A comparison of genetic variants between proficient low- and high-risk sport participants.

Athletes participating in high-risk sports consistently report higher scores on sensation-seeking measures than do low-risk athletes or non-athletic controls. To determine whether genetic variants commonly associated with sensation seeking were over-represented in such athletes, proficient practitioners of high-risk (n = 141) and low-risk sports (n = 132) were compared for scores on sensation seeking and then genotyped at 33 polymorphic loci in 14 candidate genes. As expected, athletes participating in high-risk sports score higher on sensation seeking than did low-risk sport athletes (P < .01). Genotypes were associated with high-risk sport participation for two genes (stathmin, (P = .004) and brain-derived neurotrophic factor (P = .03)) as well as when demographically matched subsets of the sport cohorts were compared (P < .05); however, in all cases, associations did not survive correction for multiple testing.

Variants in the dopamine-4-receptor gene promoter are not associated with sensation seeking in skiers.

Sensation seeking is a personality trait that has been associated with disinhibited behaviours including substance use and gambling, but also with high-risk sport practices including skydiving, paragliding, and downhill skiing. Twin studies have shown that sensation seeking is moderately heritable, and candidate genes encoding components involved in dopaminergic transmission have been investigated as contributing to this type of behaviour. To determine whether variants in the regulatory regions of the dopamine-4-receptor gene (DRD4) influenced sport-specific sensation seeking, we analyzed five polymorphisms (-1106T/C, -906T/C, -809G/A, -291C/T, 120-bp duplication) in the promoter region of the gene in a cohort of skiers and snowboarders (n = 599) that represented a broad range of sensation seeking behaviours. We grouped subjects by genotype at each of the five loci and compared impulsive sensation seeking and domain-specific (skiing) sensation seeking between groups. There were no significant associations between genotype(s) and general or domain-specific sensation seeking in the skiers and snowboarders, suggesting that while DRD4 has previously been implicated in sensation seeking, the promoter variants investigated in this study do not contribute to sensation seeking in this athlete population.

Acute mountain sickness is not repeatable across two 12-hour normobaric hypoxia exposures.

OBJECTIVE: The purposes of this experiment were to determine the repeatability of acute mountain sickness (AMS), AMS symptoms, and physiological responses across 2 identical hypoxic exposures. METHODS: Subjects (n = 25) spent 3 nights at simulated altitude in a normobaric hypoxia chamber: twice at a partial pressure of inspired oxygen (PIO2) of 90mmHg (4000 m equivalent; "hypoxia") and once at a PIO2 of 132 mmHg (1000 m equivalent; "sham") with 14 or more days between exposures. The following variables were measured at hours 0 and 12 of each exposure: AMS severity (ie, Lake Louise score [LLS]), AMS incidence (LLS ≥3), heart rate, oxygen saturation, blood pressure, and the fraction of exhaled nitric oxide. Oxygen saturation and heart rate were also measured while subjects slept. RESULTS: The incidence of AMS was not statistically different between the 2 exposures (84% vs 56%, P > .05), but the severity of AMS (ie, LLS) was significantly lower on the second hypoxic exposure (mean [SD], 3.1 [1.8]) relative to the first hypoxic exposure (4.8 [2.3]; P < .001). Headache was the only AMS symptom to have a significantly greater severity on both hypoxic exposures (relative to the sham exposure, P < .05). Physiological variables were moderately to strongly repeatable (intraclass correlation range 0.39 to 0.86) but were not associated with AMS susceptibility (P > .05). CONCLUSIONS: The LLS was not repeatable across 2 identical hypoxic exposures. Increased familiarity with the environment (not acclimation) could explain the reduced AMS severity on the second hypoxic exposure. Headache was the most reliable AMS symptom.

A prospective epidemiological study of acute mountain sickness in Nepalese pilgrims ascending to high altitude (4380 m).

