Browsing by Autor "Colleen G. Julian"

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Andean and Tibetan patterns of adaptation to high altitude
(Wiley, 2013) Abigail W. Bigham; Megan J. Wilson; Colleen G. Julian; Melisa Kiyamu; Enrique Vargas; Fabiola Lèon‐Velarde; Maria C. Rivera; Carmelo Rodriquez; Vaughn A. Browne; Esteban J. Parra
These results contribute to our understanding of the unique set of adaptations developed in different highland groups to the hypoxia of high altitude. Overall, the results provide key insights into the patterns of genetic adaptation to high altitude in Andean and Tibetan populations.
Augmented uterine artery blood flow and oxygen delivery protect Andeans from altitude-associated reductions in fetal growth
(American Physiological Society, 2009) Colleen G. Julian; Megan J. Wilson; M. de la Flor; Henry Yamashiro; Wilma Téllez; Armando Rodríguez; Abigail W. Bigham; Mark D. Shriver; Carmelo Rodriguez; Enrique Vargas
The effect of high altitude on reducing birth weight is markedly less in populations of high- (e.g., Andeans) relative to low-altitude origin (e.g., Europeans). Uterine artery (UA) blood flow is greater during pregnancy in Andeans than Europeans at high altitude; however, it is not clear whether such blood flow differences play a causal role in ancestry-associated variations in fetal growth. We tested the hypothesis that greater UA blood flow contributes to the protection of fetal growth afforded by Andean ancestry by comparing UA blood flow and fetal growth throughout pregnancy in 137 Andean or European residents of low (400 m; European n = 28, Andean n = 23) or high (3,100-4,100 m; European n = 51, Andean n = 35) altitude in Bolivia. Blood flow and fetal biometry were assessed by Doppler ultrasound, and maternal ancestry was confirmed, using a panel of 100 ancestry-informative genetic markers (AIMs). At low altitude, there were no ancestry-related differences in the pregnancy-associated rise in UA blood flow, fetal biometry, or birth weight. At high altitude, Andean infants weighed 253 g more than European infants after controlling for gestational age and other known influences. UA blood flow and O(2) delivery were twofold greater at 20 wk in Andean than European women at high altitude, and were paralleled by greater fetal size. Moreover, variation in the proportion of Indigenous American ancestry among individual women was positively associated with UA diameter, blood flow, O(2) delivery, and fetal head circumference. We concluded that greater UA blood flow protects against hypoxia-associated reductions in fetal growth, consistent with the hypothesis that genetic factors enabled Andeans to achieve a greater pregnancy-associated rise in UA blood flow and O(2) delivery than European women at high altitude.
Critical barriers for preeclampsia diagnosis and treatment in low-resource settings: An example from Bolivia
(Elsevier BV, 2019) Lilian Toledo‐Jaldin; Sheana Bull; Stephen Contag; Carlos Escudero; Simón Patricio Gutiérrez; Alexandra Heath; James M. Roberts; Jean Scandlyn; Colleen G. Julian; Lorna G. Moore
Determinants of blood oxygenation during pregnancy in Andean and European residents of high altitude
(American Physiological Society, 2007) Marco Antonio Paco Vargas; Enrique Vargas; Colleen G. Julian; J. Fernando Armaza; Armando Rodríguez; Wilma Téllez; Susan Niermeyer; Megan Wilson; Esteban J. Parra; Mark D. Shriver
High altitude decreases birth weight, but this effect is diminished in long vs. short-resident, high-altitude populations. We asked whether women from long vs. short-resident, high-altitude populations had higher arterial oxygenation levels by comparing 42 Andean and 26 European residents of La Paz, Bolivia (3,600 m), serially during pregnancy (weeks 20, 30, and 36) and again 4 mo postpartum. Pregnancy raised hypoxic ventilatory sensitivity threefold, resting ventilation (.Ve), and arterial O(2) saturation (Sa(O2)) in both groups. Ancestry, as identified using 81 genetic markers, correlated with respiratory pattern, such that greater Andean ancestry was associated with higher respiratory frequency and lower tidal volume. Pregnancy increased total blood and plasma volume approximately 40% in both groups without changing red blood cell mass relative to body weight; hence, hemoglobin fell. The hemoglobin decline was compensated for by the rise in .Ve and Sa(O2) with the result that arterial O2 content (Ca(O2)) was maintained near nonpregnant levels in both groups. Birth weights were similar for all Andean and European babies, but after adjusting for variation in gestational age, maternal height and parity, Andeans weighed 209 g more than Europeans. Babies with heavier birth weights and greater ponderal indices were born to Andean women with higher Ve during pregnancy. We concluded that while maternal .Ve and arterial oxygenation were important, some factor other than higher Ca(O2) was responsible for protecting Andeans from altitude-associated reductions in fetal growth.
