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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. [ABSTRACT FROM AUTHOR]

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-a (HIF-a), 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 (L·min-1 and mL·min-1·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 ~11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL·min-1·kg-1 vs. CC = 30.5 mL·min-1·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. [ABSTRACT FROM AUTHOR]

Chronic mountain sickness (CMS) is a pathological condition resulting from chronic exposure to high-altitude hypoxia. While its prevalence is high in native Andeans (>10%), little is known about the genetic architecture of this disease. Here, we performed the largest genome-wide association study (GWAS) of CMS (166 CMS patients and 146 controls living at 4,380 m in Peru) to detect genetic variants associated with CMS. We highlighted four new candidate loci, including the first CMS-associated variant reaching GWAS statistical significance (rs7304081; P = 4.58 × 10−9). By looking at differentially expressed genes between CMS patients and controls around these four loci, we suggested AEBP2 , CAST , and MCTP2 as candidate CMS causal genes. None of the candidate loci were under strong natural selection, consistent with the observation that CMS affects fitness mainly after the reproductive years. Overall, our results reveal new insights on the genetic architecture of CMS and do not provide evidence that CMS-associated variants are linked to a strong ongoing adaptation to high altitude. [ABSTRACT FROM AUTHOR]

Objective: In Peru, the past three decades have witnessed impressive growth in biomedical research catalyzed from a single research university and its investigators who secured international partnerships and funding. We conducted a bibliometric analysis of publications by Peruvian authors to understand the roots of this growth and the spread of research networks within the country. Methods: For 1997–2016, publications from Web of Science with at least one author affiliated with a Peruvian institution were examined by year, author affiliations, funding agencies, co-authorship linkages, and research topics. Results: From 1997–2016, the annual number of publications from Peru increased 9-fold from 75 to 672 totaling 6032. Of these, 56% of the articles had co-authors from the US, 13% from the UK, 12% from Brazil, and 10% from Spain. Universidad Peruana Cayetano Heredia (UPCH) was clearly the lead research institution noted on one-third of publications. Of the 20 most published authors, 15 were Peruvians, 14 trained at some point at UPCH, and 13 received advanced training abroad. Plotting co-authorships documented the growth of institutional collaborations, the robust links between investigators and some lineages of mentorship. Conclusions: This analysis suggests that international training of Peruvian physician-scientists who built and sustained longstanding international partnerships with funding accelerated quality research on diseases of local importance. The role of a single research university, UPCH, was critical to advance a culture of biomedical research. Increased funding from the Peruvian Government and its Council for Science, Technology and Innovation will be needed to sustain this growth in the future. Middle-income countries might consider the Peruvian experience where long-term research and training partnerships yielded impressive advances to address key health priorities of the country. [ABSTRACT FROM AUTHOR]

Objective: In Peru, the past three decades have witnessed impressive growth in biomedical research catalyzed from a single research university and its investigators who secured international partnerships and funding. We conducted a bibliometric analysis of publications by Peruvian authors to understand the roots of this growth and the spread of research networks within the country. Methods: For 1997–2016, publications from Web of Science with at least one author affiliated with a Peruvian institution were examined by year, author affiliations, funding agencies, co-authorship linkages, and research topics. Results: From 1997–2016, the annual number of publications from Peru increased 9-fold from 75 to 672 totaling 6032. Of these, 56% of the articles had co-authors from the US, 13% from the UK, 12% from Brazil, and 10% from Spain. Universidad Peruana Cayetano Heredia (UPCH) was clearly the lead research institution noted on one-third of publications. Of the 20 most published authors, 15 were Peruvians, 14 trained at some point at UPCH, and 13 received advanced training abroad. Plotting co-authorships documented the growth of institutional collaborations, the robust links between investigators and some lineages of mentorship. Conclusions: This analysis suggests that international training of Peruvian physician-scientists who built and sustained longstanding international partnerships with funding accelerated quality research on diseases of local importance. The role of a single research university, UPCH, was critical to advance a culture of biomedical research. Increased funding from the Peruvian Government and its Council for Science, Technology and Innovation will be needed to sustain this growth in the future. Middle-income countries might consider the Peruvian experience where long-term research and training partnerships yielded impressive advances to address key health priorities of the country. Author summary: One measure of a country's productivity in biomedical research is through an analysis of the publications in the peer reviewed literature. We have searched the Web of Science database of English language biomedical publications with a Peruvian author to examine the growth in the number of publications over the period 1997–2016, the most productive research institutions in the country, the distribution of foreign coauthors, and the diversity of topics of research. In the past 2 decades, the number of publications has increased 9-fold with the extensive engagement with foreign co-authors and funding, a growing diversity of topics expanding from infectious diseases to the NCDs, and with one third of all publications coming from a single research university. The early overseas training of a group of young Peruvian physician-scientists in the 1960s led them to establish a unique research university, Universidad Peruano Cayetano Heredia that seeded this new direction and engagement in research, and the seeding of researchers to other institutions in the country working on specific research challenges. The Peruvian experience provides a model for other countries seeking to expand their footprint in research while laying out the need for greater investment by the government to secure and expand these gains while retaining outstanding scientists who have been able to identify through research new ways to address the nation's priority problems in health. The use of bibliometric analyses can provide important insights in the growth of biomedical research in a country providing policy makers with evidence for making decisions on the future funding of research. [ABSTRACT FROM AUTHOR]

Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation. [ABSTRACT FROM AUTHOR]

Chronic intermittent hypoxia (CIH) and chronic hypoxia (CH) are associated with high-altitude pulmonary hypertension (HAPH). Asymmetric dimethylarginine (ADMA), a NO synthase (NOS) inhibitor, may contribute to HAPH. This study assessed changes in the ADMA/NO pathway and the underlying mechanisms in rat lungs following exposure to CIH or CH simulated in a hypobaric chamber at 428 Torr. Twenty-four adult Wistar rats were randomly assigned to three groups: CIH2x2 (2 days of hypoxia/2 days of normoxia), CH, and NX (permanent normoxia), for 30 days. All analyses were performed in whole lung tissue. L-Arginine and ADMA were analyzed using LC-MS/MS. Under both hypoxic conditions right ventricular hypertrophy was observed (p<0.01) and endothelial NOS mRNA increased (p<0.001), but the phosphorylated/nonphosphorylated vasodilator-stimulated phosphoprotein (VASP) ratio was unchanged. ADMA increased (p<0.001), whereas dimethylarginine dimethylaminohydrolase (DDAH) activity decreased only under CH (p<0.05). Although arginase activity increased (p<0.001) and L-arginine exhibited no changes, the L-arginine/ADMA ratio decreased significantly (p<0.001). Moreover, NOX4 expression increased only under CH (p<0.01), but malondialdehyde (MDA) increased (up to 2-fold) equally in CIH2x2 and CH (p<0.001). Our results suggest that ADMA and oxidative stress likely reduce NO bioavailability under altitude hypoxia, which implies greater pulmonary vascular reactivity and tone, despite the more subdued effects observed under CIH. [ABSTRACT FROM AUTHOR]

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 geneticadaptation to high altitude in Andean and Tibetan populations. Am. J. Hum. Biol. 25:190-197, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Plasma catechols and blood volume were measured in 20 male, native high-altitude residents of Cerro de Pasco, Peru (4338 m), while hypoxic and subsequently while normoxic at sea level. Ten subjects were healthy controls,with hematocrits lower than 61%, and ten had chronic mountain sickness (CMS), a syndrome of maladaptation to altitude, characterized by polycythemia (hematocrit > 61%), profound hypoxemia, and neurologic symptoms. The main aim of the study was to evaluate the chronic effects of hypoxia on plasma catechols and on blood volume, by studying these parameters during hypoxia at high altitude (HA) and shortly after exposure to normoxia at sea level (SL). Subjects were first studied at HA in their habitual hypoxic environment, and measurements were repeated within 4 hours of arrival at SL (Lima, Peru, 150 m). All subjects had higher plasma norepinephrine (NE), dopamine (DA), and dihydroxyphenylglycol (DHPG) levels in HA (NE in controls and CMS: 414±47 and 514±35 pg/mL; DA: 9±1 and 13±1 pg/mL, DHPG: 817±48 and 972±77 pg/mL) than at SL (NE: 164±9 and 243±28 pg/mL; DA: 4±0.5 and 5±1 pg/mL DHPG: 502±23 and 649±39 pg/mL). Group differences were statistically significant only for NE in the CMS group. Plasma volume was higher in HA in both groups (p<0.05); red cell volume was higher in HA only in the CMS group. The results indicate sympathetic nervous stimulation by chronic ambient hypoxia at altitude in Andean natives, independent of maladaptation to their native environment. [ABSTRACT FROM AUTHOR]

Studies the role of menopause in the development of chronic mountain sickness. Division of sample groups into postmenopausal and premenopausal for comparison; Elevation of hematocrit level in postmenopausal women; Prevalence of excessive erythrocytosis in 8.8 percent of the subjects.

This study determined how structural features of the eggshells of coots ( Fulica americana) laid at 4150 m in the Peruvian Andes differed from those at sea level in Peru and California and how these features affected exchange of water vapor, O, and CO. While barometric pressure at 4150 m was reduced to 60% of that at sea level, the conductance to water vapor, corrected to 760 torr, of montane eggs was 107% of the corresponding lowland value. When the effect of low barometric pressure on the diffusion coefficient of gases was considered, the 'effective' conductance of the montane eggs at altitude was 177% of that at sea level. As a result, daily water loss from the montane eggs was substantially greater than that from lowland ones. The oxygen consumption of montane embryos was lower than that of lowland embryos of all sizes, particularly at larger embryonic masses. Just before pipping, the oxygen consumption of montane embryos was about 60% of the corresponding value for lowland individuals. Air cell oxygen tensions in montane eggs varied between about 65 and 38 torr; these values were about 60-70 torr below those in lowland eggs at equivalent embryonic masses. Just before pipping, the air cell CO tension of montane eggs was about 20 torr below levels in sea level eggs. The eggshell conductance to gases of montane eggs appears to have been selected to promote oxygen delivery at the cost of increased losses of water vapor and CO. [ABSTRACT FROM AUTHOR]