RESUMO
To characterize host risk factors for infectious disease in Mesoamerican populations, we interrogated 857,481 SNPs assayed using the Affymetrix 6.0 genotyping array for signatures of natural selection in immune response genes. We applied three statistical tests to identify signatures of natural selection: locus-specific branch length (LSBL), the cross-population extended haplotype homozygosity (XP-EHH), and the integrated haplotype score (iHS). Each of the haplotype tests (XP-EHH and iHS) were paired with LSBL and significance was determined at the 1% level. For the paired analyses, we identified 95 statistically significant windows for XP-EHH/LSBL and 63 statistically significant windows for iHS/LSBL. Among our top immune response loci, we found evidence of recent directional selection associated with the major histocompatibility complex (MHC) and the peroxisome proliferator-activated receptor gamma (PPAR-γ) signaling pathway. These findings illustrate that Mesoamerican populations' immunity has been shaped by exposure to infectious disease. As targets of selection, these variants are likely to encode phenotypes that manifest themselves physiologically and therefore may contribute to population-level variation in immune response. Our results shed light on past selective events influencing the host response to modern diseases, both pathogenic infection as well as autoimmune disorders.
Assuntos
Doenças Transmissíveis , Genômica , Humanos , Genoma , Seleção Genética , Doenças Transmissíveis/genéticaRESUMO
BACKGROUND: Inorganic lead (Pb) is common in the environment, and is toxic to neurological, renal, and cardiovascular systems. Pb exposure influences the epigenome with documented effects on DNA methylation (DNAm). We assessed the impact of low levels of Pb exposure on DNAm among non-miner individuals from two locations in Peru: Lima, the capital, and Cerro de Pasco, a highland mining town, to study the effects of Pb exposure on physiological outcomes and DNAm. METHODS: Pb levels were measured in whole blood (n = 305). Blood leukocyte DNAm was determined for 90 DNA samples using the Illumina MethylationEPIC chip. An epigenome-wide association study was performed to assess the relationship between Pb and DNAm. RESULTS: Individuals from Cerro de Pasco had higher Pb than individuals from Lima (p-value = 2.00E-16). Males had higher Pb than females (p-value = 2.36E-04). Pb was positively associated with hemoglobin (p-value = 8.60E-04). In Cerro de Pasco, blood Pb decreased with the distance from the mine (p-value = 0.04), and association with soil Pb was approaching significance (p-value = 0.08). We identified differentially methylated positions (DMPs) associated with genes SOX18, ZMIZ1, and KDM1A linked to neurological function. We also found 45 differentially methylated regions (DMRs), seven of which were associated with genes involved in metal ion binding and nine to neurological function and development. CONCLUSIONS: Our results demonstrate that even low levels of Pb can have a significant impact on the body including changes to DNAm. We report associations between Pb and hemoglobin, Pb and distance from mining, and between blood and soil Pb. We also report associations between loci- and region-specific DNAm and Pb.
Assuntos
Metilação de DNA , Chumbo , Adulto , Epigênese Genética , Epigenoma , Feminino , Hispânico ou Latino , Histona Desmetilases , Humanos , Chumbo/toxicidade , Masculino , Peru , Fatores de Transcrição SOXFRESUMO
High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.
Assuntos
Altitude , Epigênese Genética , Adulto , Metilação de DNA , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Peru , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (Lâ min-1 and mLâ min-1â kg-1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by â¼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mLâ min-1â kg-1 vs. CC = 30.5 mLâ min-1â kg-1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.
