Association of pre-eclampsia risk with maternal levels of folate, homocysteine and vitamin B12 in Colombia: A case-control study.

BACKGROUND: Maternal serum concentrations of folate, homocysteine, and vitamin B12 have been associated with pre-eclampsia. Nevertheless, reported studies involve limited number of cases to reliably assess the nature of these associations. Our aim was to examine the relation of these three biomarkers with pre-eclampsia risk in a large Colombian population. MATERIALS AND METHODS: Design: A case-control study. Setting: Cases of pre-eclampsia and healthy pregnant controls were recruited at the time of delivery from eight different Colombian cities between 2000 and 2012. Population or Sample: 2978 cases and 4096 controls were studied. Maternal serum concentrations of folate, homocysteine, and vitamin B12 were determined in 1148 (43.6%) cases and 1300 (31.7%) controls. Also, self-reported folic acid supplementation was recorded for 2563 (84%) cases and 3155 (84%) controls. Analysis: Adjusted odds ratios (OR) for pre-eclampsia were estimated for one standard deviation (1SD) increase in log-transformed biomarkers. Furthermore, we conducted analyses to compare women that reported taking folic acid supplementation for different periods during pregnancy. Main Outcomes Measures: Odds ratio for pre-eclampsia. RESULTS: After adjusting for potential confounders in logistic regression models, the OR for pre-eclampsia was 0.80 (95% CI: 0.72, 0.90) for 1SD increase in log-folate, 1.16 (95%CI: 1.05, 1.27) for 1SD increase in log-homocysteine, and 1.10 (95%CI: 0.99, 1.22) for 1SD increase in log-vitamin B12. No interactions among the biomarkers were identified. Women who self-reported consumption of folic acid (1 mg/day) throughout their pregnancy had an adjusted OR for pre-eclampsia of 0.86 (95%CI: 0.67, 1.09) compared to women that reported no consumption of folic acid at any point during pregnancy. CONCLUSIONS: Maternal serum concentrations of folate were associated as a protective factor for pre-eclampsia while concentrations of homocysteine were associated as a risk factor. No association between maternal vitamin B12 concentrations and preeclampsia was found.

Addressing ethical challenges in the Genetics Substudy of the National Eye Survey of Trinidad and Tobago (GSNESTT).

BACKGROUND: The conduct of international collaborative genomics research raises distinct ethical challenges that require special consideration, especially if conducted in settings that are research-naïve or resource-limited. Although there is considerable literature on these issues, there is a dearth of literature chronicling approaches taken to address these issues in the field. Additionally no previous ethical guidelines have been developed to support similar research in Trinidad and Tobago. METHODS: A literature review was undertaken to identify strategies used to address common ethical issues relevant to human genetics and genomics research in research-naïve or resource-limited settings. Strategies identified were combined with novel approaches to develop a culturally appropriate, multifaceted strategy to address potential challenges in the Genetics Substudy of the National Eye Survey of Trinidad and Tobago (GSNESTT). RESULTS: Regarding the protection of study participants, we report a decision to exclude children as participants; the use of a Community Engagement and Sensitization Strategy to increase the genetic literacy of the target population; the involvement of local expertise to ensure cultural sensitivity and to address potential comprehension barriers in informed consent; and an audit of the informed consent process to ensure valid consent. Concerning the regulation of the research, we report on ethics approvals from relevant authorities; a Materials Transfer Agreement to guide sample ownership and export; and a Sample Governance Committee to oversee data use and data access. Finally regarding the protection of the interests of scientists from the host country, we report on capacity building efforts to ensure that local scientists have access to data collected through the project and appropriate recognition of their contributions in future publications. CONCLUSION: This paper outlines an ethical framework for the conduct of population-based genetics and genomics research in Trinidad and Tobago; highlights common issues arising in the field and strategies to address these.

Frequency of eNOS polymorphisms in the Colombian general population.

BACKGROUND: Nitric oxide (NO) synthesized by endothelial cells is known to be a potent vasodilator. It has been suggested that polymorphisms in endothelial nitric oxide synthase (eNOS) can affect the response of the vascular endothelium to increased oxidative stress. The objective of the present study was to determine the presence of G894T (rs1799983), intron-4 (27-bp TR) and -T786C (rs2070744) polymorphisms in the eNOS gene among the Colombian general population. RESULTS: Genotype and allele frequencies showed significant differences in their distribution. White, black and mixed populations were in HW equilibrium for the variants in 27-bp TR- and rs1799983, but the black population was in HW disequilibrium for rs2070744 (p < 0.001). Allele "T" of rs1799983 polymorphisms was more common in the white population (26,5%) than the others, while allele "C" of rs2070744 polymorphisms had a similar frequency in all populations, and the allele 4a from 27-bp TR was more frequent in the black population (26,2%) than the others. Similar differences were found when genotypes were analyzed. CONCLUSION: The findings suggest that there is a substantial difference in the distribution of eNOS polymorphisms between different ethnic groups. These results could aid the understanding of inter-ethnic differences in NO bioavailability, cardiovascular risk, and response to drugs.

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.

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.