Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial.

Importance: Early exposure to complex dietary proteins may increase the risk of type 1 diabetes in children with genetic disease susceptibility. There are no intact proteins in extensively hydrolyzed formulas. Objective: To test the hypothesis that weaning to an extensively hydrolyzed formula decreases the cumulative incidence of type 1 diabetes in young children. Design, Setting, and Participants: An international double-blind randomized clinical trial of 2159 infants with human leukocyte antigen-conferred disease susceptibility and a first-degree relative with type 1 diabetes recruited from May 2002 to January 2007 in 78 study centers in 15 countries; 1081 were randomized to be weaned to the extensively hydrolyzed casein formula and 1078 to a conventional formula. The follow-up of the participants ended on February 28, 2017. Interventions: The participants received either a casein hydrolysate or a conventional adapted cow's milk formula supplemented with 20% of the casein hydrolysate. The minimum duration of study formula exposure was 60 days by 6 to 8 months of age. Main Outcomes and Measures: Primary outcome was type 1 diabetes diagnosed according to World Health Organization criteria. Secondary outcomes included age at diabetes diagnosis and safety (adverse events). Results: Among 2159 newborn infants (1021 female [47.3%]) who were randomized, 1744 (80.8%) completed the trial. The participants were observed for a median of 11.5 years (quartile [Q] 1-Q3, 10.2-12.8). The absolute risk of type 1 diabetes was 8.4% among those randomized to the casein hydrolysate (n = 91) vs 7.6% among those randomized to the conventional formula (n = 82) (difference, 0.8% [95% CI, -1.6% to 3.2%]). The hazard ratio for type 1 diabetes adjusted for human leukocyte antigen risk group, duration of breastfeeding, duration of study formula consumption, sex, and region while treating study center as a random effect was 1.1 (95% CI, 0.8 to 1.5; P = .46). The median age at diagnosis of type 1 diabetes was similar in the 2 groups (6.0 years [Q1-Q3, 3.1-8.9] vs 5.8 years [Q1-Q3, 2.6-9.1]; difference, 0.2 years [95% CI, -0.9 to 1.2]). Upper respiratory infections were the most common adverse event reported (frequency, 0.48 events/year in the hydrolysate group and 0.50 events/year in the control group). Conclusions and Relevance: Among infants at risk for type 1 diabetes, weaning to a hydrolyzed formula compared with a conventional formula did not reduce the cumulative incidence of type 1 diabetes after median follow-up for 11.5 years. These findings do not support a need to revise the dietary recommendations for infants at risk for type 1 diabetes. Trial Registration: clinicaltrials.gov Identifier: NCT00179777.

Exploring APOE genotype effects on Alzheimer's disease risk and amyloid ß burden in individuals with subjective cognitive decline: The FundacioACE Healthy Brain Initiative (FACEHBI) study baseline results.

INTRODUCTION: Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimer's disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored. METHODS: We evaluated apolipoprotein E (APOE) ε4's effect in the risk of presenting SCD, using the Fundacio ACE Healthy Brain Initiative (FACEHBI) SCD cohort and Spanish controls, and performed a meta-analysis addressing the same question. We assessed the relationship between APOE dosage and brain amyloid burden in the FACEHBI SCD and Alzheimer's Disease Neuroimaging Initiative cohorts. RESULTS: Analysis of the FACEHBI cohort and the meta-analysis demonstrated SCD individuals presented higher allelic frequencies of APOE ε4 with respect to controls. APOE dosage explained 9% (FACEHBI cohort) and 11% (FACEHBI and Alzheimer's Disease Neuroimaging Initiative cohorts) of the variance of cerebral amyloid levels. DISCUSSION: The FACEHBI sample presents APOE ε4 enrichment, suggesting that a pool of AD patients is nested in our sample. Cerebral amyloid levels are partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this AD endophenotype.

Variable patterns of obesity and cardiometabolic phenotypes and their association with lifestyle factors in the Di@bet.es study.

