Manuel Serrano-Ríos

A functional variant of SUMO4, a new I|[kappa]|B|[alpha]| modifier, is associated with type 1 diabetes

Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 × 10−7). SUMO4 conjugates to IκBα and negatively regulates NFκB transcriptional activity. The M55V substitution resulted in 5.5 times greater NFκB transcriptional activity and ∼2 times greater expression of IL12B, an NFκB-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

A Single Factor Underlies the Metabolic Syndrome: A confirmatory factor analysis

OBJECTIVE Confirmatory factor analysis (CFA) was used to test the hypothesis that the components of the metabolic syndrome are manifestations of a single common factor. RESEARCH DESIGN AND METHODS Three different datasets were used to test and validate the model. The Spanish and Mauritian studies included 207 men and 203 women and 1,411 men and 1,650 women, respectively. A third analytical dataset including 847 men was obtained from a previously published CFA of a U.S. population. The one-factor model included the metabolic syndrome core components (central obesity, insulin resistance, blood pressure, and lipid measurements). We also tested an expanded one-factor model that included uric acid and leptin levels. Finally, we used CFA to compare the goodness of fit of one-factor models with the fit of two previously published four-factor models. RESULTS The simplest one-factor model showed the best goodness-of-fit indexes (comparative fit index 1, root mean-square error of approximation 0.00). Comparisons of one-factor with four-factor models in the three datasets favored the one-factor model structure. The selection of variables to represent the different metabolic syndrome components and model specification explained why previous exploratory and confirmatory factor analysis, respectively, failed to identify a single factor for the metabolic syndrome. CONCLUSIONS These analyses support the current clinical definition of the metabolic syndrome, as well as the existence of a single factor that links all of the core components.

Serum Circulating microRNA Profiling for Identification of Potential Type 2 Diabetes and Obesity Biomarkers

Background and Aim MicroRNAs are small non-coding RNAs that play important regulatory roles in a variety of biological processes, including complex metabolic processes, such as energy and lipid metabolism, which have been studied in the context of diabetes and obesity. Some particular microRNAs have recently been demonstrated to abundantly and stably exist in serum and to be potentially disease-specific. The aim of this profiling study was to characterize the expression of miRNA in serum samples of obese, nonobese diabetic and obese diabetic individuals to determine whether miRNA expression was deregulated in these serum samples and to identify whether any observed deregulation was specific to either obesity or diabetes or obesity with diabetes. Patients and Methods Thirteen patients with type 2 diabetes, 20 obese patients, 16 obese patients with type 2 diabetes and 20 healthy controls were selected for this study. MiRNA PCR panels were employed to screen serum levels of 739 miRNAs in pooled samples from these four groups. We compared the levels of circulating miRNAs between serum pools of each group. Individual validation of the twelve microRNAs selected as promising biomarkers was carried out using RT-qPCR. Results Three serum microRNAs, miR-138, miR-15b and miR-376a, were found to have potential as predictive biomarkers in obesity. Use of miR-138 or miR-376a provides a powerful predictive tool for distinguishing obese patients from normal healthy controls, diabetic patients, and obese diabetic patients. In addition, the combination of miR-503 and miR-138 can distinguish diabetic from obese diabetic patients. Conclusion This study is the first to show a panel of serum miRNAs for obesity, and compare them with miRNAs identified in serum for diabetes and obesity with diabetes. Our results support the use of some miRNAs extracted from serum samples as potential predictive tools for obesity and type 2 diabetes.

