acid (FA) profile of red blood cell (RBC) membranes as a comprehensive biomarker of children's obesity metabolism, together with the evaluation of their dietary intake. An observational study was carried out on 209 children (107 healthy controls, 41 who were overweight and 61 with obesity) between 6 and 16 years of age. Mature RBC membrane phospholipids were analyzed for FA composition by gas chromatography-mass spectrometry (GC-MS). Dietary habits were evaluated using validated food frequency questionnaires (FFQ) and the Mediterranean Diet Quality Index for children (KIDMED) test. Compared to children with normal weight, children with obesity showed an inflammatory profile in mature RBC FAs, evidenced by higher levels of omega-6 polyunsaturated FAs (mainly arachidonic acid, p < 0.001). Children who were overweight or obese presented lower levels of monounsaturated FA (MUFA) compared to children with normal weight (p = 0.001 and p = 0.03, respectively), resulting in an increased saturated fatty acid (SFA)/MUFA ratio. A lower intake of nuts was observed for children with obesity. A comprehensive membrane lipidomic profile approach in children with obesity will contribute to a better understanding of the metabolic differences present in these individuals.This work was supported by the Department of Environment: Territorial Planning: Agriculture and Fisheries of the Basque Country Government (ELKARTEK 2017: and Innovation Fund 2017); the Department of Health of the Basque Government (2017222033: OBESIA 2016-2019); the Centre for the Development of Industrial Technology (CDTI) of the Spanish Ministry of Science and Innovation under the grant agreement: TECNOMIFOOD project (CER-20191010); the INC (INTERNATIONAL NUT AND DRIED FRUIT COUNCIL) under the grant agreement OBINUT project (2016(II)-R01)

Genetics of Type III Bartter Syndrome in Spain, Proposed Diagnostic Algorithm

9 p.The p.Ala204Thr mutation (exon 7) of the CLCNKB gene is a "founder" mutation that causes most of type III Bartter syndrome cases in Spain. We performed genetic analysis of the CLCNKB gene, which encodes for the chloride channel protein ClC-Kb, in a cohort of 26 affected patients from 23 families. The diagnostic algorithm was: first, detection of the p.Ala204Thr mutation; second, detecting large deletions or duplications by Multiplex Ligation-dependent Probe Amplification and Quantitative Multiplex PCR of Short Fluorescent Fragments; and third, sequencing of the coding and flanking regions of the whole CLCNKB gene. In our genetic diagnosis, 20 families presented with the p.Ala204Thr mutation. Of those, 15 patients (15 families) were homozygous (57.7% of overall patients). Another 8 patients (5 families) were compound heterozygous for the founder mutation together with a second one. Thus, 3 patients (2 siblings) presented with the c. -19-?_2053+? del deletion (comprising the entire gene); one patient carried the p.Val170Met mutation (exon 6); and 4 patients (3 siblings) presented with the novel p.Glu442Gly mutation (exon 14). On the other hand, another two patients carried two novel mutations in compound heterozygosis: one presented the p.Ile398_Thr401del mutation (exon 12) associated with the c. -19-?_2053+? del deletion, and the other one carried the c.1756+1G>A splice-site mutation (exon 16) as well as the already described p.Ala210Val change (exon 7). One case turned out to be negative in our genetic screening. In addition, 51 relatives were found to be heterozygous carriers of the described CLCNKB mutations. In conclusion, different mutations cause type III Bartter syndrome in Spain. The high prevalence of the p.Ala204Thr in Spanish families thus justifies an initial screen for this mutation. However, should it not be detected further investigation of the CLCNKB gene is warranted in clinically diagnosed families.This study was supported by two grants (PI09/90888 and PI11/01412) from the FIS of the Instituto de Salud Carlos III, Madrid, Spain, and the Eitb Maratoia-Bioef (BIO08/ER/020) the Basque Foundation for Health Innovation and Research (BIOEF, from the Basque Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Spatio-temporal trends of the bottom trawling activity in a mud volcano field of the north-eastern Gulf of Cádiz (south-western Iberian Peninsula)