Do Anti-angiogenic or Angiogenic Factors Contribute to the Protection of Birth Weight at High Altitude Afforded by Andean Ancestry?
(Springer Nature, 2010) R. Daniela Dávila; Colleen G. Julian; Megan J. Wilson; Vaughn A. Browne; Carmelo Rodriguez; Abigail W. Bigham; Mark D. Shriver; Enrique Vargas; Lorna G. Moore
Do Cytokines Contribute to the Andean-Associated Protection From Reduced Fetal Growth at High Altitude?
(Springer Nature, 2010) R. Daniela Dávila; Colleen G. Julian; Megan J. Wilson; Vaughn A. Browne; Carmelo Rodriguez; Abigail W. Bigham; Mark D. Shriver; Enrique Vargas; Lorna G. Moore
Erythropoietin and Soluble Erythropoietin Receptor: A Role for Maternal Vascular Adaptation to High-Altitude Pregnancy
(Oxford University Press, 2016) Gabriel H. Wolfson; Enrique Vargas; Vaughn A. Browne; Lorna G. Moore; Colleen G. Julian
Our findings suggest that an augmented pregnancy-associated rise in Epo may be important for successful vascular adaptation to pregnancy at HA. We further speculate that the elevated sEpoR observed in PreE vs controls at HA impedes the effect of Epo to maintain endothelial function and may, in turn, be of pathological relevance for PreE at HA.
Graduated effects of high-altitude hypoxia and highland ancestry on birth size
(Springer Nature, 2013) Rudy Soria; Colleen G. Julian; Enrique Vargas; Lorna G. Moore; Dino A. Giussani
Greater uterine artery blood flow during pregnancy in multigenerational (Andean) than shorter-term (European) high-altitude residents
(American Physiological Society, 2007) Megan J. Wilson; M. de la Flor; Marco Antonio Paco Vargas; Colleen G. Julian; Wilma Téllez; Armando Rodríguez; Abigail W. Bigham; J. Fernando Armaza; Susan Niermeyer; Mark D. Shriver
Multigenerational (Andean) compared with shorter-term (European) high-altitude residents exhibit less hypoxia-associated reductions in birth weight. Because differences in arterial O(2) content are not responsible, we asked whether greater pregnancy-associated increases in uterine artery (UA) blood flow and O(2) delivery were involved. Serial studies were conducted in 42 Andean and 26 European residents of La Paz, Bolivia (3600 m) at weeks 20, 30, 36 of pregnancy and 4 mo postpartum using Doppler ultrasound. There were no differences postpartum but Andean vs. European women had greater UA diameter (0.65 +/- 0.01 vs. 0.56 +/- 0.01 cm), cross-sectional area (33.1 +/- 0.97 vs. 24.7 +/- 1.18 mm(2)), and blood flow at week 36 (743 +/- 87 vs. 474 +/- 36 ml/min) (all P < 0.05) and thus 1.6-fold greater uteroplacental O(2) delivery near term (126.82 +/- 18.47 vs. 80.33 +/- 8.69 ml O(2).ml blood(-1).min(-1), P < 0.05). Andeans had greater common iliac (CI) flow and lower external iliac relative to CI flow (0.52 +/- 0.11 vs. 0.95 +/- 0.14, P < 0.05) than Europeans at week 36. After adjusting for gestational age, maternal height, and parity, Andean babies weighed 209 g more than the Europeans. Greater UA cross-sectional area at week 30 related positively to birth weight in Andeans (r = +0.39) but negatively in Europeans (r = -0.37) (both P < 0.01). We concluded that a greater pregnancy-associated increase in UA diameter raised UA blood flow and uteroplacental O(2) delivery in the Andeans and contributed to their ability to maintain normal fetal growth under conditions of high-altitude hypoxia. These data implicate the involvement of genetic factors in protecting multigenerational populations from hypoxia-associated reductions in fetal growth, but future studies are required for confirmation and identification of the specific genes involved.