BACKGROUND AND AIM: Prevalence rates of "metabolically healthy obese" (MHO) subjects vary depending on the criteria used. This study examined the prevalence and characteristics of MHO subjects and metabolically abnormal normal-weight subjects and compared the findings with the NHANES 1999-2004 study. The aims of the present study were, first, to determine the prevalence rates of MHO and MNHNO subjects using the same criteria as those of the National Health and Nutrition Examination Survey (NHANES) (1999-2004) study, and second to compare the prevalence and correlates of obese subjects who are resistant to the development of adiposity-associated cardiometabolic abnormalities (CA) and normal-weight individuals who display cardiometabolic risk factor clustering between the Spanish and the US populations. METHODS AND RESULTS: Di@bet.es study is a national, cross-sectional population-based survey of 5728 adults conducted in 2009-2010. Clinical, metabolic, sociodemographic, and anthropometric data and information about lifestyle habits, such as physical activity, smoking habit, alcohol intake and food consumption, were collected. Subjects were classified according to their body mass index (BMI) (normal-weight, <25 kg/m(2); overweight, 25-29.9 kg/m(2); and obese, >30 kg/m(2)). CA included elevated blood pressure; elevated levels of triglycerides, fasting glucose, and high-sensitivity C-reactive protein (hs-CRP); and elevated homeostasis model assessment of insulin resistance (HOMA-IR) value and low high-density lipoprotein cholesterol (HDL-c) level. Two phenotypes were defined: metabolically healthy phenotype (0-1 CA) and metabolically abnormal phenotype (≥2 CA). The prevalence of metabolically abnormal normal-weight phenotype was slightly lower in the Spanish population (6.5% vs. 8.1%). The prevalence of metabolically healthy overweight and MHO subjects was 20.9% and 7.0%, respectively, while in NHANES study it was 17.9% and 9.7%, respectively. Cigarette smoking was associated with CA in each phenotype, while moderate physical activity and moderate alcohol intake were associated with being metabolically healthy. Olive oil intake was negatively associated with the prevalence of CA. CONCLUSIONS: Smoking, physical activity level, and alcohol intake contribute to the explanation of the prevalence of CA in the Spanish population, as in the US population. However in Spain, olive oil intake contributes significantly to the explanation of the variance in the prevalence of CA.

Factors affecting levels of urinary albumin excretion in the general population of Spain: the Di@bet.es study.

The present study was undertaken to examine the prevalence of urinary ACR (albumin/creatinine ratio) >30 mg/g and the associated clinical and environmental factors in a representative sample of the population of Spain. Di@bet.es study is a national, cross-sectional population-based survey conducted in 2009-2010. Clinical, metabolic, socio-demographic, anthropometric data and information about lifestyle habit were collected. Those subjects without KDM (known diabetes mellitus) were given an OGTT (oral glucose tolerance test). Albumin and creatinine were measured in a urinary sample and ACR was calculated. The population prevalence of ACR >30 mg/g was 7.65% (adjusted for sex and age). The prevalence of ACR >30 mg/g increased with age (P<0.001). Subjects with carbohydrate metabolism disorders had a greater prevalence of ACR >30 mg/g but after being adjusted for age, sex and hypertension, was significant only in those subjects with UKDM (unknown diabetes mellitus) {OR (odd ratio), 2.07 [95% CI (confidence interval), 1.38-3.09]; P<0.001] and KDM [OR, 3.55 (95% CI, 2.63-4.80); P<0.001]. Prevalence of ACR >30 mg/g was associated with hypertension [OR, 1.48 (95% CI, 1.12-1.95); P=0.001], HOMA-IR (homoeostasis model assessment of insulin resistance) [OR, 1.47 (95% CI, 1.13-1.92); P≤0.01], metabolic syndrome [OR, 2.17 (95% CI, 1.72-2.72); P<0.001], smoking [OR, 1.40 (95% CI, 1.06-1.83); P≤0.05], physical activity [OR, 0.68 (95% CI, 0.54-0.88); P≤0.01] and consumption of fish [OR, 0.38 (95% CI, 0.18-0.78); P≤0.01]. This is the first study that reports the prevalence of ACR >30 mg/g in the Spanish population. The association between clinical variables and other potentially modifiable environmental variables contribute jointly, and sometimes interactively, to the explanation of prevalence of ACR >30 mg/g. Many of these risk factors are susceptible to intervention.

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 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.

Incidence of type 2 diabetes in the elderly in Central Spain: Association with socioeconomic status, educational level, and other risk factors.

