title: Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude.
abstract: 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.
authors.affiliation: Department of Anthropology, University of Michigan, Ann Arbor, Michigan; awbigham@umich.edu.
authors.forename: Abigail W
authors.initials: AW
authors.lastname: Bigham
authors.affiliation: Departments of Anthropology and Health/Behavioral Sciences, University of Colorado Denver, Denver, Colorado; Department of Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Colleen G
authors.initials: CG
authors.lastname: Julian
authors.affiliation: Departments of Anthropology and Health/Behavioral Sciences, University of Colorado Denver, Denver, Colorado; Department of Biology, Western State Colorado University, Gunnison, Colorado;
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Wilson
authors.affiliation: Instituto Boliviano de Biología de Altura, La Paz, Bolivia;
authors.forename: Enrique
authors.initials: E
authors.lastname: Vargas
authors.affiliation: Altitude Research Center, Department of Emergency Medicine, University of Colorado Denver, Aurora, Colorado;
authors.forename: Vaughn A
authors.initials: VA
authors.lastname: Browne
authors.affiliation: Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania; and.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Shriver
authors.affiliation: Departments of Anthropology and Health/Behavioral Sciences, University of Colorado Denver, Denver, Colorado; Department of Obstetrics and Gynecology, University of Colorado Denver, Aurora, Colorado.
authors.forename: Lorna G
authors.initials: LG
authors.lastname: Moore
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics*; D000328:Adult; D000531:Altitude; D001724:Birth Weight / Q000235:genetics*; D001838:Bolivia; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D005838:Genotype; D005865:Gestational Age; D006706:Homeostasis; D006801:Humans; D007223:Infant; D016014:Linear Models; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011247:Pregnancy; D044022:Receptor, Endothelin A / Q000235:genetics*; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014158:Transcription, Genetic; D055988:Uterine Artery / Q000033:anatomy & histology*
chemical_list: C000588596:EDNRB protein, human; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human
keywords: Andean; genotype-phenotype association study; intrauterine growth restriction; mTOR pathway; natural selection