Browsing by Autor "Bigham, Abigail W"

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Andean and Tibetan patterns of adaptation to high altitude
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2013) Bigham, Abigail W
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. Am. J. Hum. Biol. 25:190–197, 2013.
Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2014) Bigham, Abigail W
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 highaltitude 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.