Browsing by Autor "Lorna G. Moore"

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A Genomewide Admixture Mapping Panel for Hispanic/Latino Populations
(Elsevier BV, 2007) Xianyun Mao; Abigail W. Bigham; Rui Mei; Gerardo Gutiérrez‐Gutiérrez; Ken Weiss; Tom D. Brutsaert; Fabiola Lèon‐Velarde; Lorna G. Moore; Enrique Vargas; Paul McKeigue
An Evolutionary Model for Identifying Genetic Adaptation to High Altitude
(Springer Nature, 2007) Lorna G. Moore; Mark D. Shriver; Lynne Bemis; Enrique Vargas
Comparative Aspects of High-Altitude Adaptation in Human Populations
(Springer Nature, 2002) Lorna G. Moore; V. Fernando Armaza; Mercedes Villena; Enrique Vargas
Consensus Statement on Chronic and Subacute High Altitude Diseases
(Mary Ann Liebert, Inc., 2005) Fabiola Lèon‐Velarde; Marco Maggiorini; John Τ. Reeves; Almaz Aldashev; Ingrid Asmus; Luciano Bernardi; Ri-Li Ge; Peter H. Hackett; Toshio Kobayashi; Lorna G. Moore
This is an international consensus statement of an ad hoc committee formed by the International Society for Mountain Medicine (ISMM) at the VI World Congress on Mountain Medicine and High Altitude Physiology (Xining, China; 2004) and represents the committee's interpretation of the current knowledge with regard to the most common chronic and subacute high altitude diseases. It has been developed by medical and scientific authorities from the committee experienced in the recognition and prevention of high altitude diseases and is based mainly on published, peer-reviewed articles. It is intended to include all legitimate criteria for choosing to use a specific method or procedure to diagnose or manage high altitude diseases. However, the ISMM recognizes that specific patient care decisions depend on the different geographic circumstances involved in the development of each chronic high altitude disease. These guidelines are established to inform the medical services on site who are directed to solve high altitude health problems about the definition, diagnosis, treatment, and prevention of the most common chronic high altitude diseases. The health problems associated with life at high altitude are well documented, but health policies and procedures often do not reflect current state-of-the-art knowledge. Most of the cases of high altitude diseases are preventable if on-site personnel identify the condition and implement appropriate care.
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
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
Does chronic mountain sickness (CMS) have perinatal origins?
(Elsevier BV, 2007) Lorna G. Moore; Susan Niermeyer; Enrique Vargas
Erythroid and Cardiovascular High Altitude-Selected Haplotypes in Andean Aymaras and Tibetans
(Elsevier BV, 2017) Ricardo Amaru; Jihyun Song; N. Scott Reading; Victor R. Gordeuk; Teddy Quispe; Lorna G. Moore; Rasmus Nielsen; Josef T. Prchal
Abstract Humans migrating out of Africa encountered new conditions, including living at high altitude. Tibetans and Andean Aymaras have inhabited regions of 4,000 meters or more for ~44,000 and 14,000 years respectively (Hu et al, PLoS Genet 2017, Rademaker et al, Science 2014). There is a distinct difference in erythroid phenotypes: Aymaras are polycythemic at high altitude, while most Tibetans are not. Mutations providing an advantage in highlanders will improve fitness under hypoxic conditions,including modulation of erythropoiesis through the hypoxia-inducible factor (HIF) pathway. There are few shared, naturally-selected gene regions in Aymaras and Tibetans and these have different phenotypic associations (Bigham et al, Am J Hum Biol 2013). Aymara high-altitude selected haplotypes have not been published. Tibetan EPAS 1 (encoding HIF2a protein) haplotypes