BACKGROUND: Each year, thousands of pilgrims travel to the Janai Purnima festival in Gosainkunda, Nepal (4380 m), ascending rapidly and often without the aid of pharmaceutical prophylaxis. METHODS: During the 2012 Janai Purnima festival, 538 subjects were recruited in Dhunche (1950 m) before ascending to Gosainkunda. Through interviews, subjects provided demographic information, ratings of AMS symptoms (Lake Louise Scores; LLS), ascent profiles, and strategies for prophylaxis. RESULTS: In the 491 subjects (91% follow-up rate) who were assessed upon arrival at Gosainkunda, the incidence of AMS was 34.0%. AMS was more common in females than in males (RR = 1.57; 95% CI = 1.23, 2.00), and the AMS incidence was greater in subjects >35 years compared to subjects ≤35 years (RR = 1.63; 95% CI = 1.36, 1.95). There was a greater incidence of AMS in subjects who chose to use garlic as a prophylactic compared to those who did not (RR = 1.69; 95% CI = 1.26, 2.28). Although the LLS of brothers had a moderate correlation (intraclass correlation = 0.40, p = 0.023), sibling AMS status was a weak predictor of AMS. CONCLUSIONS: The incidence of AMS upon reaching 4380 m was 34% in a large population of Nepalese pilgrims. Sex, age, and ascent rate were significant factors in the development of AMS, and traditional Nepalese remedies were ineffective in the prevention of AMS.

Twin studies in altitude and hypoxia research.

Humans exhibit high individual variation in response to acute hypoxia exposure. A number of published studies have used a classic 'twin study' model, comparing responses within pairs of monozygotic and dizygotic twins, to separate genetic from environmental contributions to the variation in altitude acclimatization. Available data suggest that some aspects of acclimatization have a heritable component. Most prominent is the hypoxic ventilatory response (HVR), which was repeatedly shown to be heritable in a number of age groups spanning infancy to adulthood (F-ratio range: 2.03 to 5.26). The ventilatory response to hypercapnia appears to only be heritable when tested in hypoxic conditions, providing additional evidence for a genetic component to the HVR (F-ratio range: 0.31, 6.92). A number of studies reported an estimate of heritability for more general hypoxic responses, such as heart rate, blood pressure, and blood gases; however, many of these studies relied on relatively small sample sizes and used inaccurate estimates of heritability and thus provided inconclusive evidence to elucidate the source of variation. Future genetic inquiries into the basis of variation in altitude acclimatization might benefit from further use of the classic twin study model: these experiments could identify the specific endophenotypes of altitude acclimatization that are heritable and therefore promising candidates for subsequent molecular studies, such as candidate-gene or genome-wide association studies.

Is poor sleep quality at high altitude separate from acute mountain sickness? Factor structure and internal consistency of the Lake Louise Score Questionnaire.

BACKGROUND: The factor structure and internal consistency of the Lake Louise Score Questionnaire (LLSQ) have not been determined in a large population at high altitude; however, a single-factor structure and a high internal consistency are preferable for accurate clinical and research applications of the LLSQ. METHODS: A large group of Nepalese pilgrims (n=491) were assessed for acute mountain sickness with a verbal Nepali translation of the LLSQ after rapidly ascending from 1950 m to 4380 m. The factor structure and internal consistency of the LLSQ were determined with a confirmatory factor analysis (CFA) and the ordinal alpha coefficient, respectively. RESULTS: A one-factor structure with all five items of the LLSQ was accepted. Four items (headache, gastrointestinal upset, fatigue/weakness, and dizziness/lightheadedness) loaded strongly on this factor (>0.70), but sleep quality had a low factor loading (0.33). The internal consistency (ordinal alpha coefficient) was 0.79, but removing the sleep quality item improved this value to 0.84. CONCLUSIONS: The sleep quality item of the LLSQ was weakly related to the other items of the LLSQ. Future research should further investigate whether impaired sleep at altitude should be considered separately from other symptoms of AMS.

Evaluation of the Balance Error Scoring System (BESS) in the diagnosis of acute mountain sickness at 4380 m.

