Variability in hypoxic response: Could genetics play a role?

Simonson, Tatum S.; Malhotra, Atul

doi:10.1113/jp279590

Cited by 6 publications

(4 citation statements)

References 5 publications

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“…Considering that elderly individuals (Peterson et al 1981) and those with diabetes (Nishimura et al 1989;Weisbrod et al 2005) exhibit a decreased ventilatory response to hypoxia and comprise a large proportion of the population impacted by COVID-19, it is plausible these individuals may experience more silent hypoxaemia and rapid decompensation. Future studies could also reevaluate COVID-19 survivors who exhibited a range of ventilatory and/or dyspnoea profiles during active infection in a post-COVID-19, controlled experiment with targeted genetic assessments (Simonson & Malhotra, 2020). If high ventilatory drive is injurious, we would advocate randomized studies to suppress respiratory drive (using narcotic or benzodiazepine) in patients at high risk of respiratory failure and only in an intensive care unit setting.…”

Section: Research Directionsmentioning

confidence: 99%

Silent hypoxaemia in COVID‐19 patients

Simonson

Baker

Banzett

et al. 2021

The Journal of Physiology

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The clinical presentation of COVID‐19 due to infection with SARS‐CoV‐2 is highly variable with the majority of patients having mild symptoms while others develop severe respiratory failure. The reason for this variability is unclear but is in critical need of investigation. Some COVID‐19 patients have been labelled with ‘happy hypoxia’, in which patient complaints of dyspnoea and observable signs of respiratory distress are reported to be absent. Based on ongoing debate, we highlight key respiratory and neurological components that could underlie variation in the presentation of silent hypoxaemia and define priorities for subsequent investigation.

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Section: Research Directionsmentioning

confidence: 99%

Silent hypoxaemia in COVID‐19 patients

Simonson

Baker

Banzett

et al. 2021

The Journal of Physiology

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“…Individual genetic variants and epigenetic markers have been correlated with aspects of HAPE pathophysiology and susceptibility but validation of these isolated ‘hits’ is lacking ( Mortimer et al, 2004 ; Maloney and Broeckel, 2005 ; Simonson, 2015 ). Our understanding of how genomic influences relate to short- and long-term hypoxic and hypobaric physiology is limited in part due to isolated candidate genes analyses ( Simonson and Malhotra, 2020 ), limited sample sizes, and lack of stratification for genotype-phenotype analyses. Recently, chronic, as opposed to acute, altitude exposure has been identified as a potential cause of a type of “mountain residence” HAPE ( Ebert-Santos, 2017 ), challenging the paradigm that all HAPE is triggered by acute altitude exposure.…”

Section: Time Domain 4: Hypoxia and Disease Throughout The Life Coursementioning

confidence: 99%

Time Domains of Hypoxia Responses and -Omics Insights

Non

Heinrich

et al. 2022

Front. Physiol.

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The ability to respond rapidly to changes in oxygen tension is critical for many forms of life. Challenges to oxygen homeostasis, specifically in the contexts of evolutionary biology and biomedicine, provide important insights into mechanisms of hypoxia adaptation and tolerance. Here we synthesize findings across varying time domains of hypoxia in terms of oxygen delivery, ranging from early animal to modern human evolution and examine the potential impacts of environmental and clinical challenges through emerging multi-omics approaches. We discuss how diverse animal species have adapted to hypoxic environments, how humans vary in their responses to hypoxia (i.e., in the context of high-altitude exposure, cardiopulmonary disease, and sleep apnea), and how findings from each of these fields inform the other and lead to promising new directions in basic and clinical hypoxia research.

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“…Many genetic variants or single nucleotide polymorphisms (SNPs), but by no means all or even a disproportionate number, reside in the hypoxia-inducible factor (HIF) pathway (Bigham et al 2009), which is a key mechanism by which hypoxia activates more than 100 genes. Among them are some involved in the formation of blood vessels (VEGF, PDGF, FLT), red cell production (EPO), cell death (TGFA, TNF, MMP), inflammation (IL6), vasodilation or constriction (EDN, NOS, PRKAA1), glucose metabolism (IGFBP, PRKAA1) and others affecting the O 2 transport system (see Beall 2014, Julian 2019, Witt & Huerta-Sanchez 2019, Simonson & Malhotra 2020. With the exception of a missense mutation in the EGLN1 gene (Lorenzo et al 2014), all the other gene regions identified thus far are not unique to high-altitude populations but rather present in different frequencies than seen in low altitude groups, indicating that natural selection has principally acted upon standing variation rather than new alleles resulting from mutations.…”

Section: Introductionmentioning

confidence: 99%

HYPOXIA AND REPRODUCTIVE HEALTH: Reproductive challenges at high altitude: fertility, pregnancy and neonatal well-being

Moore

2021

Reproduction

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High altitude offers a natural laboratory for studying the effects of chronic hypoxia on reproductive health. Counter to early accounts, fertility (the number of livebirths) appears little affected although stillbirths are more common. Birth weights are lower due to fetal growth restriction, not shortened gestation. Multigenerational (Andean or Tibetan) compared with newcomer residents appear relatively protected from pregnancy loss as well as altitude-associated fetal growth restriction, perhaps due in part to preservation of the normal rise in uterine artery blood flow. Myometrial artery vasodilator response, a key determinant of uterine blood flow, is blunted in healthy Colorado high-altitude residents, similar to what occurs in IUGR or preeclampsia at low altitude. The high-altitude vessels are also more sensitive to the vasodilatory actions of adenosine monophosphate kinase (AMPK) activation. The gene region containing PRKAA1 (coding for AMPK’s alpha-1 catalytic subunit) has been acted upon by natural selection in Andeans and is related to preservation of normal blood flow and fetal growth at high altitude, suggesting one mechanism by which high-altitude adaptation may have been achieved. Preeclampsia is more common at high altitudes but unknown is whether multigenerational residents are protected relative to newcomers. Postnatal loss is diminished in Tibetans vs. Han with equal access to health care, perhaps due in part to better maintained arterial O2 saturation during infancy. Finally, pregnancy and intrauterine development not only affect immediate survival but also susceptibility to the later-in-life cardiovascular disease, chronic mountain sickness.

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Variability in hypoxic response: Could genetics play a role?

Cited by 6 publications

References 5 publications

Silent hypoxaemia in COVID‐19 patients

Silent hypoxaemia in COVID‐19 patients

Time Domains of Hypoxia Responses and -Omics Insights

HYPOXIA AND REPRODUCTIVE HEALTH: Reproductive challenges at high altitude: fertility, pregnancy and neonatal well-being

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