Assuntos
Altitude , Prolina Dioxigenases do Fator Induzível por Hipóxia/fisiologia , Hipóxia/genética , Oxigênio/metabolismo , Polimorfismo de Nucleotídeo Único , Aclimatação , Adaptação Fisiológica , Feminino , Frequência do Gene , Genótipo , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Povos Indígenas , Masculino , Peru , Seleção Genética , Estresse FisiológicoRESUMO
OBJECTIVES: Andean and Tibetan high-altitude natives exhibit a high concentration of nitric oxide (NO) in the lungs, suggesting that NO plays an adaptive role in offsetting hypobaric hypoxia. We examined the exhaled NO concentration as well as partial pressure of several additional high-altitude native populations in order to examine the possibility that this putative adaptive trait, that is, high exhaled NO, is universal. METHODS: We recruited two geographically diverse highland native populations, Tawang Monpa (TM), a Tibetan derived population in North-Eastern India (n = 95, sampled at an altitude of ~3,200 m), and Peruvian Quechua from the highland Andes (n = 412). The latter included three distinct subgroups defined as those residing at altitude (Q-HAR, n = 110, sampled at 4,338 m), those born and residing at sea-level (Q-BSL, n = 152), and those born at altitude but migrant to sea-level (Q-M, n = 150). In addition, we recruited a referent sample of lowland natives of European ancestry from Syracuse, New York. Fraction of exhaled NO concentrations were measured using a NIOX NIMO following the protocol of the manufacturer. RESULTS: Partial pressure of exhaled nitric oxide (PENO) was significantly lower (p < .05) in both high-altitude resident groups (TM = 6.2 ± 0.5 nmHg and Q-HAR = 5.8 ± 0.5 nmHg), as compared to the groups measured at sea level (USA = 14.6 ± 0.7 nmHg, Q-BSL = 18.9 ± 1.6 nmHg, and Q-M = 19.2 ± 1.7 nmHg). PENO was not significantly different between TM and Q-HAR (p < .05). CONCLUSION: In contrast to previous work, we found lower PENO in populations at altitude (compared to sea-level) and no difference in PENO between Tibetan and Andean highland native populations. These results do not support the hypothesis that high nitric oxide in human lungs is a universal adaptive mechanism of highland native populations to offset hypobaric hypoxia.
Assuntos
Expiração , Óxido Nítrico/metabolismo , Adaptação Fisiológica , Adulto , Altitude , Feminino , Humanos , Índia , Indígenas Sul-Americanos , Masculino , Peru , Tibet/etnologia , Adulto JovemRESUMO
Dengue has become one of the most important worldwide arthropod-borne diseases. Dengue phenotypes are based on laboratorial and clinical exams, which are known to be inaccurate. OBJECTIVE: We present a machine learning approach for the prediction of dengue fever severity based solely on human genome data. METHODS: One hundred and two Brazilian dengue patients and controls were genotyped for 322 innate immunity single nucleotide polymorphisms (SNPs). Our model uses a support vector machine algorithm to find the optimal loci classification subset and then an artificial neural network (ANN) is used to classify patients into dengue fever or severe dengue. RESULTS: The ANN trained on 13 key immune SNPs selected under dominant or recessive models produced median values of accuracy greater than 86%, and sensitivity and specificity over 98% and 51%, respectively. CONCLUSION: The proposed classification method, using only genome markers, can be used to identify individuals at high risk for developing the severe dengue phenotype even in uninfected conditions. SIGNIFICANCE: Our results suggest that the genetic context is a key element in phenotype definition in dengue. The methodology proposed here is extendable to other Mendelian based and genetically influenced diseases.
Assuntos
Genoma Humano , Aprendizado de Máquina , Dengue Grave/genética , Brasil , Estudos de Casos e Controles , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Valor Preditivo dos Testes , Prognóstico , Sensibilidade e EspecificidadeRESUMO
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.
Assuntos
Proteínas Quinases Ativadas por AMP/genética , Altitude , Peso ao Nascer/genética , Homeostase , Receptor de Endotelina A/genética , Artéria Uterina/anatomia & histologia , Adulto , Bolívia , Estudos Transversais , Feminino , Frequência do Gene/genética , Redes Reguladoras de Genes , Estudos de Associação Genética , Genótipo , Idade Gestacional , Humanos , Lactente , Modelos Lineares , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Receptor de Endotelina B , Receptores de Endotelina , Serina-Treonina Quinases TOR/metabolismo , Transcrição GênicaRESUMO
OBJECTIVES: High-altitude hypoxia, or decreased oxygen levels caused by low barometric pressure, challenges the ability of humans to live and reproduce. Despite these challenges, human populations have lived on the Andean Altiplano and the Tibetan Plateau for millennia and exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. We and others have identified natural selection candidate genes and gene regions for these adaptations using dense genome scan data. One gene previously known to be important in cellular oxygen sensing, egl nine homolog 1 (EGLN1), shows evidence of positive selection in both Tibetans and Andeans. Interestingly, the pattern of variation for this gene differs between the two populations. Continued research among Tibetan populations has identified statistical associations between hemoglobin concentration and single nucleotide polymorphism (SNP) genotype at EGLN1 and a second gene, endothelial PAS domain protein 1 (EPAS1). METHODS: To measure for the effects of EGLN1 and EPAS1 altitude genotypes on hemoglobin concentration among Andean highlanders, we performed a multiple linear regression analysis of 10 candidate SNPs in or near these two genes. RESULTS: Our analysis did not identify significant associations between EPAS1 or EGLN1 SNP genotypes and hemoglobin concentration in Andeans. CONCLUSIONS: 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.