Prevalencia del síndrome metabólico (criterios del ATP-III). Estudio de base poblacional en áreas rural y urbana de la provincia de Segovia

Fundamento y objetivo Estimar la prevalencia del sindrome metabolico (SM) en areas rural y urbana de Segovia (Espana), segun los criterios del ATP-III (National Cholesterol Education Programs Adults Treatment Panel III Report) modificados. Sujetos y metodo Estudio transversal realizado con una muestra aleatoria y representativa formada por 809 individuos (un 46% varones) de 35 a 74 anos de edad residentes en areas rural y urbana de la provincia de Segovia (Espana). El periodo de estudio fue de enero de 2000 a enero de 2003. Resultados La prevalencia global del SM ajustada por edad y sexo fue del 17% (un 15,7% en varones y un 18,1% en mujeres) y no se observaron diferencias entre las poblaciones de las areas rural y urbana. La combinacion de componentes del SM mas frecuente, tanto en varones como en mujeres, fue la de obesidad abdominal, glucosa alterada en ayunas e hipertension arterial. La prevalencia de SM se asocio a la edad y a la obesidad en un modelo de regresion logistico multivariado. En otro modelo, la obesidad abdominal fue mas frecuente en los individuos con obesidad, definida por un indice de masa corporal de 30 kg/m2 o mayor, en aquellos con estudios secundarios, o con edad superior a 45 anos y en las mujeres residentes en el area rural. Conclusiones La prevalencia global ajustada por sexo/edad fue menor que la obtenida en otros estudios con los mismos criterios de definicion de SM (ATP-III), lo que induce a pensar en la existencia de diferencias geograficas en Espana. La obesidad abdominal fue el componente aislado del SM de mayor prevalencia en mujeres, mientras que la hipertension arterial lo fue en varones.

Leptin and adipose tissue maldistribution in HIV-infected male patients with predominant fat loss treated with antiretroviral therapy

&NA; Background: Metabolic disturbances and fat maldistribution are main features of the antiretroviral‐related lipodystrophy syndrome (LDS). Different phenotypes of fat distribution abnormalities can be observed: fat loss, fat accumulation, or a mixed pattern. In patients with predominant loss of fat, the roles of leptin, lipids, and glucose homeostasis disturbances have not yet been clearly established. Methods: The study comprised 34 HIV‐infected male patients receiving antiretroviral treatment that included protease inhibitors. A lipoatrophic phenotype, defined as fat loss in face or extremities, both normal weight and waist:hip ratio, and absence of fat accumulation elsewhere, was present in all cases. Fat distribution disturbances were confirmed by abdominal and midthigh computed tomography‐calculated adipose tissue content. Fasting plasma glucose, insulin, proinsulin, total leptin, testosterone, and lipid profiles were measured. After 2 hours, 75‐g oral glucose tolerance test (OGTT), glucose, insulin, and proinsulin levels were also obtained. Insulin resistance was calculated using the homeostasis model assesment for insulin resistance (HOMA‐r) method. Both healthy study subjects (n = 385) and antiretroviral‐naive HIV‐positive patients (n = 13) were used as controls. Results: Of these LDS patients, 5.8% showed diagnostic criteria for diabetes and 17.8% for impaired glucose tolerance. A lipid pattern characterized by high total cholesterol and high low density lipoprotein (LDL) plasma levels, hypertriglyceridemia, and normal high density lipoprotein (HDL) levels was observed. Fasting insulin and 2‐hour post OGTT insulin levels, and insulin resistance index were significantly higher in LDS patients than in antiretroviral‐naive HIV‐positive patients. Plasma leptin levels were significantly lower in lipoatrophic patients than in healthy control individuals. Patients with LDS presented with significant midthigh fat reduction and visceral fat accumulation compared with findings in antiretroviral‐naive HIV‐positive patients. A significant correlation was found between plasma leptin levels and midthigh fat content. Conclusion: Peripheral fat loss in extremities in LDS patients with lipoatrophic phenotype is also associated with low plasma leptin levels, visceral fat accumulation, and metabolic disturbances related to an increased cardiovascular risk. In LDS patients, plasma leptin levels could be a marker of subcutaneous adipose tissue content.

The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease.

