Juan Carlos Martín-Escudero

Epidemiology of Acute Carbon Monoxide Poisoning in a Spanish Region

Background: In Spain, as in most of the world, the incidence of acute carbon monoxide poisoning is probably underestimated. Methods: During an eighteen-month period we studied, by means of a standardized data collection form, all the cases of acute carbon monoxide poisoning that were diagnosed in 2 university hospitals. Results: During the study, 154 patients were diagnosed with carbon monoxide poisoning. The mean age was 32.2 ± 15.5 years. The two principal exposure sites were the kitchen (43%) and bathroom (23%). The majority of the cases related to malfunction of the water heater (30%) and of the central heating (23%) and 68% occurred in the home. Improper combustion of butane (31%), propane (13%), and natural gas (12%) were most frequent. The most prevalent clinical manifestations were headache (94%), dizziness (56%), nausea (45%), loss of consciousness (38%), and weakness (34%). Five patients died. In 14.4%, symptoms suggested delayed neurological syndrome. The largest number of cases of poisoning occurred during the months of December and January. Conclusions: Compared with previous Spanish series or with the antecedent year, acute carbon monoxide poisoning has a high prevalence in our region. Two factors appear to be essential to the accurate diagnosis of acute carbon monoxide poisoning: 1) the ability of emergency room physicians to recognize the clinical symptoms of carbon monoxide poisoning and 2) access to a carbon monoxide-oximeter.

Common Variants of the Liver Fatty Acid Binding Protein Gene Influence the Risk of Type 2 Diabetes and Insulin Resistance in Spanish Population

Summary The main objective was to evaluate the association between SNPs and haplotypes of the FABP1-4 genes and type 2 diabetes, as well as its interaction with fat intake, in one general Spanish population. The association was replicated in a second population in which HOMA index was also evaluated. Methods 1217 unrelated individuals were selected from a population-based study [Hortega study: 605 women; mean age 54 y; 7.8% with type 2 diabetes]. The replication population included 805 subjects from Segovia, a neighboring region of Spain (446 females; mean age 52 y; 10.3% with type 2 diabetes). DM2 mellitus was defined in a similar way in both studies. Fifteen SNPs previously associated with metabolic traits or with potential influence in the gene expression within the FABP1-4 genes were genotyped with SNPlex and tested. Age, sex and BMI were used as covariates in the logistic regression model. Results One polymorphism (rs2197076) and two haplotypes of the FABP-1 showed a strong association with the risk of DM2 in the original population. This association was further confirmed in the second population as well as in the pooled sample. None of the other analyzed variants in FABP2, FABP3 and FABP4 genes were associated. There was not a formal interaction between rs2197076 and fat intake. A significant association between the rs2197076 and the haplotypes of the FABP1 and HOMA-IR was also present in the replication population. Conclusions The study supports the role of common variants of the FABP-1 gene in the development of type 2 diabetes in Caucasians.

Renin polymorphisms and haplotypes are associated with blood pressure levels and hypertension risk in postmenopausal women

Background Renin is a key protein of the renin–angiotensin system involved in the physiological control of blood pressure; the renin gene is therefore a candidate for essential hypertension in humans. We tested the association between polymorphisms and haplotypes of the renin gene and the risk of hypertension and blood pressure levels in two Spanish populations. Methods Two population-based studies from different regions of Spain were performed. Study A included 1502 individuals (748 women) 40–70 years old, and Study B included 670 women 45–70 years old. Fourteen polymorphisms of the renin gene were selected based on position, spacing, heterozygosity (> 10% for the minor allele frequency) and previous information, and were assessed by SNPlex. Results Genotype GG of the rs5707 polymorphism was significantly associated with blood pressure levels (P = 0.005) and with the risk of having hypertension (odds ratio, 6.16; 95% confidence interval, 1.19–31.8) in women 40–70 years old from study A, but not the men. This association was also present in the women of study B (P < 0.001 for blood pressure values; odds ratio, 2.11 and 95% confidence interval, 1.07–4.17 for hypertension). Two haplotypes defined by five selected polymorphisms were associated with increased risk of hypertension in these aged women. Conclusion Polymorphisms of the renin gene were associated with blood pressure levels and risk of hypertension in women over 40 years old. The interaction between the potential functional impact of this genetic background and the estrogen fall could explain the association in women of this age group.