AIMS: To analyze the incidence of type 2 diabetes (T2D) in Central Spain and its association with the socioeconomic status (SES), educational level, and other risk factors (RF) in the elderly population of three communities. METHODS: Data for 5278 elderly participants (≥65 years old) were obtained using a census population-based survey. There was a first and a second survey three years later. The association between SES, educational level, RF, and T2D incidence was analyzed. RESULTS: The incidence rate for T2D was 9.8/1000 person-years without gender differences. Incident T2D was associated with low SES and lower educational levels. Baseline and follow-up BMI were also the main RFs for T2D. Communities' incidence rates were: (1) Margarita, working-class area: 11.3/1000 person-years; (2) Arévalo, agricultural region: 10.1/1000 person-years and; (3) Lista, professional high-income class area: 7.6/1000 person-years. CONCLUSION: We found an incidence rate of 9.8/1000 person-years of T2D in the elderly population. The risk of T2D was associated with a lower income and educational level. An increase in BMI may mediate this association. Our results emphasize the necessity of strategies for the prevention of diabetes that includes an approach to SES, educational levels, and other RF among older individuals in Spanish community settings.

A Body Shape Index (ABSI) and Hip Index (HI) Adjust Waist and Hip Circumferences for Body Mass Index, But Only ABSI Predicts High Cardiovascular Risk in the Spanish Caucasian Population.

Background: Our aim in this study was to investigate if Hip index (HI) improves the identification of cardiovascular risk (CVR) beyond that achieved with either the waist-to-height ratio (WHtR) or body mass index (BMI)-adjusted waist circumference (A body shape index [ABSI]) in the Spanish Caucasian population. Methods: Three thousand eight hundred forty-four subjects (1754 males, response rate 75.8%) were included. Anthropometric indices (AIs) included were HI, ABSI, and WHtR. CVR was estimated using the Framingham, Systematic COronary Risk Evaluation (SCORE), and American College of Cardiology/American Heart Association (ACC/AHA) charts. Areas under the receiver operating characteristic curve (AUC) were obtained to evaluate the performance of AIs in detecting CVR. We also estimated the AIs' standardized Z-scores and compared them against the CVR. Results: AUC demonstrated that the best AI in males to estimate higher CVR according to Framingham and ACC/AHA charts was WHtR. In females, WHtR also achieved good performance and showed higher prediction capacity than the other AIs. After transforming to Z-scores, ABSI was the best linear predictor for CVR according to SCORE and ACC/AHA, although WHtR also proved to be good. HI did not associate with the measures of CVR. Conclusions: HI does not predict high CVR in the Spanish Caucasian Population. However, ABSI is directly and linearly related to high CVR, with a higher performance than WHtR when standardized and evaluated as a linear predictor.

Genetic structure of the Spanish population.

BACKGROUND: Genetic 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. RESULTS: In 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. CONCLUSIONS: In 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.

WWOX gene is associated with HDL cholesterol and triglyceride levels.

BACKGROUND: Altered lipid profile, and in particular low HDL and high triglyceride (TG) plasma levels, are within the major determinants of cardiovascular diseases. The identification of quantitative trait loci (QTL) affecting these lipid levels is a relevant issue for predictive purposes. The WWOX gene has been recently associated with HDL levels. This gene is located at chromosome 16q23, a region previously linked to familial combined hyperlipidemia (FCHL) and HDL. Our objective is to perform a genetic association analysis at the WWOX gene region with HDL, TG and TG/HDL ratio. METHODS: A quantitative association analysis performed in 801 individuals selected from the Spanish general population. RESULTS: For HDL levels, two regions of intron 8 display clustering of positive signals (p < 0.05) but none of them was associated in the haplotypic analysis (0.07 ≤ p ≤ 0.165). For TG levels not only intron 8 but also a 27 kb region spanning from the promoter region to intron 4 are associated in this study. For the TG/HDL genetic association analysis, positive signals are coincident with those of the isolated traits. Interestingly, haplotypic analysis at the 5' region showed that variation in this region modified both HDL and TG levels, especially the latter (p = 0.003). CONCLUSIONS: Our results suggest that WWOX is a QTL for both TG and HDL.

[Prevalence of metabolic syndrome and consistency in its diagnosis in type 2 diabetic patients in Spain]. / Prevalencia del síndrome metabólico y grado de concordancia en su diagnóstico en pacientes con diabetes mellitus tipo 2 en España.