Multi-species bottom trawl fisheries are one of the human activities with a great impact on the benthic habitats and their associated biota. This study provides estimates of the bottom trawling activity (effort), catches and landings of the main commercial species as well as an estimation of the total revenue (TR) generated inside a mud volcano field located in the Spanish margin of the Gulf of Cádiz, during a time series from 2007 to 2012. To date, no studies have been carried out to analyse the temporal evolution of bottom trawling activity and TR in a mud volcano fied, or the economic consequences of possible potential bottom trawling regulation of certain sectors harbouring vulnerable and/or threatened habitats. In this study, Vessel Monitoring System data, logbooks and sales slips were used. The spatial distribution of the bottom trawling activity, catches and TR were related to the seafloor morphology and specific bottom types of the mud volcano field. During the time series, a high bottom trawling activity and associated catches was detected in flat sandy and muddy bottoms, including the Anastasya sector and between the Guadalquivir and Cádiz Diapiric Ridges. Low bottom trawling activity and catches were detected in the deepest areas but also in areas with hard and detritic bottoms such as Gazul and Chica sectors as well as in the Diapiric Ridges. A similar spatial pattern was detected for the TR asociated with these bottom trawling fisheries. An increase in bottom trawling activity was detected during the time series, mainly at the end, probably for increasing the TR and mantaining the economic profit due to the instability and increases in fuel prices and offset the increased costs. Based on the obtained information, bottom trawling regulations should be implemented in certain sectors harboring singular and/or threatened habitats and species. In some of these sectors, a low TR from bottom trawling was detected and, bottom trawling regulation may potentially have a low socioeconomic impact. This specific bottom trawling regulation could provide a sustainable balance between bottom trawling activities and habitat conservation in this mud volcano field according to the aims of the Habitats Directive (92/43/EEC) and the European Marine Strategy Framework Directive (2008/56/EEC).En prens

Incidence of Diabetes Mellitus and Associated Risk Factors in the Adult Population of the Basque Country, Spain

The aim of this study was to estimate the incidence of diabetes mellitus in the Basque Country and the risk factors involved in the disease by reassessing an adult population after 7 years of follow-up. In the previous prevalence study, 847 people older than 18 years were randomly selected from all over the Basque Country and were invited to answer a medical questionnaire, followed by a physical examination and an oral glucose tolerance test. In the reassessment, the same variables were collected and the resulting cohort comprised 517 individuals of whom 43 had diabetes at baseline. The cumulative incidence of diabetes was 4.64% in 7 years and the raw incidence rate was 6.56 cases/1000 person-years (95%CI: 4.11-9.93). Among the incident cases, 59% were undiagnosed. The most strongly associated markers by univariate analyses were age >60 years, dyslipidaemia, prediabetes and insulin resistance. We also found association with hypertension, obesity, family history of diabetes and low education level. Multivariate analysis adjusted for age and sex showed that a set of risk factors assessed together (dyslipidaemia, waist-to-hip-ratio and family history of diabetes) had great predictive value (AUC-ROC=0.899, 95%CI: 0.846-0.953, p=0.942), which suggests the need for early intervention before the onset of prediabetesThis work was partially supported by grants from the Department of Health of the Basque Country Government (2015111020); ISCIII (PI14/01104), co-funded by ERDF/ESF, "A way to make Europe"/"Investing in your future"; UPV/EHU (IT1281-19); Menarini Group Spain (BCA16/029); Endocrine-European Reference Network (EndoERN 739527); and CIBERDEM (Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders). The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report

Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes

[EN] The partial remission (PR) phase, a period experienced by most patients with type 1 diabetes (T1D) soon after diagnosis, is characterized by low insulin requirements and improved glycemic control. Given the great potential of this phase as a therapeutic window for immunotherapies because of its association with immunoregulatory mechanisms and beta-cell protection, our objective was to find peripheral immunological biomarkers for its better characterization, monitoring, and prediction. The longitudinal follow-up of 17 pediatric patients with new-onset T1D over one year revealed that, during the PR phase, remitter patients show increased percentages of effector memory (EM) T lymphocytes, terminally differentiated EM T lymphocytes, and neutrophils in comparison to non-remitter patients. On the contrary, remitter patients showed lower percentages of naive T lymphocytes, regulatory T cells (T-REG), and dendritic cells (DCs). After a year of follow-up, these patients also presented increased levels of regulatory B cells and transitional T1 B lymphocytes. On the other hand, although none of the analyzed cytokines (IL-2, IL-6, TGF-beta 1, IL-17A, and IL-10) could distinguish or predict remission, IL-17A was increased at T1D diagnosis in comparison to control subjects, and remitter patients tended to maintain lower levels of this cytokine than non-remitters. Therefore, these potential monitoring immunological biomarkers of PR support that this stage is governed by both metabolic and immunological factors and suggest immunoregulatory attempts during this phase. Furthermore, since the percentage of T-REG, monocytes, and DCs, and the total daily insulin dose at diagnosis were found to be predictors of the PR phase, we next created an index-based predictive model comprising those immune cell percentages that could potentially predict remission at T1D onset. Although our preliminary study needs further validation, these candidate biomarkers could be useful for the immunological characterization of the PR phase, the stratification of patients with better disease prognosis, and a more personalized therapeutic management.Funding for this study was provided by the Spanish Government (FIS PI18/00436) co-financed with the European Regional Development funds (FEDER), and by DiabetesCero Foundation. LGM is supported by the Generalitat de Catalunya (PERIS PIF-Salut Grant No. SLT017/20/000049). This work has been supported by positive discussion through Consolidated Research Group #2017 SGR 103, AGAUR, Generalitat de Catalunya

Serum vascular endothelial growth factor b and metabolic syndrome incidence in the population based cohort [email protected] study

Background/Objectives Although vascular endothelial growth factor b (VEGFb) might have an impact on the development of obesity, diabetes and related disorders, the possible relationship between VEGFb serum levels and the incidence of these metabolic complications in humans is still unknown. The aim of our study was to evaluate the association between VEGFb serum levels and the new-onset of metabolic syndrome (MS) and its components in the Spanish adult population after 7.5 years of follow-up. Subjects/Methods A total of 908 subjects from the [email protected] cohort study without MS at cross-sectional stage according to International Diabetes Federation (IDF) or Adult Treatment Panel III (ATP-III) criteria were included. Additionally, five sub-populations were grouped according to the absence of each MS component at baseline. Socio-demographic, anthropometric and clinical data were recorded. The Short Form of International Physical Activity Questionnaire (SF-IPAQ) was used to estimate physical activity. A fasting blood extraction and an oral glucose tolerance test were performed. Serum determinations of glucose, lipids, hsCRP and insulin were made. VEGFb levels were determined and categorized according to the 75th percentile of the variable. New cases of MS and its components were defined according to ATPIII and IDF criteria. Results A total of 181 or 146 people developed MS defined by IDF or ATP-III criteria respectively. Serum triglyceride levels, hs-CRP and systolic blood pressure at the baseline study were significantly different according to the VEGFb categories. Adjusted logistic regression analysis showed that the likelihood of developing MS and abdominal obesity was statistically reduced in subjects included in the higher VEGFb category. Conclusion Low serum levels of VEGFb may be considered as early indicators of incident MS and abdominal obesity in the Spanish adult population free of MS, independently of other important predictor variables.This investigation has been supported by CIBERDEM (Ministerio de Economia, Industria y Competitividad-ISCIII), Ministerio de Sanidad, Servicios Sociales e IgualdadISCIII, Instituto de Salud Carlos III (research grants PI20/01322, PI18/01165, PI17/02136, PI14/00710) and cofunding by the European Regional Development Fund (ERDF) "A way to build Europe". LifeScan Espana (Madrid, Spain) kindly donated the glucometers and test strips for capillary glucose measurements. Cristina MaldonadoAraque is a researcher in the `Rio Hortega' program (CM19/00186) financed by the Instituto de Salud Carlos III. Natalia Colomo is a member of the regional "Accion B para clinicos investigadores" research program of the Consejeria de Salud of the Junta de Andalucia, Spain (B-0002-17). Gemma Rojo-Martinez belongs to the Nicolas Monardes research program of the Consejeria de Salud (C-0060-2012; Junta de Andalucia, Spain)