Norma C. Serrano

Endothelial NO Synthase Genotype and Risk of Preeclampsia: A Multicenter Case-Control Study

Polymorphisms in the endothelial NO synthase (eNOS) gene have been evaluated as risk factors for preeclampsia. However, data from small studies are conflicting. We assessed whether eNOS genotypes alter the risk of preeclampsia in a population in which the incidence of this disorder is high. A total of 844 young pregnant women (322 preeclamptic and 522 controls) were recruited from 5 cities. Genotyping for the Glu298Asp, intron-4 and –786T→C polymorphisms in the eNOS gene was conducted. Multivariate odds ratios (ORs) were obtained to estimate the association of individual polymorphisms and haplotypes with preeclampsia risk. No increase in the risk of preeclampsia for the intron-4 or –786T→C polymorphisms was observed under any model of inheritance. In contrast, in women homozygous for the Asp298 allele, the adjusted OR for preeclampsia was 4.60 (95% confidence interval [CI], 1.73 to 12.22) compared with carriers of the Glu298 allele. After a multivariate analysis, carriage of the “Asp298–786C-4b” haplotype was also associated with increased risk of preeclampsia (OR, 2.11 [95% CI, 1.33 to 3.34]) compared with carriers of the “Glu298–786T-4b” haplotype. The eNOS Glu298Asp polymorphism and the Asp298–786C-4b haplotype are risk factors for preeclampsia.

Preeclampsia: from epidemiological observations to molecular mechanisms.

Preeclampsia is the main cause of maternal mortality and is associated with a five-fold increase in perinatal mortality in developing countries. In spite of this, the etiology of preeclampsia is unknown. The present article analyzes the contradictory results of the use of calcium supplementation in the prevention of preeclampsia, and tries to give an explanation of these results. The proposal of an integrative model to explain the clinical manifestations of preeclampsia is discussed. In this proposal we suggest that preeclampsia is caused by nutritional, environmental and genetic factors that lead to the creation of an imbalance between the free radicals nitric oxide, superoxide and peroxynitrate in the vascular endothelium. The adequate interpretation of this model would allow us to understand that the best way of preventing preeclampsia is the establishment of an adequate prenatal control system involving adequate antioxidant vitamin and mineral supplementation, adequate diagnosis and early treatment of asymptomatic urinary and vaginal infections. The role of infection in the genesis of preeclampsia needs to be studied in depth because it may involve a fundamental change in the prevention and treatment of preeclampsia.

Using waist circumference as a screening tool to identify colombian subjects at cardiovascular risk

Objective A cut-off value for waist circumference (WC) of 94 cm associated with cardiovascular risk factors (CVRF) has been recommended in Caucasian populations. However, it is unclear if recommendations derived from Western studies should be extrapolated to populations from developing countries. The present study evaluated a group of Colombian subjects to determine and evaluate the level of WC capable of identifying subjects with CVRF. Research design and methods (Study 1) A cross-sectional study in 145 healthy men, to determine the level of WC associated with the following lipid profile (triglycerides 2.25mmol/L and total-cholesterol/HDL-cholesterol ratio >5) was performed. (Study 2) Two hundred and thirty-eight unrelated male adults were recruited to test whether the new WC cut-off point would identify subjects with CVRF. Results (Study 1) A WC cut-off point of 88 cm identified subjects with the pre-established lipid profile with a sensitivity of 80.6% and specificity of 80.1%, while the WC of 94 cm had a low sensitivity (48.3%) and a high specificity (93.3%). Additionally, the values of C-reactive protein, fasting glucose and insulin levels in subjects with a WC 88cm were significantly higher compared to subjects with WC <88cm. (Study 2) The diagnostic accuracy of the new WC cut-off point (88 cm) to identify subjects with two or more CVRF remained acceptable in the new sample studied (sensitivity: 83.7% and specificity: 84.8%); while the WC value of 94 cm suggested in Caucasians showed a very low sensitivity (43.2%) and a high specificity (93.9%). Conclusion This study demonstrates a higher prevalence of CVRF in our population at lower levels of WC than those suggested previously in Caucasians, suggesting that ethnic background should be taken into account when using WC as a screener for CVRF. Eur J Cardiovasc Prevention Rehab 10:328-335