BackgroundIn order to identify novel loci associated with Alzheimers disease (AD), we conducted a genome-wide association study (GWAS) in the Spanish population.MethodsWe genotyped 1,128 individuals using the Affymetrix Nsp I 250K chip. A sample of 327 sporadic AD patients and 801 controls with unknown cognitive status from the Spanish general population were included in our initial study. To increase the power of the study, we combined our results with those of four other public GWAS datasets by applying identical quality control filters and the same imputation methods, which were then analyzed with a global meta-GWAS. A replication sample with 2,200 sporadic AD patients and 2,301 controls was genotyped to confirm our GWAS findings.ResultsMeta-analysis of our data and independent replication datasets allowed us to confirm a novel genome-wide significant association of AD with the membrane-spanning 4-domains subfamily A (MS4A) gene cluster (rs1562990, P = 4.40E-11, odds ratio = 0.88, 95% confidence interval 0.85 to 0.91, n = 10,181 cases and 14,341 controls).ConclusionsOur results underscore the importance of international efforts combining GWAS datasets to isolate genetic loci for complex diseases.

Lipid accumulation product: a powerful marker of metabolic syndrome in healthy population

OBJECTIVE The metabolic syndrome (MS) is a cluster of cardiometabolic factors, which predisposes to diabetes and cardiovascular disease (CVD). Early detection of high-risk individuals for MS using accurate measures of insulin resistance (IR) could improve detection and prevention of CVD and diabetes. The aim of this study was to explore the ability of lipid accumulation product (LAP), compared with traditional measures of IR, to identify MS. DESIGN In total, 768 Spanish adults were recruited. MS was assessed using the revised criteria of National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) and International Diabetes Federation (IDF). Measures of IR such as homeostasis model assessment of IR and LAP, an index of lipid accumulation based on a combination of waist circumference and serum triglycerides, were calculated. Receiver operating characteristic analysis was performed in order to detect the parameter with the best predictive capability for MS. RESULTS The prevalence of MS-NCEP/ATP III and MS-IDF was 15.1 and 20.5% for men respectively, and 15.4 and 17.5% for women. LAP showed the highest diagnostic accuracy for MS-NCEP/ATP III (area under the curve 0.91 and 0.90 among males and females) and MS-IDF (0.88 for both males and females). This was confirmed by internal validation using 20 000 bootstrap samples. Among males and females, different LAP cut-off values exhibited high sensitivity (78-85%) and specificity (78-85%) for MS-NCEP/ATP III and MS-IDF identification with elevated efficiency (proportion of positives and negatives classified correctly by the test=78-85%). When the sample was stratified according to decades of life, LAP exhibited a slightly lower performance among women than men, especially for MS-IDF detection. CONCLUSIONS In non-diabetic adults LAP has a strong and reliable diagnostic accuracy for MS-IDF and, especially, MS-NCEP/ATP III among females and, in particular, among males from Spain.

Which Obesity Index Best Explains Prevalence Differences in Type 2 Diabetes Mellitus

Objective: Obesity drives the diabetes epidemic. However, it is not known which obesity index best explains variations in type 2 diabetes mellitus prevalence across populations.

Variant rs9939609 in the FTO gene is associated with obesity in an adult population from Spain

Objective  Recently independent studies, including genome‐wide scans, have shown that variation in the fat mass and obesity associated gene (FTO) were significantly associated with obesity in populations of European origin.

Genetic Structure of the Spanish Population

BackgroundGenetic admixture is a common caveat for genetic association analysis. Therefore, it is important to characterize the genetic structure of the population under study to control for this kind of potential bias.ResultsIn this study we have sampled over 800 unrelated individuals from the population of Spain, and have genotyped them with a genome-wide coverage. We have carried out linkage disequilibrium, haplotype, population structure and copy-number variation (CNV) analyses, and have compared these estimates of the Spanish population with existing data from similar efforts.ConclusionsIn general, the Spanish population is similar to the Western and Northern Europeans, but has a more diverse haplotypic structure. Moreover, the Spanish population is also largely homogeneous within itself, although patterns of micro-structure may be able to predict locations of origin from distant regions. Finally, we also present the first characterization of a CNV map of the Spanish population. These results and original data are made available to the scientific community.