High-altitude ancestry protects against hypoxia-associated reductions in fetal growth
(BMJ, 2007) Colleen G. Julian; Enrique Vargas; J. Fernando Armaza; Megan J. Wilson; Susan Niermeyer; Lorna G. Moore
Andean relative to European ancestry protects against altitude-associated reductions in fetal growth. The intermediate protection seen in the admixed (Mestizo) group is consistent with the influence of genetic or other Andean-specific protective characteristics.
High-end arteriolar resistance limits uterine artery blood flow and restricts fetal growth in preeclampsia and gestational hypertension at high altitude
(American Physiological Society, 2011) Vaughn A. Browne; Lilian Toledo‐Jaldin; R. Daniela Dávila; Luis P. Lopez; Henry Yamashiro; Darleen Cioffi‐Ragan; Colleen G. Julian; Megan J. Wilson; Abigail W. Bigham; Mark D. Shriver
The reduction in infant birth weight and increased frequency of preeclampsia (PE) in high-altitude residents have been attributed to greater placental hypoxia, smaller uterine artery (UA) diameter, and lower UA blood flow (Q(UA)). This cross-sectional case-control study determined UA, common iliac (CI), and external iliac (EI) arterial blood flow in Andeans residing at 3,600-4,100 m, who were either nonpregnant (NP, n = 23), or experiencing normotensive pregnancies (NORM; n = 155), preeclampsia (PE, n = 20), or gestational hypertension (GH, n = 12). Pregnancy enlarged UA diameter to ~0.62 cm in all groups, but indices of end-arteriolar vascular resistance were higher in PE or GH than in NORM. Q(UA) was lower in early-onset (≤34 wk) PE or GH than in NORM, but was normal in late-onset (>34 wk) illness. Left Q(UA) was consistently greater than right in NORM, but the pattern reversed in PE. Although Q(CI) and Q(EI) were higher in PE and GH than NORM, the fraction of Q(CI) distributed to the UA was reduced 2- to 3-fold. Women with early-onset PE delivered preterm, and 43% had stillborn small for gestational age (SGA) babies. Those with GH and late-onset PE delivered at term but had higher frequencies of SGA babies (GH=50%, PE=46% vs. NORM=15%, both P < 0.01). Birth weight was strongly associated with reduced Q(UA) (R(2) = 0.80, P < 0.01), as were disease severity and adverse fetal outcomes. We concluded that high end-arteriolar resistance, not smaller UA diameter, limited Q(UA) and restricted fetal growth in PE and GH. These are, to our knowledge, the first quantitative measurements of Q(UA) and pelvic blood flow in early- vs. late-onset PE in high-altitude residents.
Higher Estrogen Levels During Pregnancy in Andean Than European Residents of High Altitude Suggest Differences in Aromatase Activity
(Oxford University Press, 2014) Shelton M. Charles; Colleen G. Julian; Enrique Vargas; Lorna G. Moore
Chronic hypoxia does not lower but rather raises estrogen levels in multigenerational Andeans vs shorter-term Europeans, possibly as the result of greater aromatase activity. Because hypoxia alone does not lower estrogen, other attributes of the disease may be responsible for the lower estrogen levels seen previously in preeclamptic women.