An integrated proposal to explain the epidemic of cardiovascular disease in a developing country - From socioeconomic factors to free radicals

An increase of coronary artery disease has been observed in developing countries during the last years. Various factors may explain this accelerated increase. We propose that inappropriate diet and inadequate sanitary infrastructure may act as triggers to create an imbalance between nitric oxide (NO) and superoxide (O–2). An increase in the concentrations of oxidizedLDL produces both decreased NO and increased O–2 endothelial synthesis, by accumulation of asymmetrical NG-NG-dimethyl-L-arginine, the endogenous inhibitor of NO, and by activation of NAD(P)H oxidase. On the other hand, high rates of chronic infection-inflammation, due to inappropriate sanitary environment stimulate higher circulating levels of proinflammatory cytokines. These cytokines also contribute to reduced NO and increased O–2 endothelial production through the same mechanisms of oxidized LDL. The net result of this imbalance is an increased generation of peroxynitrate that injures the endothelium in a proatherogenic, prothrombotic and vasoconstrictive manner.

Angiotensin-Converting Enzyme I/D Polymorphism and Preeclampsia Risk: Evidence of Small-Study Bias

Background Inappropriate activation of the renin–angiotensin system may play a part in the development of preeclampsia. An insertion/deletion polymorphism within the angiotensin-I converting enzyme gene (ACE-I/D) has shown to be reliably associated with differences in angiotensin-converting enzyme (ACE) activity. However, previous studies of the ACE-I/D variant and preeclampsia have been individually underpowered to detect plausible genotypic risks. Methods and Findings A prospective case-control study was conducted in 1,711 unrelated young pregnant women (665 preeclamptic and 1,046 healthy pregnant controls) recruited from five Colombian cities. Maternal blood was obtained to genotype for the ACE-I/D polymorphism. Crude and adjusted odds ratio (OR) and 95% confidence interval (CI) using logistic regression models were obtained to evaluate the strength of the association between ACE-I/D variant and preeclampsia risk. A meta-analysis was then undertaken of all published studies to February 2006 evaluating the ACE-I/D variant in preeclampsia. An additive model (per-D-allele) revealed a null association between the ACE-I/D variant and preeclampsia risk (crude OR = 0.95 [95% CI, 0.81–1.10]) in the new case-control study. Similar results were obtained after adjusting for confounders (adjusted per-allele OR = 0.90 [95% CI, 0.77–1.06]) and using other genetic models of inheritance. A meta-analysis (2,596 cases and 3,828 controls from 22 studies) showed a per-allele OR of 1.26 (95% CI, 1.07–1.49). An analysis stratified by study size showed an attenuated OR toward the null as study size increased. Conclusions It is highly likely that the observed small nominal increase in risk of preeclampsia associated with the ACE D-allele is due to small-study bias, similar to that observed in cardiovascular disease. Reliable assessment of the origins of preeclampsia using a genetic approach may require the establishment of a collaborating consortium to generate a dataset of adequate size.

Genetic association studies in pre-eclampsia: systematic meta-analyses and field synopsis

BACKGROUND Pre-eclampsia is thought to have a polygenic basis, but the identification of susceptibility genes and the quantification of associated risks have been elusive owing to lack of replication from published genetic association studies. OBJECTIVE To perform a systematic review and meta-analysis of genetic association studies to evaluate the evidence for the associations of various candidate genes with pre-eclampsia. METHODS For inclusion, studies had to involve unrelated subjects and examine the associations between pre-eclampsia (excluding publications without a measurement of proteinuria) and any candidate variant. Authors were contacted to obtain unpublished data when necessary. A meta-analysis was conducted for all variants with three or more independent samples available. Summary odds ratios (ORs), 99% confidence intervals (CIs) and P-values were calculated using random effects models. RESULTS Data from 192 genetic association studies met the selection criteria and were included in 25 independent meta-analyses. There was some evidence of association for F5 rs6025 (OR = 1.74; 99% CI 1.43-2.12), F2 rs1799963 (OR = 1.72; 99% CI 1.31-2.26), ACE rs4646994 (OR = 1.17; 99% CI 0.99-1.40), AGT rs699 (OR = 1.26; 99% CI 1.00-1.59) and AGTR1 rs5186 (OR = 1.22; 99% CI 0.96-1.56), but only the first two associations reached moderate epidemiological credibility. Possible bias resulting from small study size and poor reporting of individual studies were the most important factors affecting the reported associations. CONCLUSION To date, candidate gene studies in pre-eclampsia have not robustly documented any associations with strong epidemiological credibility. Large-scale replication of the most promising associations, exhibited by two genetic variants, and incorporation of agnostic high-throughput data may improve our genetic knowledge base for this complex phenotype.

