Ancestry dependent balancing selection of placental dysferlin at high-altitude.

Introduction: The placenta mediates fetal growth by regulating gas and nutrient exchange between the mother and the fetus. The cell type in the placenta where this nutrient exchange occurs is called the syncytiotrophoblast, which is the barrier between the fetal and maternal blood. Residence at high-altitude is strongly associated with reduced 3rd trimester fetal growth and increased rates of complications such as preeclampsia. We asked whether altitude and/or ancestry-related placental gene expression contributes to differential fetal growth under high-altitude conditions, as native populations have greater fetal growth than migrants to high-altitude. Methods: We have previously shown that methylation differences largely accounted for altitude-associated differences in placental gene expression that favor improved fetal growth among high-altitude natives. We tested for differences in DNA methylation between Andean and European placental samples from Bolivia [La Paz (∼3,600 m) and Santa Cruz, Bolivia (∼400 m)]. One group of genes showing significant altitude-related differences are those involved in cell fusion and membrane repair in the syncytiotrophoblast. Dysferlin (DYSF) shows greater expression levels in high- vs. low-altitude placentas, regardless of ancestry. DYSF has a single nucleotide variant (rs10166384;G/A) located at a methylation site that can potentially stimulate or repress DYSF expression. Following up with individual DNA genotyping in an expanded sample size, we observed three classes of DNA methylation that corresponded to individual genotypes of rs10166384 (A/A < A/G < G/G). We tested whether these genotypes are under Darwinian selection pressure by sequencing a ∼2.5 kb fragment including the DYSF variants from 96 Bolivian samples and compared them to data from the 1000 genomes project. Results: We found that balancing selection (Tajima's D = 2.37) was acting on this fragment among Andeans regardless of altitude, and in Europeans at high-altitude (Tajima's D = 1.85). Discussion: This supports that balancing selection acting on dysferlin is capable of altering DNA methylation patterns based on environmental exposure to high-altitude hypoxia. This finding is analogous to balancing selection seen frequency-dependent selection, implying both alleles are advantageous in different ways depending on environmental circumstances. Preservation of the adenine (A) and guanine (G) alleles may therefore aid both Andeans and Europeans in an altitude dependent fashion.

Maternal and fetoplacental hypoxia do not alter circulating angiogenic growth effectors during human pregnancy.

One causal model of preeclampsia (PE) postulates that placental hypoxia alters the production of angiogenic growth effectors (AGEs), causing an imbalance leading to maternal endothelial cell dysfunction. We tested this model using the natural experiment of high-altitude (HA) residence. We hypothesized that in HA pregnancies 1) circulating soluble fms-like tyrosine kinase 1 (sFlt-1) is increased and placental growth factor (PlGF) decreased, and 2) AGE concentrations correlate with measures of hypoxia. A cross-sectional study of healthy pregnancies at low altitude (LA) (400 m) versus HA (3600 m) compared normal (n = 80 at HA, n = 90 at LA) and PE pregnancies (n = 20 PE at HA, n = 19 PE at LA). Blood was collected using standard serum separation and, in parallel, by a method designed to inhibit platelet activation. AGEs were measured by enzyme-linked immunosorbent assays. AGEs did not differ between altitudes in normal or PE pregnancies. AGE concentrations were unrelated to measures of maternal or fetal hypoxia. PlGF was lower and sFlt-1 higher in PE, but overlapped considerably with the range observed in normal samples. PlGF correlated with placental mass in both normal and PE pregnancies. The contribution of peripheral cells to the values measured for AGEs was similar at LA and HA, but was greater in PE than in normotensive women. Hypoxia, across a wide physiological range in pregnancy, does not alter levels of circulating AGEs in otherwise normal pregnancies. Peripheral cell release of AGEs with the hemostasis characteristic of standard blood collection is highly variable and contributes to a doubling of the amount of sFlt-1 measured in PE as compared to normal pregnancies.

Hypoglycemia and the origin of hypoxia-induced reduction in human fetal growth.

BACKGROUND: The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA. METHODS: Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated. PRINCIPAL FINDINGS: The maternal arterial - venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced. CONCLUSION/SIGNIFICANCE: Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia.

Where the O2 goes to: preservation of human fetal oxygen delivery and consumption at high altitude.