OBJECTIVE: To determine the prevalence of metabolic syndrome, the degree of consistency among World Health Organization (WHO), The Third Report National Cholesterol Education Program (NCEP-ATP III) and the International Diabetes Federation (IDF) diagnostic criteria and the relationship with cardiovascular risk in a Spanish population of patients with type 2 diabetes. MATERIAL AND METHODS: This descriptive, epidemiologic, multicenter and cross-sectional study included 1259 patients with type 2 diabetes. The primary variable was diagnosis of metabolic syndrome according to WHO, NCEP-ATP III and IDF criteria. RESULTS: The prevalence of metabolic syndrome was 71.5% (WHO), 78.2% (NCEP-ATP III), and 89.5% (IDF). The prevalence of metabolic syndrome was higher in sedentary diabetic patients (WHO=79.3%, NCEP-ATP III=86.2%, and IDF=93.9) than in those who exercised moderately (WHO=61.4%, NCEP-ATP III=73.2%, and IDF=85.5%, [p<0.001]). The percentage of patients with metabolic syndrome and moderate/high cardiovascular risk was 38.9% (WHO), 33.6% (NCEP-ATP III), and 30.1%, (IDF). Consistency among WHO, NCEP-ATP III and IDF criteria was low. Only comparison of WHO vs NCEP-ATP III criteria was acceptable (k=0.52 [0.46-0.58]). CONCLUSIONS: The prevalence of metabolic syndrome in patients with type 2 diabetes in Spain is high, even when the low consistency among WHO, NCEP-ATP III and IDF criteria is considered. A standard definition of metabolic syndrome, according to routine clinical practice, is needed. Cardiovascular risk is greater when OMS and NCEP-ATP III criteria are used for the diagnosis of metabolic syndrome compared with IDF criteria.

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. DESIGN AND METHODS: In this study we examined the association between rs9939609 FTO variant and obesity related parameters in a population based-study of 732 unrelated individuals (46.9% males and 53.1% females; ages 35-74 years) from the province of Segovia in Central Spain (Castille). RESULTS: The AA genotype was significantly more frequent in obese individuals (defined as body mass index >or= 30 kg/m(2), n = 207; 80 males and 127 females) than in non-obese (19.9%vs. 13.7%, P = 0.026). In addition to increased obesity, AA homozygous individuals had higher waist circumference than individuals with AT heterozygous and TT homozygous genotypes. The minor A-allele of rs9939609 was associated with an increased odds ratio (OR) for obesity [OR 1.51, 95% confidence interval (CI) 1.10-2.12] as compared to the TT genotype. This difference was also statistically significant even after the adjustment for sex and age (OR 1.46, 95% CI 1.02-2.07). CONCLUSIONS: Our results support the association of FTO gene variants with obesity, including parameters of visceral (abdominal) obesity, in an adult general population from Spain. Overall we confirm the previously reported association studies between variants in FTO gene and the risk of obesity.

The FTO obesity gene. Genotyping and gene expression analysis in morbidly obese patients.

BACKGROUND: Obesity has emerged as one of the most serious public health concerns in the twenty-first century. the fat mass and obesity associated gene (FTO) has been found to contribute to the risk of obesity in humans. Our aims in this study were to investigate the association of rs9939609 single nucleotide polymorphism (SNP) of the FTO gene with different obesity-related parameters, to assess the FTO gene expression in subcutaneous and visceral adipose tissues from morbidly obese and its correlations with other adipocytokine gene expressions. METHODS: The association between the rs9939609 FTO gene variant and obesity related parameters in 75 obese/morbidly obese adult patients and 180 subjects with body mass index (BMI) < 30 kg/m(2) (control group) was examined. Gene expression analyses: subcutaneous adipose tissue samples were obtained from 52 morbidly obese and five subjects with BMI < 30 kg/m(2). Visceral adipose tissue was also obtained from 35 morbidly obese patients. Weight, height, BMI, SBP, DBP, fasting glucose, lipid profile, proinsulin, insulin, leptin, and adiponectin (RIA) of patients were also obtained. Insulin resistance by HOMA(IR). rs9939609 of FTO genotyping using allele discrimination in real-time PCR. Genomic study of RNA extraction of adipose tissue and real-time PCR (RT-PCR) of adipocytokines and a housekeeping gene were quantified using TaqMan probes. Relative quantification was calculated using the DeltaDelta Ct formula. RESULTS: The minor-(A) allele frequency of rs9939609 FTO gene in the whole population was 0.39. A strong association between this A allele and obesity was found, even after age-sex adjustment (p = 0.013). We found higher levels of FTO mRNA in subcutaneous adipose tissue from morbidly obese than in the control group (p = 0.021). FTO gene expression was lower in visceral than in subcutaneous adipose depot. However, this finding did not reach the level of statistical significance. A negative correlation between subcutaneous FTO gene expression and serum triglyceride levels and a positive correlation with leptin, perilipin, and visfatin gene expressions was found. In the visceral adipose tissue, these positive correlations were statistically significant only for perilipin. CONCLUSIONS: Our results show: (1) A strong association between rs9939609 SNP of the FTO gene variant and obesity in Spanish morbidly obese adult patients; (2) positive correlations between FTO mRNA and leptin, perilipin, and visfatin gene expressions in subcutaneous adipose tissue; (3) FTO and perilipin gene expressions were positively correlated in visceral fat depot. Overall these results may suggest a role of FTO in the regulation of lipolysis as well as in total body fat rather in fat distribution patterns.