Physiological and pathological implications of laminins: From the gene to the protein

The extracellular matrix plays an important role in modulating the behavior of cells with which it interacts. There are a number of families of extracellular matrix (ECM) proteins including collagens, proteoglycans and laminins (LM). LM are the major component of the basal lamina (BL). Here, we review the current knowledge on their structure, self-assembly, binding mechanisms, diverse tissue-expression patterns and its impact on pathology. Studies and hypothesis exploring the role of LM and their polymorphic genes on autoimmune diseases (AIDs) such as systemic lupus erythematosus and Sjögrens syndrome (SS) are also discussed.

Ausencia de asociación entre síndrome metabólico y síntomas depresivos en adultos colombianos

Background: There is a possible association depressive symptoms (DS) and metabolic syndrome (MS), to the extent that treating one condition improves the other. Aim: To estimate the association between MS and DS among the employees of a medical school. Material and methods: Cross sectional study of 159 people aged 41±11 years (88 men). MS was evaluated according to International Diabetes Federation (IDF), National Cholesterol Education Program (NCEP)ZAdult Treatment Panel III (ATP-III) and ATP-IIIa criteria and the depression questionnaire of the Center for Epidemiologica! Studies (CES-D) was used for DS. A multivariate logistic regression was performed adjusting for age and gender. Results: The prevalence of MS according to ATP-III was 13.2% (95% CI: 8.4-19.5), to ATP-IIIa was 34.0% (95% CI: 26.6-41.9) and to IDF was 33.3% (95% CI: 26.1-41.2). The prevalence of clinically relevant SD was 15.1% (95% CI: 9.9-21.6). No significant association was found between DS and MS according to the different criteria: ATP-III OR 1.30 (95% CI: 0.40-4.24), ATP-IIIa OR 0.94 (95% CI: 0.37-2.33), IDF OR 1.20 (95% CI: 0.49-2.95). Conclusions: In this series, no association was observed between MS and depression (Rev Med Chile 2007; 135: 990-6)

Laminin-1 (LM-111) in preeclampsia and systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of antibodies. SLE has been associated with placental pathology, a finding that is also the determinant in preeclampsia (PE). Genetic evidence and serologic reports suggest laminin-1 (LM-111) as an immunogenic molecule and its polymorphic gene as a candidate gene for both disorders. Objective: To evaluate the association between LAMA1 (rs543355) and LAMC1 (rs20563) polymorphisms and the presence of SLE and PE as well as to determine serum levels of anti-LM-111 autoantibodies in the PE group. Methods: Group A: 169 women with PE and 172 healthy pregnant women. Group B: 204 women with SLE and 204 healthy women. Anti-LM-111 for group A was measured by ELISA and the genotyping was done by using a PCR system. Results: Group A: Levels of anti-LM-111 was similar in women with PE and the control group (p = 0.3). The allelic frequencies and genotypes did not show statistically significant differences for LAMA1 and LAMC1 polymorphisms. Group B: Significant differences between SLE patients and controls for rs543355 polymorphism were not observed. Nevertheless, LAMC1 rs20563 A-allele provided protection against the development of SLE (OR 0.73, 95%CI 0.55-0.96). Conclusions: Serum levels of anti-LM-111 at the third trimester of gestation do not seem to have any direct relationship with the presence of PE, and the SNPs evaluated are not associated with the risk of developing this disorder. LAMC1 polymorphism could be a protective factor for SLE.

Mobile phone text messaging to improve adherence to cardiovascular disease secondary prevention interventions

Fil: Mariani, J. Hospital de Alta Complejidad en Red El Cruce Dr. Nestor C. Kirchner. Servicio de Cardiologia. Florencio Varela, Argentina.