in part originated from ancient Denisovans and entered the Tibetan genome through introgression (Huerta-Sanchez et al, Nature 2014). Tibetan variant prolyl hydroxylase 2 (PHD2), a negative regulator of HIFs encoded by EGLN1 gene, encodes in cis both PHD2D4E and PHD2C127S which together have increased activity in hypoxia (Lorenzo et al, Nature Genetics 2014) and, together with a Tibetan EPAS 1 haplotype, protects from high altitude polycythemia (Tashi et al, JMM 2017). We and others previously identified other Tibetans haplotypes that are not unique but are enriched in Tibetans, including a “Tibetan” haplotype of PKLR encoding liver- and red cell-specific pyruvate kinase (PK) (Simonson et al, Science 2010, and Yi et al, Science 2010). We studied Tibetan-enriched haplotypes of EGLN1, EPAS1 and PKLR in 72 Bolivian Andean Aymaras, all residing at 4,000 m, and compared them with 347 Tibetans living at altitudes of 200 m and 4,300 m (Table). We genotyped PHD2D4E and PHD2C127S variants of EGLN1 and 10 Tibetan specific single nucleotide polymorphisms (SNPs) of EPAS1, 5 Denisovan and 5 non-Denisovan, each under different linkage disequilibrium (Hu et all, PLoS Genet 2017), 7 Tibetan enriched PKLR SNPs, and searched for Aymara selected variants by whole genome sequencing. The prevalence of the Tibetan-selected EGLN1 and EPAS1 haplotypes increased with increasing altitude of residence in Tibetans, suggesting a continuous evolutionary advantage (Tashi et al, JMM 2017). Aymaras did not have the PHD2D4E haplotype, and PHD2C127S was found at lower prevalence in heterozygote form. Aymaras shared two of five non-Denisovan EPAS1 SNPs selected in Tibetans; one, rs130005507 G allele, had a similar prevalence to Tibetans, but another, rs142764723 C allele, had a lower prevalence. We report that >90% of Tibetans and ~50% of Aymaras, but only ~10% of Europeans, have the “Tibetan ” PKLR haplotype. Aymara females with homozygous PKLR haplotypes have lower hemoglobins than heterozygotes (p=0.022). Further, the PKLR transcript in reticulocytes decreases with increasing altitude and this progressive decrease is even more pronounced in the “Tibetan” haplotype. We found Aymaras' selected haplotypes encoding BRINP3, NOS2, TBX5 ; these genes are associated with cardiovascular development and function but not hypoxia sensing. They are not enriched in Tibetans. We conclude that Aymara highlanders do not have the Tibetan PHD2D4E mutation or Denisovan-like EPAS1 variants. Furthermore, they share only two of five Tibetan non- Denisovan EPAS1 variants. The absence of these variants in Aymaras supports that Tibetan and Aymara high altitude inhabitants do not have the same ancestry, that they developed different evolutionary adaptations (Bigham et al, Am J Hum Biol 2013), and that Tibetans' EGLN1 and EPAS1 mutations are unique to that part of the world. We hypothesize that decreased PK enzyme activity would be expected to increase 2,3-diphosphoglycerate (2,3-DPG) (as is shown in people with PK enzyme deficiency) and thus be beneficial to high altitude adaptation by progressively augmenting tissue oxygen delivery with increasing altitude. Based on its association with lower hemoglobin in Aymara females, the selected “Tibetan” PKLR haplotype, present in about half of Aymaras, may contribute to their hypoxic adaptation. Additional evaluation of evolutionary selected genes including PKLR, BRINP3, NOS 2, and TBX5 and their functional consequences are in progress with Aymaras living at El Alto (4,150 m), Cochabamba (2,500 m) and Santa Cruz, (416m), Bolivia. Download : Download high-res image (320KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.
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.