Assuntos
Aclimatação , Regulação da Expressão Gênica , Polimorfismo de Nucleotídeo Único , Adaptação Fisiológica , Altitude , Povo Asiático , Hemoglobinas/genética , Hemoglobinas/metabolismo , Humanos , Indígenas Sul-Americanos , Seleção Genética , América do Sul , TibetRESUMO
High altitude natives have enlarged vital capacities and residual volumes (RV). Because pulmonary volumes are an indication of functionally relevant traits, such as diffusion capacity, the understanding of the factors (genetic/developmental) that influence lung volumes provides insight into the adaptive responses of highlanders. In order to test for the effect of growth and development at high altitude on lung volumes, we obtained forced vital capacities (FVC), RV, and total lung capacities (TLC) for a sample of 65 Peruvian females of mostly Quechua origins (18-34 years) who were sub-divided into two well-matched groups: 1) sea-level born and raised females (BSL, n = 34) from Lima, Peru (150 m), and 2) high-altitude born and raised females (BHA, n = 31) from Cerro de Pasco, Peru (4,338 m). To determine Quechua origins, Native American ancestry proportion (NAAP) for each individual was assessed using a panel of 70 ancestry informative markers. NAAP was similar between groups (BSL = 91.71%; BHA = 89.93%; P = 0.240), and the analysis confirmed predominantly Quechua origins. After adjusting for body size and NAAP, BHA females had significantly higher FVC (3.79 ± 0.06 l; P < 0.001), RV (0.98 ± 0.03 l; P < 0.001) and TLC (4.80 ± 0.07 l; P < 0.001) compared to BSL females (FVC = 3.33 ± 0.05 l; RV = 0.69 ± 0.03 l; TLC = 4.02 ± 0.06 l). NAAP was not associated with FVC (P = 0.352) or TLC (P = 0.506). However, NAAP was positively associated with RV (P = 0.004). In summary, results indicate that developmental exposure to high altitude in females constitutes an important factor for all lung volumes, whereas both genetic and developmental factors seem to be important for RV.
Assuntos
Adaptação Biológica/fisiologia , Indígenas Sul-Americanos/genética , Capacidade Pulmonar Total/fisiologia , Adaptação Biológica/genética , Adolescente , Adulto , Altitude , Análise de Variância , Antropologia Física , Antropometria , Feminino , Marcadores Genéticos/genética , Humanos , Modelos Lineares , Peru , Polimorfismo de Nucleotídeo Único , Testes de Função Respiratória , Capacidade Pulmonar Total/genéticaRESUMO
Oxidative stress has been implicated in the uteroplacental ischemia characteristic of preeclampsia and small-for-gestational-age (SGA) birth, both of which are more common at high (>2500 m) vs low altitude. Since Andeans are protected relative to Europeans from the altitude-associated rise in SGA, we asked whether alterations in maternal antioxidant status or oxidative stress contributed to their protection. Enzymatic antioxidant (erythrocyte catalase and superoxide dismutase [SOD]) activity and a plasma marker of lipid peroxidation (8-iso-PGF2α) were measured during pregnancy and in the non-pregnant state in Andean or European residents of low (400 m) or high altitude (3600-4100 m). Pregnancy and altitude increased catalase and/or SOD activity to a greater extent in Andeans than Europeans. 8-iso-PGF2α levels were independent of altitude and pregnancy. SOD was lower in mothers of SGA infants at weeks 20 and 36. Our findings are consistent with the possibility that elevated enzymatic antioxidant activity contributes to Andean protection against altitude-associated SGA.