Study of six X-linked tetranucleotide microsatellites: population data from five Spanish regions

We studied six X-linked microsatellites in a large group of Spanish individuals (n=614) from five different regions located in northern, central and southern Spain. All the markers had tetranucleotide repeat units (DXS9895, DXS9898, DXS7130, DXS7132, GATA172D05 and DXS6789). They were amplified in two triplex PCR reactions. There were no significant sex- or region-related differences in allelic frequencies, suggesting that general national databases can be adequate as a reference for X-linked markers. The analysis of those six short tandem repeats combined in 316 males revealed 300 different “temporary haplotypes”, 283 of which were found only once. There was no evidence for statistically significant linkage disequilibrium among the loci studied. Therefore these markers are quite polymorphic and useful for forensic purposes.

Influence of Sympathetic Activity on Blood Pressure and Vascular Damage Evaluated by Means of Urinary Albumin Excretion

To analyze the influence of sympathetic activity on blood pressure (BP) and its effects on urinary albumin excretion (UAE), the authors carried out a cross‐sectional study in their local health coverage area. The following variables were monitored in a representative sample of the general population made up of 495 individuals: anthropometric parameters; blood glucose, creatinine, and lipid levels; 24‐hour urinary albumin, norepinephrine, and epinephrine excretion; and BP of patients with known hypertension and newly discovered BP ≥140/90 mm Hg, evaluated by ambulatory monitoring. In the multivariate analysis, only gender, systolic BP, and UAE were associated with norepinephrine levels; only gender, systolic BP, and body mass index were associated with epinephrine. After excluding those patients with chronic kidney disease, the multivariate analysis showed a strong association between UAE ≥30 mg/d and elevated norepinephrine and epinephrine levels. The authors concluded that in the subject population there is an association between elevated adrenergic activity and higher UAE, independent of factors such as age and BP.

Risk factors associated with retinal vein occlusion

Retinal vein occlusion (RVO) is the most frequent retinal vascular disease after diabetic retinopathy in which arterial risk factors are much more relevant than venous factors. The objective was to evaluate the role of risk factors in the development of the first episode of RVO.

Oxidative stress in susceptibility to breast cancer: study in Spanish population

BackgroundAlterations in the redox balance are involved in the origin, promotion and progression of cancer. Inter-individual differences in the oxidative stress regulation can explain a part of the variability in cancer susceptibility.The aim of this study was to evaluate if polymorphisms in genes codifying for the different systems involved in oxidative stress levels can have a role in susceptibility to breast cancer.MethodsWe have analyzed 76 single base polymorphisms located in 27 genes involved in oxidative stress regulation by SNPlex technology. First, we have tested all the selected SNPs in 493 breast cancer patients and 683 controls and we have replicated the significant results in a second independent set of samples (430 patients and 803 controls). Gene-gene interactions were performed by the multifactor dimensionality reduction approach.ResultsSix polymorphisms rs1052133 (OGG1), rs406113 and rs974334 (GPX6), rs2284659 (SOD3), rs4135225 (TXN) and rs207454 (XDH) were significant in the global analysis. The gene-gene interactions demonstrated a significant four-variant interaction among rs406113 (GPX6), rs974334 (GPX6), rs105213 (OGG1) and rs2284659 (SOD3) (p-value = 0.0008) with high-risk genotype combination showing increased risk for breast cancer (OR = 1.75 [95% CI; 1.26-2.44]).ConclusionsThe results of this study indicate that different genotypes in genes of the oxidant/antioxidant pathway could affect the susceptibility to breast cancer. Furthermore, our study highlighted the importance of the analysis of the epistatic interactions to define with more accuracy the influence of genetic variants in susceptibility to breast cancer.

A New PCSK9 Gene Promoter Variant Affects Gene Expression and Causes Autosomal Dominant Hypercholesterolemia