Evidence that parent‐of‐origin affects birth‐weight reductions at high altitude
(Wiley, 2008) Adam Bennett; Stephen R. Sain; Enrique Vargas; Lorna G. Moore
Hypoxia exerts a profound depressant effect on fetal growth, lowering birth weight, and raising mortality risk. Multigenerational high-altitude populations are relatively protected from this birth-weight decline, leading us to hypothesize that genetic factors were involved. We asked if the amount of high- versus low-altitude ancestry influenced birth weight at high altitude and, specifically, whether such influences were affected by parent-of-origin effects (i.e., genomic imprinting). Medical records were reviewed from 1,343 consecutive, singleton deliveries in La Paz, Bolivia (3,600 m) of high- (Andean) or low- (European) altitude ancestry. Parental surnames were used to classify ancestry as Andean, European, Mestizo ("mixed") or some combination thereof. The effects of population ancestry on birth weight were determined by categorical, conditional linear regression. Babies born at altitude with two Andean parents weighed 252 g more than their European counterparts, with the protective effect being proportional to the amount of Andean parentage and independent of maternal parity, body size, smoking, or socioeconomic status. Paternal compared with maternal transmission raised birth weight 81 g for a given ancestry group. We concluded that indigenous high-altitude ancestry protected against hypoxia-associated fetal growth reduction in a dose-dependent fashion consistent with the involvement of genetic factors. Further, some of the genes involved appeared to be influenced by parent-of-origin effects, given that maternal transmission restricted and paternal transmission enhanced fetal growth.
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
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.
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.
Human physiological adaptation to pregnancy: Inter‐ and intraspecific perspectives
(Wiley, 2003) L. Christie Rockwell; Enrique Vargas; Lorna G. Moore
Reproductive success requires successful maternal physiological adaptation to pregnancy. An interspecific perspective reveals that the human species has modified features of our haplorhine heritage affecting the uteroplacental circulation. We speculate that such modifications - including early implantation and deep, widespread invasion of fetal (trophoblast cells) into and resultant remodeling of maternal uterine vessels - are responses to or compensation for the biomechanical constraints imposed by bipedalism which, in turn, render our species susceptible to the pregnancy complication of preeclampsia. Preeclampsia is characterized by incomplete remodeling of maternal uterine vessels as the result of shallow trophoblast invasion, which in turn reduces uteroplacental blood flow and frequently leads to intrauterine growth restriction (IUGR). Using an intraspecific perspective, we consider the fitness-related consequences of variation in uteroplacental blood flow during high-altitude pregnancy. Although birth weights are reduced at high altitudes in Bolivia, multigenerational Andean residents are relatively protected from altitude-associated IUGR. Our preliminary data suggest that Andean women have greater uteroplacental oxygen delivery than European high-altitude residents due to more complete growth and remodeling of maternal uterine vessels. Identification of the physiological and genetic mechanisms involved in such inter- and intraspecific variations in pregnancy physiology will likely be useful for understanding human evolution and contemporary challenges to successful reproduction.
Impaired maternal central hemodynamics precede the onset of vascular disorders of pregnancy at high altitude
(American Physical Society, 2024) Rosalieke E. Wiegel; Kori Baker; Carla Calderon Toledo; Richard B. Gomez; Sergio Gutiérrez-Cortez; Julie A. Houck; Andima Larrea; Litzi Lazo‐Vega; Lorna G. Moore; Julia A. Pisc