Body fat anthropometric indexes: Which of those identify better high cardiovascular risk subjects? A comparative study in Spanish population.

AIM: To determine the association of body mass index (BMI), waist circumference (WC), waist to hip ratio (WHR), waist to height ratio (WHtr) and Body Shape Index (ABSI) with high cardiovascular risk (CVR), as well as to determine whether how strong are these relationships. MATERIAL AND METHODS: A cross-sectional study was carried out in Spanish Caucasian adults. 3,456 subjects completed the study, 45.78% males, aged < 65 years and non-diabetic subjects. Anthropometric/biochemical variables were measured. We determined ABSI based on WC adjusted for height and weight. High CVR was defined as ≥ 20% according to the Framingham chart, ≥ 5% with the SCORE chart, and ≥ 7.5% with the ACC/AHA guide. Areas under the receiver operating characteristic curves (AUCs) were estimated for each anthropometric measure. RESULTS: Most significant AUCs in males were: WHtr and ABSI for Framingham ≥ 20% and SCORE ≥ 5%. Also significant were WHtr, WC and ABSI for ACCA/AHA ≥ 7.5%. On the other hand, most significant AUCs in females were: WHtr and WC for Framingham ≥ 20%; and WHtr and WHR for SCORE ≥ 5%, WHtr, and WC for ACC/AHA guide ≥ 7.5%. CONCLUSIONS: Overall, the best anthropometric index identifying Spanish males and females who are at high risk for CV events is WHtr. ABSI was also found to be a good anthropometric index to predict high CVR in Spanish males according to FR, SCORE and ACC/AHA charts. For Spanish females, WC is a good anthropometric index according to FR and ACC/AHA guide, while WHR is better according to SCORE.

Association of ENPP1 (PC-1) K121Q polymorphism with obesity-related parameters in subjects with metabolic syndrome.

BACKGROUND: The metabolic syndrome (MS), a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), originally described as a plasma cell allo-antigen and named plasma cell membrane glycoprotein (PC-1), is an inhibitor of insulin-induced activation of the insulin receptor. The single nucleotide polymorphism (SNP) K121Q in the ENPP1 gene has been studied in relation to obesity, insulin resistance and other features of MS in several populations with conflicting results. We therefore investigate the role of the K121Q SNP in the ENPP1 gene in MS in Caucasians from the province of Segovia in Central Spain (Castille). DESIGN AND METHODS: We recruited 794 unrelated persons (46.5% males and 53.5% females), ages 35-74 years from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille). Obesity-related anthropometric measurements included BMI, waist circumference, blood pressure and lipid profile. MS was defined by International Diabetes Federation (IDF) guidelines. K121Q PC-1 genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The 121Q allele was associated with an increased BMI and waist circumference among subjects fulfilling the criteria for MS. These differences remained statistically significant even after the adjustment for sex, age and degree of glucose tolerance (beta = 1.347, P = 0.017 and beta = 2.824, P = 0.046; for BMI and waist circumference, respectively). Moreover, among type 2 diabetic patients those carrying the 121Q allele had higher BMI and higher leptin levels than subjects carrying the K121K genotype. CONCLUSIONS: Our results suggest that the ENPP1121Q allele might contribute to the genetic susceptibility to abdominal obesity among subjects with MS.

Interaction between Calpain 5, Peroxisome proliferator-activated receptor-gamma and Peroxisome proliferator-activated receptor-delta genes: a polygenic approach to obesity.