Fetal growth is decreased at high altitude (> 2700 m). We hypothesized that variation in fetal O(2) delivery might account for both the altitude effect and the relative preservation of fetal growth in multigenerational natives to high altitude. Participants were 168 women of European or Andean ancestry living at 3600 m or 400 m. Ancestry was genetically confirmed. Umbilical vein blood flow was measured using ultrasound and Doppler. Cord blood samples permitted calculation of fetal O(2) delivery and consumption. Andean fetuses had greater blood flow and oxygen delivery than Europeans and weighed more at birth, regardless of altitude (+208 g, P < 0.0001). Fetal blood flow was decreased at 3600 m (P < 0.0001); the decrement was similar in both ancestry groups. Altitude-associated decrease in birth weight was greater in Europeans (-417 g) than Andeans (-228 g, P < 0.005). Birth weight at 3600 m was > 200 g lower for Europeans at any given level of blood flow or O(2) delivery. Fetal haemoglobin concentration was increased, decreased, and the fetal / curve was left-shifted at 3600 m. Fetuses receiving less O(2) extracted more (r(2) = 0.35, P < 0.0001). These adaptations resulted in similar fetal O(2) delivery and consumption across all four groups. Increased umbilical venous O(2) delivery correlated with increased fetal O(2) consumption per kg weight (r(2) = 0.50, P < 0.0001). Blood flow (r(2) = 0.16, P < 0.001) and O(2) delivery (r(2) = 0.17, P < 0.001) correlated with birth weight at 3600 m, but not at 400 m (r(2) = 0.04, and 0.03, respectively). We concluded that the most pronounced difference at high altitude is reduced fetal blood flow, but fetal haematological adaptation and fetal capacity to increase O(2) extraction indicates that deficit in fetal oxygen delivery is unlikely to be causally associated with the altitude- and ancestry-related differences in fetal growth.

Maternal oxygen delivery is not related to altitude- and ancestry-associated differences in human fetal growth.

Fetal growth is reduced at high altitude, but the decrease is less among long-resident populations. We hypothesized that greater maternal uteroplacental O(2) delivery would explain increased fetal growth in Andean natives versus European migrants to high altitude. O(2) delivery was measured with ultrasound, Doppler and haematological techniques. Participants (n=180) were pregnant women of self-professed European or Andean ancestry living at 3600 m or 400 m in Bolivia. Ancestry was quantified using ancestry-informative single nucleotide polymorphism. The altitude-associated decrement in birth weight was 418 g in European versus 236 g in Andean women (P<0.005). Altitude was associated with decreased uterine artery diameter, volumetric blood flow and O(2) delivery regardless of ancestry. But the hypothesis was rejected as O(2) delivery was similar between ancestry groups at their respective altitudes of residence. Instead, Andean neonates were larger and heavier per unit of O(2) delivery, regardless of altitude (P<0.001). European admixture among Andeans was negatively correlated with birth weight at both altitudes (P<0.01), but admixture was not related to any of the O(2) transport variables. Genetically mediated differences in maternal O(2) delivery are thus unlikely to explain the Andean advantage in fetal growth. Of the other independent variables, only placental weight and gestational age explained significant variation in birth weight. Thus greater placental efficiency in O(2) and nutrient transport, and/or greater fetal efficiency in substrate utilization may contribute to ancestry- and altitude-related differences in fetal growth. Uterine artery O(2) delivery in these pregnancies was 99 +/- 3 ml min(-1), approximately 5-fold greater than near-term fetal O(2) consumption. Deficits in maternal O(2) transport in third trimester normal pregnancy are unlikely to be causally associated with variation in fetal growth.

Efectos del acullico de coca en la prueba de tolerancia a la glucosa / Effects of the chewing coca in the test of tolerance to the flocose

Fueron determinados los efectos de la coca, durante el curso de la tolerancia a la glucosa; en 14 sujetos que acullicaron coca durante 3 horas y media y en 14 sujtos que no acullicaron coca. Ambos grupos son de población aymara, procedentes de comunidades rurales cercanos a la ciudad de La Paz. Los sujetos que no acullicaron coca, presentaron hipoglucemia estadísticamente significativa a los 120 minutos de la prueba, efecto que no se manifestó en los acullicadores de coca. La respuesta de contra regulación hormonal, frente a la hipoglucemia funcionó positivamente en los no acullicadores de coca, puesto que los niveles de glucosa se normalizaron a los 180 minutos de la prueba. Estos aspectos sugieren que los acullicadores de coca, en las grandes alturas no presentan hipoglucemia, por una acción antogónica que ejercen los metabolitos de la coca sobre la insulina. Permitiendo de este modo, una mejor biodisponibilidad del sustrato glucosa en el organismo para su mejor metabolismo frente a un entorno de hipoxia hipobárica, que conlleva muchas veces a situaciones de extrema hipoglucemia

Prevalence of Trypanosoma cruzi infection in blood banks of seven departments of Bolivia

Trypanosoma cruzi infection was studied in 1,298 sera samples of blood banks from 7 capital departments of Bolivia, using the immunofluorescence test (IFI) and Enzyme Linked Immunosorbent Assay (Elisa). The percentages of positivity in these 7 departments have an average of 28% and are distributed as follows: Sta. Cruz 51%, Tarija 45%, Cochabamba 28%, Sucre 39%, La Paz 4.9%, Oruro 6% and Potosi 24%. The prevalence is related with the altitude levels of the different departments. However in Potosi (3,945 m) we found a 24% of prevalence, probably due to the proximity of endemic valleys to the city. The authors suggest a strict control in blood donors since there exists a great risk of infection