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Abstract 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.

Abstract 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 ≥ 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.

Abstract 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 ≤ 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 ≤ p ≤ 0.006) and total cholesterol levels (0.001 ≤ p ≤ 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.

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. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of morbidity and mortality in the industrialized world. Familial aggregation of cardiovascular risk factors is a frequent finding, but genetic factors affecting its presentation are still poorly understood. The calpain 10 gene (CAPN10) has been associated with type 2 diabetes (T2DM), a complex metabolic disorder with increased risk of cardiovascular disease. Moreover, the CAPN10 gene has been associated with the presence of metabolic syndrome (MS) in T2DM and in polycystic ovary syndrome (PCOS). In this work, we have analysed whether the polymorphisms UCSNP44, -43, -19 and -63 are related to several cardiovascular risk factors in the context of MS. Molecular analysis of CAPN10 gene was performed in 899 individuals randomly chosen from a cross-sectional population-based epidemiological survey. We have found that CAPN10 gene in our population is mainly associated with two indicators of the presence of insulin resistance: glucose levels two hours after a 75-g oral glucose tolerance test (OGTT) and HOMA values, although cholesterol levels and blood pressure values are also influenced by CAPN10 variants. In addition, the 1221/1121 haplogenotype is under-represented in individuals that fulfil the International Diabetes Federation (IDF) diagnostic criteria for MS. Our results suggest that CAPN10 gene is associated with insulin resistance phenotypes in the Spanish population. [ABSTRACT FROM AUTHOR]

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 ≥ 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. [ABSTRACT FROM AUTHOR]

The article presents the results of a study on which obesity index can explain the prevalence differences in patients with type 2 diabetes in Mexico, Spain and Texas. Body mass index (BMI) is higher among Mexican-American men while waist circumference was higher among men in San, Antonio, Texas. Height correlated with age in men and women in Mexico City and Spain. The area under the receiver operating characteristic curve (AUC) for BMI was smaller than any other indices.

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 ≤ 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 ≤ p ≤ 0.006) and total cholesterol levels (0.001 p ≤ 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. [ABSTRACT FROM AUTHOR]

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.

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.

Background: The metabolic syndrome, a cluster of several metabolic disorders, is increasingly being recognized as a risk factor for cardiovascular disease. Endothelium-derived nitric oxide facilitates skeletal muscle glucose uptake, and data from animal models indicate that endothelial nitric oxide synthase (eNOS) gene-null mice present with a phenotype of insulin resistance, hypertension, and hypertriglyceridemia, much like that observed in humans with metabolic syndrome. We used haplotype tagging single nucleotide polymorphisms (htSNPs) to investigate the role of genetic variation in the eNOS gene (NOS3) in metabolic syndrome in humans., Methods: We recruited 738 unrelated persons from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille). Metabolic syndrome was defined according to the recently modified National Cholesterol Education Program Adult Treatment Panel III guidelines., Results: Haplotype analysis showed a statistically significant association between some NOS3 gene variants and features of metabolic syndrome. Relative to the most common haplotype, 121, the haplotype 212 was associated with an increased odds ratio (OR) for metabolic syndrome [OR = 1.81, 95% confidence interval (CI) 1.15-2.84], and for decreased HDL-cholesterol concentrations (OR 1.52, 95% CI 1.01-2.29), and with increased mean values for the homeostasis model assessment of insulin resistance (P = 0.043), and triglycerides (P = 0.026)., Conclusions: Our results suggest that genetic variation at the eNOS locus is associated with features of metabolic syndrome, and might represent a new genetic susceptibility component for insulin resistance, hypertriglyceridemia, and low HDL-cholesterol concentrations.