CONTEXT: Obesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed. OBJECTIVE: To investigate the possibility of the existence of a crosstalk between the CALPAIN 10 homologue CALPAIN 5 and nuclear receptors of the peroxisome proliferator-activated receptors family. DESIGN: Cross-sectional, genetic association study and gene-gene interaction analysis. SUBJECTS: The study sample comprise 1953 individuals, 725 obese (defined as body mass index > or = 30) and 1228 non obese subjects. RESULTS: In the monogenic analysis, only the peroxisome proliferator-activated receptor delta (PPARD) gene was associated with obesity (OR = 1.43 [1.04-1.97], p = 0.027). In addition, we have found a significant interaction between CAPN5 and PPARD genes (p = 0.038) that reduces the risk for obesity in a 55%. CONCLUSION: Our results suggest that CAPN5 and PPARD gene products may also interact in vivo.

Prevalence, Treatment, and Associated Factors of Hypertension in Spain: A Comparative Study between Populations.

The prevalence and related factors of hypertensive subjects according to the resident area (rural versus urban) were investigated in two population-based studies from Spain. Medical questionnaires were administered and anthropometrics were measured, using standardized protocols. Hypertension was diagnosed in pharmacology treated subjects or those with blood pressure (BP) ≥140/90 mm Hg. Regarding BP control, it was defined as under control if BP was <140/90 or <140/85 mm Hg in type 2 diabetic subjects. Information on educational status, social class, smoking habit, and alcohol intake was obtained. 3,816 subjects (54.38 % women) were included. Prevalence of diagnosed hypertension was higher in women and showed no differences according to the living area (men: urban 21.88 versus rural 21.92 %, p = 0.986; women: urban 28.73 versus rural 30.01 %, p = 0.540). Women living in rural areas and men with secondary or tertiary education levels had a lower probability of being BP uncontrolled (OR (95 % CI): 0.501 (0.258-0.970)/p=0.040, 0.245 (0.092-0.654)/p=0.005, and 0.156 (0.044-0.549)/p=0.004, respectively). Urban young men (31-45 years) and medium aged women (46-60 years) were less BP controlled than their rural counterparts (41.30 versus 65.79 %/p=0.025 and 35.24 versus 53.27 %/p=0.002, respectively).

Genome-wide significant risk factors on chromosome 19 and the APOE locus.

The apolipoprotein E (APOE) gene on chromosome 19q13.32, was the first, and remains the strongest, genetic risk factor for Alzheimer's disease (AD). Additional signals associated with AD have been located in chromosome 19, including ABCA7 (19p13.3) and CD33 (19q13.41). The ABCA7 gene has been replicated in most populations. However, the contribution to AD of other signals close to APOE gene remains controversial. Possible explanations for inconsistency between reports include long range linkage disequilibrium (LRLD). We analysed the contribution of ABCA7 and CD33 loci to AD risk and explore LRLD patterns across APOE region. To evaluate AD risk conferred by ABCA7 rs4147929:G>A and CD33 rs3865444:C>A, we used a large Spanish population (1796 AD cases, 2642 controls). The ABCA7 rs4147929:G>A SNP effect was nominally replicated in the Spanish cohort and reached genome-wide significance after meta-analysis (odds ratio (OR)=1.15, 95% confidence interval (95% CI)=1.12-1.19; P = 1.60 x 10-19). CD33 rs3865444:C>A was not associated with AD in the dataset. The meta-analysis was also negative (OR=0.98, 95% CI=0.93-1.04; P=0.48). After exploring LRLD patterns between APOE and CD33 in several datasets, we found significant LD (D' >0.20; P <0.030) between APOE-Ɛ2 and CD33 rs3865444C>A in two of five datasets, suggesting the presence of a non-universal long range interaction between these loci affecting to some populations. In conclusion, we provide here evidence of genetic association of the ABCA7 locus in the Spanish population and also propose a plausible explanation for the controversy on the contribution of CD33 to AD susceptibility.

Is the plasminogen activator inhibitor-1 gene a candidate gene predisposing to hypertension? Results from a population-based study in Spain.