Assuntos
Altitude , Antioxidantes/análise , Antioxidantes/fisiologia , Enzimas/sangue , Retardo do Crescimento Fetal/prevenção & controle , Recém-Nascido Pequeno para a Idade Gestacional , Gravidez/sangue , Adulto , Antioxidantes/metabolismo , Bolívia/epidemiologia , Estudos de Coortes , Enzimas/metabolismo , Etnicidade/estatística & dados numéricos , Feminino , Retardo do Crescimento Fetal/enzimologia , Retardo do Crescimento Fetal/epidemiologia , Retardo do Crescimento Fetal/etnologia , Geografia , Nível de Saúde , Humanos , Recém-Nascido , Gravidez/metabolismo , Regulação para Cima , Adulto JovemRESUMO
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.
Assuntos
Altitude , Retardo do Crescimento Fetal/etiologia , Hipertensão Induzida pela Gravidez/fisiopatologia , Pré-Eclâmpsia/fisiopatologia , Artéria Uterina/fisiopatologia , Resistência Vascular , Adulto , Análise de Variância , Velocidade do Fluxo Sanguíneo , Bolívia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Idade Gestacional , Humanos , Hipertensão Induzida pela Gravidez/diagnóstico por imagem , Artéria Ilíaca/fisiopatologia , Fluxometria por Laser-Doppler , Nascido Vivo , Pré-Eclâmpsia/diagnóstico por imagem , Gravidez , Nascimento Prematuro , Fluxo Sanguíneo Regional , Natimorto , Ultrassonografia Doppler , Ultrassonografia Pré-Natal , Artéria Uterina/diagnóstico por imagem , Adulto JovemRESUMO
Pro- versus anti-inflammatory cytokine balance is important for successful pregnancy. Chronic hypoxia alters cytokine levels and increases the frequency of fetal growth restriction (FGR). Multigenerational Andean (AND) versus shorter duration European (EUR) high-altitude (HA) residents are protected from altitude-associated FGR. To address whether ancestry group differences in cytokine levels were involved, we conducted serial studies in 56 low-altitude ([LA]; 400 m; n = 29 AND and n = 27 EUR) and 42 HA residents (3600-4100 m; n = 19 ANDs and n = 23 EURs). Pregnancy raised pro- (interleukin 1ß [IL-1ß]) and anti- (IL-10) inflammatory cytokines and HA lowered IL-6 and tumor necrosis factor-α (TNF-α) near term. There were no ancestry group differences in cytokine levels at any time, but HA reduced IL-1ß in ANDs only near term. Higher IL-1ß levels correlated with uterine artery (UA) blood flow at 20 weeks in ANDs at HA, suggesting that IL-1ß may play a role in AND protection from altitude-associated reductions in fetal growth.
Assuntos
Altitude , Citocinas/fisiologia , Retardo do Crescimento Fetal , Interleucina-1beta/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo , Bolívia , Citocinas/sangue , Feminino , Retardo do Crescimento Fetal/etiologia , Retardo do Crescimento Fetal/fisiopatologia , Retardo do Crescimento Fetal/prevenção & controle , Idade Gestacional , Humanos , Indígenas Sul-Americanos , Proteína Antagonista do Receptor de Interleucina 1/sangue , Interleucina-10/sangue , Interleucina-1beta/sangue , Interleucina-4/sangue , Interleucina-6/sangue , Gravidez , Fator de Necrose Tumoral alfa/sangue , Artéria Uterina/fisiopatologia , População BrancaRESUMO
High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.
Assuntos
Altitude , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Genética Populacional , Genoma Humano/genética , Seleção Genética , Adaptação Fisiológica/genética , Variações do Número de Cópias de DNA/genética , Geografia , Globinas/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia , Filogenia , Polimorfismo de Nucleotídeo Único/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Sistema Renina-Angiotensina/genética , América do Sul , TibetRESUMO
OBJECTIVE: This prospective study was designed to determine whether variation in angiogenic (placental growth factor [PlGF]) and/or anti-angiogenic (soluble fms-like tyrosine kinase [sFlt-1]) factors contribute to the protective effect of highland ancestry (Andean) from altitude-associated reductions in fetal growth. STUDY DESIGN: Plasma sFlt-1 and PlGF levels, uterine artery (UA) blood flow, and fetal biometry were determined in low-altitude (400 m; Andean n = 27, European n = 28) and high-altitude (3600 m; Andean n = 51, European n = 44) residents during pregnancy (20 and 36 weeks) and 4 months postpartum. RESULTS: High-altitude decreased sFlt-1 levels in both groups, Andeans had lower sFlt-1, comparable PlGF, lower sFlt-1/PlGF ratios, and higher UA blood flow throughout pregnancy relative to Europeans. Altitude decreased birth weight in Europeans but not Andeans. In high-altitude Europeans sFlt-1/PlGF and sFlt-1 levels were negatively associated with UA diameter and birth weight, respectively. CONCLUSIONS: Lower sFlt-1 and sFlt-1/PLGF ratio may contribute to or result from variations in maternal vascular adaptation to pregnancy between Andean and Europeans at high altitude. Subsequently, these effects could potentially influence ancestry-associated differences in birth weight.