Background: We investigated whether interactions of the -308G/A polymorphism in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene with single-nucleotide polymorphisms (SNPs) 45 and 276 of the adiponectin gene are associated with circulating adiponectin and soluble TNF-alpha receptor 2 (sTNFR2) concentrations in a Spanish population., Methods: We performed anthropometric and physiologic measurements in 809 unrelated participants recruited with a simple random sampling approach from respondents to a cross-sectional population-based epidemiologic survey in the province of Segovia in central Spain (Castille)., Results: The 2-h postload glucose and serum insulin concentrations were higher in -308A allele carriers than in -308G/G individuals homozygous for the TNF-alpha gene. Plasma concentrations of sTNFR2 were positively correlated with body mass index, waist-to-hip ratio, and sagittal abdominal diameter among individuals with type 2 diabetes. Individuals with type 2 diabetes and the -308A allele had higher sTNFR2 and lower adiponectin concentrations than -308G homozygotes. Moreover, individuals carrying both the TNF-alpha -308A allele and the G allele of SNP 45 in the adiponectin gene had the highest prevalence of impaired glucose tolerance (adjusted odds ratio, 1.26; 95% confidence interval, 1.01-1.56; P = 0.038) and had lower adiponectin concentrations (beta = -0.090; P = 0.005) than individuals without these genotypes., Conclusions: Our findings are the first to indicate that a higher incidence of impaired glucose tolerance and low circulating adiponectin concentration may be associated with interaction between the -308G/A promoter polymorphism of the TNF-alpha gene and SNP 45 in the adiponectin gene.

Adiponectin is a plasma protein produced by the adipose tissue. Hypoadiponectinemia has been associated with insulin resistance and several components of the metabolic syndrome (MS): type 2 diabetes, obesity, and dyslipidemia. We investigated whether single nucleotide polymorphisms (SNPs) at positions 45 and 276 in the adiponectin gene were associated with features of the MS in 747 unrelated Spanish subjects. The G allele of SNP45 and the G/G genotype of SNP276 were associated with impaired glucose tolerance (p = 0.020 and 0.042, respectively). The G/G genotype for SNP276 was associated with lower serum adiponectin levels as compared with the G/T and T/T genotypes (G/G, 10.10 +/- 0.24 microg/mL; G/T, 10.98 +/- 0.32 microg/mL; T/T, 12.00 +/- 0.92 microg/mL; p = 0.015) even after adjustment for sex, age, BMI, waist-to-hip ratio, homeostasis model assessment index, and the degree of glucose tolerance (p = 0.040). We found a significant negative association of circulating adiponectin levels with waist-to-hip ratio (r = -0.42, p < 0.001), sagittal abdominal diameter (r = -0.24, p < 0.001), triglycerides (r = -0.32, p < 0.001), homeostasis model assessment index (r = -0.14, p = 0.001), and uric acid (r = -0.36, p < 0.001) and positive association with high-density lipoprotein-cholesterol (r = 0.41, p < 0.001). Our findings indicate that serum adiponectin levels are associated with several components of the MS. The SNP276 of the adiponectin gene may affect impaired glucose tolerance and hypoadiponectinemia.

Objective: To compare the expression of the metabolic syndrome in Spain and San Antonio, TX, two populations with major differences regarding their cardiovascular risk profile., Research Methods and Procedures: Cross-sectional analysis of population-based, epidemiological surveys using the metabolic syndrome definition of the National Cholesterol Education Program. In San Antonio, we limited our analysis to non-Hispanic whites because non-Hispanic whites are largely of European ancestry (n = 1339 in San Antonio and 2947 in Spain), Results: In men, increased central adiposity was more prevalent in San Antonio than in Spain (29.7 vs. 23.0%, p < 0.0001); in women, it was less prevalent in San Antonio than in Spain (40.2 vs. 66.4%, p < 0.0001). The metabolic syndrome followed that same pattern: more prevalent in men (28.9 vs. 20.8%, p = 0.019) and less in women from San Antonio (27.1 vs. 30.9%, p < 0.0001). In subjects with the metabolic syndrome, most women had increased central adiposity (92.6% in San Antonio and 97.5% in Spain), and most men had either increased central adiposity or blood pressure (99.2% in San Antonio and 95.0% in Spain)., Discussion: Contrary to men, the metabolic syndrome is more prevalent in Spanish women than in women from San Antonio with differences that mirror differences in central adiposity. Central adiposity and blood pressure may be used to exclude the metabolic syndrome. Considering recent secular trends in obesity, we predict there will be an increase in the prevalence of the metabolic syndrome in both populations in the coming years.