BACKGROUND: Studies in humans and mice suggest that plasminogen activator inhibitor-1 (PAI-1) might be a candidate gene for arterial hypertension. Our aims were to analyse whether the functional 4G/5G PAI-1 polymorphism represents a risk marker for the development of arterial hypertension regardless of hypertension-related metabolic variables. METHODS: Eight hundred and fifteen unrelated individuals (387 men, age 35-74 years) from a cross-sectional, population-based, epidemiological survey in the province of Segovia (Spain) were studied. Anthropometric/biochemical parameters--body mass index, waist circumference, diastolic and systolic blood pressures, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting glucose, insulin, C-reactive protein, and PAI-1 levels--were analysed. The 4G/5G PAI-1 genotypes were established by restriction fragment length polymorphism. Insulin resistance was estimated by the homeostasis model assessment. Tobacco consumption data were obtained using a standard questionnaire. RESULTS: The 4G/4G PAI-1 genotype was significantly associated with a high prevalence of arterial hypertension. This association remained statistically significant even after adjustment for hypertension-related metabolic variables in our population (adjusted odds ratio, 1.858; 95% confidence interval, 1.135-3.018; P = 0.013). CONCLUSION: Our results show that the 4G/4G PAI-1 genotype appears to be associated with an elevated relative risk of developing arterial hypertension, regardless of PAI-1 levels and other hypertension-related factors, in a representative sample of the Spanish population.

Common haplotypes of the C-reactive protein gene and circulating leptin levels influence the interindividual variability in serum C-reactive protein levels. The Segovia study.

C-reactive protein (CRP) is a marker of systemic inflammation significantly associated with an increased risk of cardiovascular disease in the general population. The aim of our current work was to study those clinical and genetic variables potentially associated with interindividual variability in serum CRP levels. A random sample of 844 participants (450 women, mean age 55 years) from a study carried out on the general Spanish population (The Segovia Study) was studied. Our results showed that age, gender, waist circumference, leptin, impaired glucose tolerance and smoking were the clinical variables significantly associated with variations in serum CRP levels. Among those, leptin showed the strongest association, explaining 11% of the interindividual variability in circulating CRP levels (p<0.001). To study the effect of genetic variants on serum CRP levels, 10 SNPs within the CRP locus were genotyped in 756 participants. Four of these SNPs (rs1417938, rs1800947, rs1130864, rs1205) were significantly associated with CRP levels after adjustment for clinical variables. Among the common haplotypes inferred from eight SNPs, two (CCATGCCT, p=0.025; CTATCCTT, p=0.004) explained 2.9% of the total variation in serum CRP. The results here reported show that 2.9% of the total variation in circulating CRP levels seems to be explained by genetics variations within CRP locus. Furthermore, serum leptin levels are strongly associated with serum CRP levels in our Spanish population.

Calpain-5 gene variants are associated with diastolic blood pressure and cholesterol levels.

BACKGROUND: Genes implicated in common complex disorders such as obesity, type 2 diabetes mellitus (T2DM) or cardiovascular diseases are not disease specific, since clinically related disorders also share genetic components. Cysteine protease Calpain 10 (CAPN10) has been associated with T2DM, hypertension, hypercholesterolemia, increased body mass index (BMI) and polycystic ovary syndrome (PCOS), a reproductive disorder of women in which isunlin resistance seems to play a pathogenic role. The calpain 5 gene (CAPN5) encodes a protein homologue of CAPN10. CAPN5 has been previously associated with PCOS by our group. In this new study, we have analysed the association of four CAPN5 gene variants(rs948976A>G, rs4945140G>A, rs2233546C>T and rs2233549G>A) with several cardiovascular risk factors related to metabolic syndrome in general population. METHODS: Anthropometric measurements, blood pressure, insulin, glucose and lipid profiles were determined in 606 individuals randomly chosen from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille), recruited to investigate the prevalence of anthropometric and physiological parameters related to obesity and other components of the metabolic syndrome. Genotypes at the four polymorphic loci in CAPN5 gene were detected by polymerase chain reaction (PCR). RESULTS: Genotype association analysis was significant for BMI (p < or = 0.041), diastolic blood pressure (p = 0.015) and HDL-cholesterol levels (p = 0.025). Different CAPN5 haplotypes were also associated with diastolic blood pressure (DBP) (0.0005 < or = p < or = 0.006) and total cholesterol levels (0.001 < or = p < or = 0.029). In addition, the AACA haplotype, over-represented in obese individuals, is also more frequent in individuals with metabolic syndrome defined by ATPIII criteria (p = 0.029). CONCLUSION: As its homologue CAPN10, CAPN5 seems to influence traits related to increased risk for cardiovascular diseases. Our results also may suggest CAPN5 as a candidate gene for metabolic syndrome.