Assuntos
Aclimatação/genética , Altitude , Indígena Americano ou Nativo do Alasca/genética , Proteínas Angiogênicas/sangue , Proteínas Angiostáticas/sangue , Peso ao Nascer/genética , Retardo do Crescimento Fetal/prevenção & controle , População Branca/genética , Adulto , Bolívia , Distribuição de Qui-Quadrado , Feminino , Desenvolvimento Fetal/genética , Retardo do Crescimento Fetal/sangue , Retardo do Crescimento Fetal/genética , Retardo do Crescimento Fetal/fisiopatologia , Predisposição Genética para Doença , Idade Gestacional , Humanos , Linhagem , Fator de Crescimento Placentário , Gravidez , Proteínas da Gravidez/sangue , Estudos Prospectivos , Fluxo Sanguíneo Regional , Medição de Risco , Fatores de Risco , Artéria Uterina/fisiopatologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto JovemRESUMO
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.
Assuntos
Altitude , Indígena Americano ou Nativo do Alasca/genética , Artérias/fisiologia , Desenvolvimento Fetal/genética , Oxigênio/metabolismo , Fluxo Sanguíneo Regional/genética , Útero/irrigação sanguínea , Adulto , Indígena Americano ou Nativo do Alasca/etnologia , Transporte Biológico/genética , Transporte Biológico/fisiologia , Peso ao Nascer/genética , Peso ao Nascer/fisiologia , Bolívia/etnologia , Estudos de Casos e Controles , Europa (Continente)/etnologia , Feminino , Desenvolvimento Fetal/fisiologia , Humanos , Gravidez , Fluxo Sanguíneo Regional/fisiologia , População Branca/etnologia , População Branca/genéticaRESUMO
The I-allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with performance benefits at high altitude (HA). In n = 142 young males and females of largely Quechua origins in Peru, we evaluated 3 specific hypotheses with regard to the HA benefits of the I-allele: (1) the I-allele is associated with higher arterial oxygen saturation (Sa(O(2))) at HA, (2) the I-allele effect depends on the acclimatization state of the subjects, and (3) the putative I-allele effect on Sa(O(2)) is mediated by the isocapnic hypoxic ventilatory response (HVR, l/min(1)/% Sa(O(2))(1)). The subject participants comprised two different study groups including BLA subjects (born at low altitude) who were lifelong sea-level residents transiently exposed to hypobaric hypoxia (<24 h) and BHA subjects (born at HA) who were lifelong residents of HA. To control for the possibility of population stratification, Native American ancestry proportion (NAAP) was estimated as a covariate for each individual using a panel of 70 ancestry-informative molecular markers (AIMS). At HA, resting and exercise Sa(O(2)) was strongly associated with the ACE genotype, p = 0.008 with approximately 4% of the total variance in Sa(O(2)) attributed to ACE genotype. Moreover, I/I individuals maintained approximately 2.3 percentage point higher Sa(O(2)) compared to I/D and D/D. This I-allele effect was evident in both BLA and BHA groups, suggesting that acclimatization state has little influence on the phenotypic expression of the ACE gene. Finally, ACE genotype was not associated with the isocapnic HVR, although HVR had a strong independent effect on Sa(O(2)) (p = 0.001). This suggests that the I-allele effect on Sa(O(2)) is not mediated by the peripheral control of breathing, but rather by some other central cardiopulmonary effect of the ACE gene on the renin-angiotensin-aldosterone system (RAAS).
Assuntos
Aclimatação/genética , Indígenas Sul-Americanos/genética , Consumo de Oxigênio/fisiologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Alelos , Feminino , Deleção de Genes , Humanos , Masculino , Peru , Artéria Pulmonar , Valores de ReferênciaRESUMO
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.