Increased adherence to ACOG diagnostic guidelines for HDP following a workshop in Bolivia, a LMIC
(Elsevier BV, 2023) Lilian Toledo‐Jaldin; Litzi Lazo‐Vega; Laura Grau; Ian Lawrence; Alison Larrea-Alvarado; Rodrigo Mizutani; Sebastian Rocabado; Vikram Vasan; Mary D. Sammel; Colleen G. Julian
Inhibition of peroxisome proliferator‐activated receptor γ: a potential link between chronic maternal hypoxia and impaired fetal growth
(Wiley, 2013) Colleen G. Julian; Ivana V. Yang; Vaughn A. Browne; Enrique Vargas; Carmelo Rodriguez; Brent S. Pedersen; Lorna G. Moore; David A. Schwartz
Chronic exposure to hypoxia raises the risk of pregnancy disorders characterized by maternal vascular dysfunction and diminished fetal growth. In an effort to identify novel pathways for these hypoxia-related effects, we assessed gene expression profiles of peripheral blood mononuclear cells (PBMCs) obtained from 43 female, high-altitude or sea-level residents in the nonpregnant state or during pregnancy (20 or 36 wk). Hypoxia-related fetal growth restriction becomes apparent between 25 and 29 wk of gestation and continues until delivery. Our sampling strategy was designed to capture changes occurring before (20 wk) and during (36 wk) the time frame of slowed fetal growth. PBMC gene expression profiles were generated using human gene expression microarrays and compared between altitudes. Biological pathways were identified using pathway analysis. Modest transcriptional differences were observed between altitudes in the nonpregnant state. Of the genes that were differentially expressed at high altitude vs. sea level during pregnancy (20 wk: 59 probes mapped to 41 genes; 36 wk: 985 probes mapped to 700 genes), several are of pathological relevance for fetal growth restriction. In particular, transcriptional changes were consistent with the negative regulation of peroxisome proliferator-activated receptor γ (PPARγ) at high altitude; such effects were accompanied by reduced birth weight (P <0.05) and head circumference (P <0.01) at high altitude vs. sea level. Our findings indicate that chronic exposure to hypoxia during pregnancy alters maternal gene expression patterns in general and, in particular, expression of key genes involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of fetal growth restriction.
Lowland origin women raised at high altitude are not protected against lower uteroplacental O2 delivery during pregnancy or reduced birth weight
(Wiley, 2011) Colleen G. Julian; Jennifer L. Hageman; Megan J. Wilson; Enrique Vargas; Lorna G. Moore
Lifelong compared with newcomer high-altitude residents have lower uteroplacental O(2) delivery and similar infant birth weights, suggesting that developmental factors are likely not responsible for the protective effect of highland ancestry.
MaternalPRKAA1andEDNRAgenotypes are associated with birth weight, andPRKAA1with uterine artery diameter and metabolic homeostasis at high altitude
(American Physical Society, 2014) Abigail W. Bigham; Colleen G. Julian; Megan J. Wilson; Enrique Vargas; Vaughn A. Browne; Mark D. Shriver; Lorna G. Moore
Low birth weight and intrauterine growth restriction (IUGR) increase the risk of mortality and morbidity during the perinatal period as well as in adulthood. Environmental and genetic factors contribute to IUGR, but the influence of maternal genetic variation on birth weight is largely unknown. We implemented a gene-by-environment study wherein we utilized the growth restrictive effects of high altitude. Multigenerational high-altitude residents (Andeans) are protected from altitude-associated IUGR compared with recent migrants (Europeans). Using a combined cohort of low- and high-altitude European and Andean women, we tested 63 single nucleotide polymorphisms (SNPs) from 16 natural selection-nominated candidate gene regions for associations with infant birth weight. We identified significant SNP associations with birth weight near coding regions for two genes involved in oxygen sensing and vascular control, PRKAA1 and EDNRA, respectively. Next, we identified a significant association for the PRKAA1 SNP with an intermediate phenotype, uterine artery diameter, which has been shown to be related to Andean protection from altitude-associated reductions in fetal growth. To explore potential functional relationships for the effect of maternal SNP genotype on birth weight, we evaluated the relationship between maternal PRKAA1 SNP genotype and gene expression patterns in general and, in particular, of key pathways involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of IUGR. Our observations suggest that maternal genetic variation within genes that regulate oxygen sensing, metabolic homeostasis, and vascular control influence fetal growth and birth weight outcomes and hence Andean adaptation to high altitude.
Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans
(Elsevier BV, 2017) Jacob E. Crawford; Ricardo Amaru; Jihyun Song; Colleen G. Julian; Fernando Racimo; Jade Yu Cheng; Xiuqing Guo; Jie Yao; Bharath Ambale‐Venkatesh; João A.C. Lima
Parental ancestry and risk of early pregnancy loss at high altitude
(Wiley, 2020) Imogen Grant; Rudy Soria; Colleen G. Julian; Enrique Vargas; Lorna G. Moore; Catherine Aiken; Dino A. Giussani
High altitude pregnancy is associated with increased frequency of low birth weight infants and neonatal complications, the risks of which are higher in women of low-altitude ancestry. Does ancestry also influence the risk of miscarriage (pregnancy loss <20 weeks) in high-altitude pregnancy? To answer this, 5386 women from La Paz, Bolivia (3300-4150 m) with ≥1 live-born infant were identified. Data were extracted from medical records including maternal and paternal ancestry, demographic factors, and reproductive history. The risk of miscarriage by ancestry was assessed using multivariate logistic regression, adjusting for parity, and maternal age. Andean women experienced first live-births younger than Mestizo or European women (21.7 ± 4.6 vs 23.4 ± 8.0 vs 24.1 ± 5.1, P < .001). Andeans experienced more pregnancies per year of reproductive life (P < .001) and had significantly higher ratios of live-births to miscarriages than women of Mestizo or European ancestry (P < .001). Andean women were 24% less likely to have ever experienced a miscarriage compared to European women (OR:0.76; CI:0.62-0.90, P < .001). The woman's partner's ancestry wasn't a significant independent predictor of miscarriage. In conclusion, the risk of miscarriage at high altitude is lower in Andean women. The lack of a paternal ancestry effect suggests underlying mechanisms relate more to differential maternal adaptation in early pregnancy than fetal genetics.
Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction
(American Physical Society, 2015) Colleen G. Julian; Marcelino Gonzales; Armando Rodríguez; Diva Bellido; Carlos Salinas Salmón; Anne Ladenburger; Lindsay Reardon; Enrique Vargas; Lorna G. Moore
Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects ∼10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600-4,100 m) residents aged 18-25 yr with excessive erythrocytosis (EE, Hb concentration ≥18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey (n = 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio = 5.25, P = 0.05 and odds ratio = 6.44, P = 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension.
PlGF is greater and sFLT‐1 lower in multigenerational vs. shorter‐term pregnant residents of high altitude
(Wiley, 2008) R. Daniela Dávila; Colleen G. Julian; Vaughn A. Browne; Megan J. Wilson; Jennifer L. Hageman; Henry Yamashiro; Armando Rodríguez; Carmelo Rodriguez; Enrique Vargas; Lorna G. Moore
INTRODUCTION. An imbalance between angiogenic and anti‐angiogenic factors likely plays an etiological role in fetal growth restriction. Since multigenerational high‐altitude (HA) Andean (AND) vs. shorter‐term, European (EUR) ancestry protects against fetal growth restriction at HA, we hypothesized that the angiogenic factor PlGF was elevated and the anti‐angiogenic factor sFlt‐1 reduced. MATERIALS AND METHODS. Pregnant women residing at low (400 m; AND n=36, EUR n=39) or high (3600m; AND n=46, EUR n=33) altitude in Bolivia were studied at 20 and 36 wk of pregnancy and 4 mo postpartum. Plasma sFlt1 and PlGF levels were determined by ELISA and data analyzed by ANOVA. RESULTS. Pregnancy increased PlGF and sFlt‐1 in EUR and AND women (p<0.001). PlGF increased in AND women at HA in early pregnancy and declined at 36 wk compared EUR values (interaction between pregnancy, altitude and ancestry, p<0.05). At HA, sFlt‐1 was greater in EUR than AND women at 20 and 36 wk (p<0.001). The sFlt‐1/PlGF ratio rose from 20 wk to 36 wk in EUR women at both altitudes and in HA AND women but not in the LA AND, and tended to be lower in AND vs. EUR women near term (p<0.10). CONCLUSIONS. Lower sFLT‐1 and higher PlGF levels may help protect multigenerational AND compared with shorter‐term EUR HA‐residents from fetal growth restriction. (NIH HL079647 and HL 14985)