Genomic Selection Signals in Andean Highlanders Reveal Adaptive Placental Metabolic Phenotypes That Are Disrupted in Preeclampsia.

Autor:	O'Brien KA; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.).; Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine (K.A.O., W.G., T.S.S.), University of California San Diego, La Jolla, CA.; Department of Biomedical Informatics (K.A.O., J.A.H., J.A.S., C.J.M., H.Y., C.G.J.), University of Colorado School of Medicine, Aurora, CO., Gu W; Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine (K.A.O., W.G., T.S.S.), University of California San Diego, La Jolla, CA.; Herbert Wertheim School of Public Health and Longevity Sciences (W.G.), University of California San Diego, La Jolla, CA., Houck JA; Department of Biomedical Informatics (K.A.O., J.A.H., J.A.S., C.J.M., H.Y., C.G.J.), University of Colorado School of Medicine, Aurora, CO.; Department of Obstetrics and Gynecology, Division of Reproductive Sciences (J.A.H., L.G.M.), University of Colorado School of Medicine, Aurora, CO., Holzner LMW; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.)., Yung HW; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.)., Armstrong JL; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.)., Sowton AP; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.)., Baxter R; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.)., Darwin PM; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.)., Toledo-Jaldin L; Department of Obstetrics, Hospital Materno-Infantil, La Paz, Bolivia (L.T.-J., L.L.-V., A.E.M.-M., V.M.-G.)., Lazo-Vega L; Department of Obstetrics, Hospital Materno-Infantil, La Paz, Bolivia (L.T.-J., L.L.-V., A.E.M.-M., V.M.-G.)., Moreno-Aramayo AE; Department of Obstetrics, Hospital Materno-Infantil, La Paz, Bolivia (L.T.-J., L.L.-V., A.E.M.-M., V.M.-G.)., Miranda-Garrido V; Department of Obstetrics, Hospital Materno-Infantil, La Paz, Bolivia (L.T.-J., L.L.-V., A.E.M.-M., V.M.-G.)., Shortt JA; Department of Biomedical Informatics (K.A.O., J.A.H., J.A.S., C.J.M., H.Y., C.G.J.), University of Colorado School of Medicine, Aurora, CO., Matarazzo CJ; Department of Biomedical Informatics (K.A.O., J.A.H., J.A.S., C.J.M., H.Y., C.G.J.), University of Colorado School of Medicine, Aurora, CO., Yasini H; Department of Biomedical Informatics (K.A.O., J.A.H., J.A.S., C.J.M., H.Y., C.G.J.), University of Colorado School of Medicine, Aurora, CO., Burton GJ; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.)., Moore LG; Department of Obstetrics and Gynecology, Division of Reproductive Sciences (J.A.H., L.G.M.), University of Colorado School of Medicine, Aurora, CO., Simonson TS; Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine (K.A.O., W.G., T.S.S.), University of California San Diego, La Jolla, CA., Murray AJ; Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom (K.A.O., L.M.W.H., H.W.Y., J.L.A., A.P.S., R.B., P.M.D., G.J.B., A.J.M.)., Julian CG; Department of Biomedical Informatics (K.A.O., J.A.H., J.A.S., C.J.M., H.Y., C.G.J.), University of Colorado School of Medicine, Aurora, CO.
Jazyk:	angličtina
Zdroj:	Hypertension (Dallas, Tex. : 1979) [Hypertension] 2024 Feb; Vol. 81 (2), pp. 319-329. Date of Electronic Publication: 2023 Nov 29.
DOI:	10.1161/HYPERTENSIONAHA.123.21748
Abstrakt:	Background: The chronic hypoxia of high-altitude residence poses challenges for tissue oxygen supply and metabolism. Exposure to high altitude during pregnancy increases the incidence of hypertensive disorders of pregnancy and fetal growth restriction and alters placental metabolism. High-altitude ancestry protects against altitude-associated fetal growth restriction, indicating hypoxia tolerance that is genetic in nature. Yet, not all babies are protected and placental pathologies associated with fetal growth restriction occur in some Andean highlanders. Methods: We examined placental metabolic function in 79 Andeans (18-45 years; 39 preeclamptic and 40 normotensive) living in La Paz, Bolivia (3600-4100 m) delivered by unlabored Cesarean section. Using a selection-nominated approach, we examined links between putatively adaptive genetic variation and phenotypes related to oxygen delivery or placental metabolism. Results: Mitochondrial oxidative capacity was associated with fetal oxygen delivery in normotensive but not preeclamptic placenta and was also suppressed in term preeclamptic pregnancy. Maternal haplotypes in or within 200 kb of selection-nominated genes were associated with lower placental mitochondrial respiratory capacity ( PTPRD [protein tyrosine phosphatase receptor-δ]), lower maternal plasma erythropoietin ( CPT2 [carnitine palmitoyl transferase 2], proopiomelanocortin, and DNMT3 [DNA methyltransferase 3]), and lower VEGF (vascular endothelial growth factor) in umbilical venous plasma ( TBX5 [T-box transcription factor 5]). A fetal haplotype within 200 kb of CPT2 was associated with increased placental mitochondrial complex II capacity, placental nitrotyrosine, and GLUT4 (glucose transporter type 4) protein expression. Conclusions: Our findings reveal novel associations between putatively adaptive gene regions and phenotypes linked to oxygen delivery and placental metabolic function in highland Andeans, suggesting that such effects may be of genetic origin. Our findings also demonstrate maladaptive metabolic mechanisms in the context of preeclampsia, including dysregulation of placental oxygen consumption. Competing Interests: Disclosures None.
Databáze:	MEDLINE
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