Hypertensive disorders of pregnancy represent an escalating global health concern with increasing incidence in low- to middle-income countries and high-income countries alike. The current lack of methods to detect the subclinical stages of preeclampsia (PE) and fetal growth restriction (FGR), two common vascular disorders of pregnancy, limits treatment options to minimize acute- and long-term adverse outcomes for both mother and child. To determine whether impaired maternal cardiovascular or uteroplacental vascular function precedes the onset of PE and/or FGR (PE-FGR), we used noninvasive techniques to obtain serial measurements of maternal cardiac output (CO), stroke volume (SV), systemic vascular resistance (SVR), and uterine and fetal arterial resistance at gestational weeks 10-16, 20-24, and 30-34 for 79 maternal-infant pairs in La Paz-El Alto, Bolivia (3,850 m), where the chronic hypoxia of high altitude increases the incidence of PE and FGR. Compared with controls (n = 55), PE-FGR cases (n = 24) had lower SV, higher SVR, and greater uterine artery resistance at 10-16 wk. In addition, fetuses of women with lower SV and higher SVR at 10-16 wk showed evidence of brain sparing at 30-34 wk and had lower birth weights, respectively. Although the trajectory of SV and SVR across pregnancy was similar between groups, PE-FGR cases had a comparatively blunted rise in CO from the first to the third visit. Impaired maternal central hemodynamics and increased uteroplacental resistance precede PE-FGR onset, highlighting the potential use of such measures for identifying high-risk pregnancies at high altitudes.NEW & NOTEWORTHY In this prospective study of maternal central hemodynamics at high altitude, pregnancies later affected by preeclampsia (PE) and/or fetal growth restriction (FGR) show elevated systemic and uterine vascular resistance and reduced stroke volume as early as 10-16 wk gestation. Maternal hemodynamic assessments could facilitate early detection of high-risk pregnancies, improving resource allocation and reducing adverse outcomes. We propose an integrated model linking maternal cardiovascular performance to placental insufficiency, enhancing the understanding of PE-FGR in high-altitude settings.
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.
Intrauterine Growth Restriction, Preeclampsia, and Intrauterine Mortality at High Altitude in Bolivia
(Springer Nature, 2003) Linda E. Keyes; Fernando J Armaza; Susan Niermeyer; Enrique Vargas; David A. Young; Lorna G. Moore
Is Maternal Cardiovascular Performance Impaired in Altitude-Associated Fetal Growth Restriction?
(Mary Ann Liebert, Inc., 2022) William Mundo; Lilian Toledo‐Jaldin; Alexandrea Heath-Freudenthal; Jaime Huayacho; Litzi Lazo‐Vega; Alison Larrea-Alvarado; Valquiria Miranda‐Garrido; Rodrigo Mizutani; Lorna G. Moore; Any Moreno-Aramayo
Mundo, William, Lilian Toledo-Jaldin, Alexandrea Heath-Freudenthal, Jaime Huayacho, Litzi Lazo-Vega, Alison Larrea-Alvarado, Valquiria Miranda-Garrido, Rodrigo Mizutani, Lorna G. Moore, Any Moreno-Aramayo, Richard Gomez, Patricio Gutierrez, and Colleen G. Julian. Is maternal cardiovascular performance impaired in altitude-associated fetal growth restriction? High Alt Med Biol. 23:352-360, 2022. Introduction: The incidence of fetal growth restriction (FGR) is elevated in high-altitude resident populations. This study aims to determine whether maternal central hemodynamics during the last trimester of pregnancy are altered in high-altitude FGR. Methods: In this cross-sectional study of maternal-infant pairs (FGR, n = 27; controls, n = 26) residing in La Paz, Bolivia, maternal heart rate, cardiac output (CO), stroke volume, and systemic vascular resistance (SVR) were assessed using continuous-wave Doppler ultrasound. Transabdominal Doppler ultrasound was used for uterine artery (UtA) resistance indices and fetal measures. Maternal venous soluble fms-like tyrosine kinase-1 (sFlt1) levels were measured. Results: FGR pregnancies had reduced CO, elevated SVR and UtA resistance, fetal brain sparing, and increased maternal sFlt1 versus controls. Maternal SVR was positively associated with UtA resistance and inversely associated with middle cerebral artery resistance and birth weight. Maternal sFlt1 was greater in FGR than controls and positively associated with UtA pulsatility index. Women with elevated sFlt1 levels also tended to have lower CO and higher SVR. Conclusion: Noninvasive assessment of maternal cardiovascular function may be an additional method for detecting high-risk pregnancies at high altitudes, thereby informing the need for increased surveillance and appropriate allocation of resources to minimize adverse outcomes.
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.