Sea‐level haemoglobin concentration is associated with greater exercise capacity in Tibetan males at 4200 m

Wagner, Peter D.; Simonson, Tatum S.; Guan, Wei; Wagner, Harrieth; Wuren, Tana; Ga, Qin; Yan, Ma; Ge, Ri Li

doi:10.1113/ep085036

Cited by 14 publications

(13 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unlike high VO 2 max, the adaptive benefit of lower [Hb] in Tibetans is not clear, given opposing effects of [Hb] on O 2 delivery (i.e., increased blood flow and tissue perfusion vs. decreased blood oxygen content). Interestingly, 1 study shows higher VO 2 max in Tibetans with lower [Hb] (42) and underscores a strength of the current study. That is, inferring genetic adaptation depends on identifying a phenotype with adaptive benefit (criteria 1).…”

Section: Discussionsupporting

confidence: 58%

Association ofEGLN1gene with high aerobic capacity of Peruvian Quechua at high altitude

Brutsaert

Kiyamu

Revollendo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (L⋅min−1 and mL⋅min−1⋅kg−1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min−1⋅kg−1 vs. CC = 30.5 mL⋅min−1⋅kg−1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.

show abstract

Section: Discussionsupporting

confidence: 58%

Association ofEGLN1gene with high aerobic capacity of Peruvian Quechua at high altitude

Brutsaert

Kiyamu

Revollendo

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…State-specific results also indicate a genome-level association with minimum SpO 2 during NREM sleep (S5 Table). Hexokinase is the first enzyme and the rate-limiting step in the glycolysis pathway [30,31] and its activity is regulated by hypoxia inducible factor 1a ( HIF1A ) [5,32,33]. Obstructive sleep apnea following CPAP withdrawal increases glucose during sleep [34].…”

Section: Discussionmentioning

confidence: 99%

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep

et al. 2019

View full text Add to dashboard Cite

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p < 1 × 10 −6 were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO 2 (rs78136548 p = 2.70 × 10 −10 ). SNPs at 10q22 were associated with all three traits including average SpO 2 (rs72805692 p = 4.58 × 10 −8 ). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia.

show abstract

“…Birth weight, developmental processes, patterns of ventilatory control, cardiac and cerebral adaptations, nitric oxide levels and oxygen utilization are collectively distinct in each population (Moore, 2001;Beall et al 2006;Gilbert-Kawai et al 2014;Petousi & Robbins, 2014;Simonson, 2015). Clearly, relatively lower [Hb], while a hallmark of Tibetan physiology and of recent focus in the high-altitude genomics literature, is not the only factor involved in Tibetan adaptation and may influence or be the result of changes at one or more steps of the oxygen transport system Wagner et al 2015). The timing and sequence of adaptive events, as estimated by genetic dating, and links with molecular and physiological functions will provide valuable insights into the sequence of evolutionary changes in this unique population (Simonson, 2015).…”

Section: Adaptations Over Many Generations In Tibetan Highlandersmentioning

confidence: 99%

“…Interdisciplinary studies will be necessary not only to uncover associations between genetic variants and whole-system physiology but for unravelling the sequence of events and orchestrated mechanisms that have resulted in the current physiological state of the Tibetan population. Searching for and then dating genetic changes associated not only with [Hb] but also with other components of oxygen transport Wagner et al 2015) will be helpful in resolving the direct targets of selection and order of adaptive events. Thus far, different dates are estimated for positive selection (ranging from ß3000 years (Yi et al 2010), ß18,000 years (Peng et al 2011) and ß12,803 years) in a region of the genome that contains a nearly Tibetan-specific copy-number deletion downstream of the EPAS1 gene (Lou et al 2015).…”

Section: Genetic Relationships and Insights Beyond Haemoglobin Concenmentioning

confidence: 99%

Adaptive genetic changes related to haemoglobin concentration in native high‐altitude Tibetans

Simonson

Huff

Witherspoon

et al. 2015

Experimental Physiology

Self Cite

View full text Add to dashboard Cite

New Findings r What is the topic of this review?Tibetans have genetic adaptations that are hypothesized to underlie the distinct set of traits they exhibit at altitude. r What advances does it highlight?Several adaptive signatures in the same genomic regions have been identified among Tibetan populations resident throughout the Qinghai-Tibetan Plateau. Many highland Tibetans exhibit a haemoglobin concentration within the range expected at sea level, and this trait is associated with putatively adaptive regions harbouring the hypoxia-inducible factor pathway genes EGLN1, EPAS1 and PPARA. Precise functional variants at adaptive loci and relationships to physiological traits, beyond haemoglobin concentration, are currently being examined in this population.Some native Tibetan, Andean and Ethiopian populations have lived at altitudes ranging from 3000 to >4000 m above sea level for hundreds of generations and exhibit distinct combinations of traits at altitude. It was long hypothesized that genetic factors contribute to adaptive differences in these populations, and recent advances in genomics provide evidence that some of the strongest signatures of positive selection in humans are those identified in Tibetans. Many of the top adaptive genomic regions highlighted thus far harbour genes related to hypoxia sensing and response. Putatively adaptive copies of three hypoxia-inducible factor pathway genes, EPAS1, EGLN1 and PPARA, are associated with sea-level range, rather than elevated, haemoglobin concentration observed in many Tibetans at high altitude, and recent studies provide insight into some of the precise adaptive variants, timing of adaptive events and functional roles. While several studies in highland Tibetans have converged on a few hypoxia-inducible factor pathway genes, additional candidates have been reported in independent studies of Tibetans located throughout the Qinghai-Tibetan Plateau. Various aspects of adaptive significance have yet to be identified, integrated, and fully explored. Given the rapid technological advances and interdisciplinary efforts in genomics, physiology and molecular biology, careful examination of Tibetans and comparisons with other distinctively adapted highland populations will provide valuable insight into evolutionary processes and models for both basic and clinical research.

show abstract

Sea‐level haemoglobin concentration is associated with greater exercise capacity in Tibetan males at 4200 m

Cited by 14 publications

References 25 publications

Association ofEGLN1gene with high aerobic capacity of Peruvian Quechua at high altitude

Association ofEGLN1gene with high aerobic capacity of Peruvian Quechua at high altitude

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep

Adaptive genetic changes related to haemoglobin concentration in native high‐altitude Tibetans

Contact Info

Product

Resources

About