Ascent to altitude is associated with a decrease in balance; however, the effect of acute mountain sickness (AMS) status on balance is variable depending on the test used and the altitude at which the test is performed. Here, we report preliminary findings on the relationship between the balance error scoring system (BESS) and AMS at the 2010 Janai Purnima festival at Gosainkunda, Nepal (4380 m). All subjects (n=37) completed a shortened BESS test (mBESS) while a subset completed the full BESS test (n=27). Pulse oximetry was used to measure heart rate and oxygen saturation, and blood pressure was measured by sphygmomanometer. Balance test scores (BESS and mBESS) and physiological measurements were compared between groups with AMS (AMS⁺) and without AMS (AMS⁻). Receiver-operator characteristic (ROC) curves were used to compare the abilities of the BESS and mBESS tests to correctly identify the AMS status of subjects. The AMS⁺ group had significantly higher Lake Louise scores than the AMS⁻ group (mean=4.0 (standard deviation=1.3) vs. 0.3 (0.6), p<0.001). The AMS⁺ group also scored significantly higher on both the mBESS (6.6 (3.5) vs. 2.7 (1.7) errors, p=0.018) and the BESS tests (19.2 (8.8) vs. 10.4 (6.0) errors, p=0.001) compared to the AMS⁻ group, indicating inferior balance in the AMS⁺ group. The area under the ROC curve was significantly greater for the BESS test (0.895) compared to the mBESS test (0.690, p=0.02), implying that the full BESS test more accurately identified a subject's AMS status. Additional studies are needed to determine if BESS could be a useful adjunct to the clinical diagnosis of AMS.

Human genetic variation: new challenges and opportunities for doping control.

Sport celebrates differences in competitors that lead to the often razor-thin margins between victory and defeat. The source of this variation is the interaction between the environment in which the athletes develop and compete and their genetic make-up. However, a darker side of sports may also be genetically influenced: some anti-doping tests are affected by the athlete's genotype. Genetic variation is an issue that anti-doping authorities must address as more is learned about the interaction between genotype and the responses to prohibited practices. To differentiate between naturally occurring deviations in indirect blood and urine markers from those potentially caused by doping, the "biological-passport" program uses intra-individual variability rather than population values to establish an athlete's expected physiological range. The next step in "personalized" doping control may be the inclusion of genetic data, both for the purposes of documenting an athlete's responses to doping agents and doping-control assays as well facilitating athlete and sample identification. Such applications could benefit "clean" athletes but will come at the expense of risks to privacy. This article reviews the instances where genetics has intersected with doping control, and briefly discusses the potential role, and ethical implications, of genotyping in the struggle to eliminate illicit ergogenic practices.

The effects of exercise in hypoxic and normoxic conditions on endothelin-1 and arterial compliance.

The purpose of this study was to determine the effects of short-term normoxic and hypoxic exercise on plasma endothelin-1 and nitric oxide levels, and the relationship of arterial compliance and pulmonary artery pressure to endothelin-1. Seven endurance-trained males completed two incremental and two steady-state exercise tests performed at ventilatory threshold in normoxia and hypoxia (fraction of inspired oxygen = 0.14). Plasma endothelin-1was measured throughout steady-state tests. Arterial compliance using applanation tonometry, plasma nitric oxide and pulmonary artery pressure using Doppler echocardiography were measured before and after exercise. Small arterial compliance and pulmonary artery pressure significantly increased following exercise. There were no main effects of condition or time for plasma endothelin-1and nitric oxide levels. There were no significant relationships between plasma endothelin-1 and arterial compliance or pulmonary artery pressure. In conclusion, mechanisms other than the endothelial system may play a role in the exercise-induced changes in small artery compliance in this study population. Moderate hypoxia and a 30-minute steady-state exercise have limited effects on plasma endothelin-1 in endurance-trained males.

'ome on the Range: altitude adaptation, positive selection, and Himalayan genomics.

