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Genomic Selection Signals in Andean Highlanders Reveal Adaptive Placental Metabolic Phenotypes That Are Disrupted in Preeclampsia.
O'Brien, Katie A; Gu, Wanjun; Houck, Julie A; Holzner, Lorenz M W; Yung, Hong Wa; Armstrong, Jenna L; Sowton, Alice P; Baxter, Ruby; Darwin, Paula M; Toledo-Jaldin, Lilian; Lazo-Vega, Litzi; Moreno-Aramayo, Any Elena; Miranda-Garrido, Valquiria; Shortt, Jonathan A; Matarazzo, Christopher J; Yasini, Hussna; Burton, Graham J; Moore, Lorna G; Simonson, Tatum S; Murray, Andrew J; Julian, Colleen G.
Affiliation
  • 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.).
  • 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.
  • 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.
  • Holzner LMW; 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.
  • Yung HW; Herbert Wertheim School of Public Health and Longevity Sciences (W.G.), University of California San Diego, La Jolla, CA.
  • Armstrong JL; 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.
  • Sowton AP; Department of Obstetrics and Gynecology, Division of Reproductive Sciences (J.A.H., L.G.M.), University of Colorado School of Medicine, Aurora, CO.
  • 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 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.).
  • Lazo-Vega L; 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.).
  • Moreno-Aramayo AE; 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.).
  • Miranda-Garrido V; 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.).
  • Shortt JA; Department of Obstetrics, Hospital Materno-Infantil, La Paz, Bolivia (L.T.-J., L.L.-V., A.E.M.-M., V.M.-G.).
  • Matarazzo CJ; Department of Obstetrics, Hospital Materno-Infantil, La Paz, Bolivia (L.T.-J., L.L.-V., A.E.M.-M., V.M.-G.).
  • Yasini H; Department of Obstetrics, Hospital Materno-Infantil, La Paz, Bolivia (L.T.-J., L.L.-V., A.E.M.-M., V.M.-G.).
  • Burton GJ; Department of Obstetrics, Hospital Materno-Infantil, La Paz, Bolivia (L.T.-J., L.L.-V., A.E.M.-M., V.M.-G.).
  • Moore LG; 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.
  • Simonson TS; 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.
  • Murray AJ; 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.
  • Julian CG; 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.).
Hypertension ; 81(2): 319-329, 2024 Feb.
Article in En | MEDLINE | ID: mdl-38018457
ABSTRACT

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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Placenta / Pre-Eclampsia Limits: Female / Humans / Pregnancy Language: En Journal: Hypertension Year: 2024 Type: Article
Fulltext
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PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Placenta / Pre-Eclampsia Limits: Female / Humans / Pregnancy Language: En Journal: Hypertension Year: 2024 Type: Article