CONTEXT Autosomal dominant hypercholesterolemia (ADH) is a genetic disorder characterized by increased low-density lipoprotein (LDL)-cholesterol levels, leading to high risk of premature cardiovascular disease. More than 900 mutations in LDL receptor, six in APOB and 10 in PCSK9 have been identified as a cause of the disease in different populations. All known mutations in PCSK9 causing hypercholesterolemia produce an increase in the enzymatic activity of this protease. Up to now, there are data about the implication of PCSK9 in ADH in a low number of populations, not including a Spanish population. OBJECTIVE The objective of the study was to study the prevalence of PCSK9 mutations in ADH Spanish population. PARTICIPANTS We screened PCSK9 gene in 42 independent ADH patients in whom mutations in LDL receptor and APOB genes had been excluded. RESULTS None of the known mutations causing ADH was detected in our sample, but we found two variations in the promoter region that could cause ADH, c.-288G>A and c.-332C>A (each in one proband). The analysis of the effect of these two variations on the transcription activity of the PCSK9 promoter showed that c.-288G>A did not modify the transcription, whereas c.-332C>A variant caused a 2.5-fold increase when compared with the wild-type sequence, either with or without lovastatin. CONCLUSIONS PCSK9 is a rare cause of ADH in Spanish population and, up to what we know, none of the previously described mutations has been detected. We have identified a new mutation that could cause ADH by increasing the transcription of PCSK9.

Prevalence of Osteoporosis Using DXA Bone Mineral Density Measurements at the Calcaneus: Cut-Off Points of Diagnosis and Exclusion of Osteoporosis

The objective of this article is to evaluate different T-score cut-off points in the calcaneus in order to establish the prevalence of osteoporosis in the general population and to evaluate the clinical value of bone mineral density at the calcaneus as a tool to identify patients with spine or hip osteoporosis. A total of 1455 people (727 women and 728 men) from the Hortega cohort were studied. The densitometric studies were carried out in the calcaneal region using a Peripheral Instantaneous X-ray Imaging (PIXI) Lunar bone densitometer. We established three cut-off points (-1.6, -2.0, -2.5). One-hundred twenty-five patients (67 men with a mean age of 47 +/- 13 yr and 58 women with a mean age of 66 +/- 8 yr) from internal medicine outpatient clinics who were undergoing densitometry of the calcaneus, spine, and hip were subsequently studied. The prevalence of osteoporosis in women with a calcaneus T-score -1.6 was 12.4%, which is comparable to the 12.7% obtained with an axial densitometer in a Spanish population. The prevalence in men was 7.8%, with a calcaneus T-score of <-2.0. In women, the highest sensitivity (85%) was obtained with a calcaneus T-score of <-1.0 and the highest specificity with a calcaneus T-score of <-2.5. In men, the best sensitivity (61%) was obtained with a calcaneus T-score of <-1.0 and the best specificity (98%) with a calcaneus T-score of <-2.5. A calcaneus T-score <-1.6 is an adequate cut-off to establish the prevalence of osteoporosis in population studies. In women, a calcaneus T-score of >-1.0 enables the diagnosis of the disease to be excluded, whereas a calcaneus T-score of <-2.5 enables the diagnosis to be confirmed and treatment to be initiated in both men and women.

Plasma selenium levels and oxidative stress biomarkers: A gene-environment interaction population-based study

The role of selenium exposure in preventing chronic disease is controversial, especially in selenium-repleted populations. At high concentrations, selenium exposure may increase oxidative stress. Studies evaluating the interaction of genetic variation in genes involved in oxidative stress pathways and selenium are scarce. We evaluated the cross-sectional association of plasma selenium concentrations with oxidative stress levels, measured as oxidized to reduced glutathione ratio (GSSG/GSH), malondialdehyde (MDA), and 8-oxo-7,8-dihydroguanine (8-oxo-dG) in urine, and the interacting role of genetic variation in oxidative stress candidate genes, in a representative sample of 1445 men and women aged 18-85 years from Spain. The geometric mean of plasma selenium levels in the study sample was 84.76 µg/L. In fully adjusted models the geometric mean ratios for oxidative stress biomarker levels comparing the highest to the lowest quintiles of plasma selenium levels were 0.61 (0.50-0.76) for GSSG/GSH, 0.89 (0.79-1.00) for MDA, and 1.06 (0.96-1.18) for 8-oxo-dG. We observed nonlinear dose-responses of selenium exposure and oxidative stress biomarkers, with plasma selenium concentrations above ~110 μg/L being positively associated with 8-oxo-dG, but inversely associated with GSSG/GSH and MDA. In addition, we identified potential risk genotypes associated with increased levels of oxidative stress markers with high selenium levels. Our findings support that high selenium levels increase oxidative stress in some biological processes. More studies are needed to disentangle the complexity of selenium biology and the relevance of potential gene-selenium interactions in relation to health outcomes in human populations.