In 2010, a number of papers were published describing data from genome-wide studies designed to identify genes and genetic variants that contribute (or contributed) to human adaptation to altitude in the Himalaya. The results were exciting, intriguing, and controversial. Several genes, most notably EGLN1 and EPAS1, were identified as strong candidates for a role in evolutionary adaptation to high altitude, and the time course over which this adaptation occurred was calculated by one team to be remarkably brief. Overall, the data suggest that, at least in the ancestors of the modern Tibetans, there was a powerful selective pressure favoring variants in genes central to the molecular response to hypoxia. The most obvious manifestation of this selection seems to be the Tibetan's well known blunted erythropoietic response to hypoxemia. This article briefly reviews recent developments in 'omic' analysis of Tibetan highland natives, with a focus both on the answers found and the questions raised.

The genetics of altitude tolerance: the evidence for inherited susceptibility to acute mountain sickness.

OBJECTIVE: Acute mountain sickness (AMS) has become a significant environmental health issue as improvements in transportation, "environmental tourism," and resource development lure more people to the highlands. Whether there is a genetic contribution to AMS susceptibility is a central question in high-altitude medicine. This article provides a systematic review of the evidence supporting such an innate predisposition. METHODS: Scientific literature databases were screened using the terms "acute mountain sickness/AMS" and "altitude illness" combined with the terms "DNA," "gene," "genetic," or "polymorphism." RESULTS: Sixteen genes from a variety of pathways have been tested for association with AMS and variants in eight showed positive associations suggesting that AMS is an environmentally mediated polygenic disorder. CONCLUSIONS: The data suggest that genotype contributes to capacity to rapidly and efficiently acclimatize to altitude; nevertheless, the mechanisms by which this occurs have yet to be elucidated.

Evidence for a genetic basis for altitude illness: 2010 update.

Altitude illness refers to a group of environmentally mediated pathophysiologies. Many people will suffer acute mountain sickness shortly after rapidly ascending to a moderately hypoxic environment, and an unfortunate few will develop potentially fatal conditions such as high altitude pulmonary edema or high altitude cerebral edema. Some individuals seem to be predisposed to developing altitude illness, suggesting an innate contribution to susceptibility. The implication that there are altitude-sensitive and altitude-tolerant individuals has stimulated much research into the contribution of a genetic background to the efficacy of altitude acclimatization. Although the effect of altitude attained and rate of ascent on the etiology of altitude illness is well known, there are only tantalizing, but rapidly accumulating, clues to the genes that may be involved. In 2006, we reviewed what was then known about the genetics of altitude illness. This article updates that review and attempts to tabulate all the available genetic data pertaining to these conditions. To date, 58 genes have been investigated for a role in altitude illness. Of these, 17 have shown some association with the susceptibility to, or the severity of, these conditions, although in many cases the effect size is small or variable. Caution is recommended when evaluating the genes for which no association was detected, because a number of the investigations reviewed in this article were insufficiently powered to detect small effects. No study has demonstrated a clear-cut altitude illness gene, but the accumulating data are consistent with a polygenic condition with a strong environmental component. The genes that have shown an association affect a variety of biological pathways, suggesting that either multiple systems are involved in altitude pathophysiology or that gene-gene interactions play a role. Although numerous studies have been performed to investigate specific genes, few have looked for evidence of heritability or familial transmission, or for epidemiological patterns that would be consistent with genetically influenced conditions. Future trends, such as genome-wide association studies and epigenetic analysis, should lead to enhanced understanding of the complex interactions within the genome and between the genome and hypoxic environments that contribute to an individual's capacity to acclimatize rapidly and effectively to altitude.

No association between alleles of the bradykinin receptor-B2 gene and acute mountain sickness.

The pathophysiological mechanism(s) of the development of acute mountain sickness (AMS) is still unclear. Although the chance of developing AMS and the severity of the condition are influenced by ascent rate and altitude attained, previous history is a reliable predictor of subsequent affliction, and some individuals and families are clearly predisposed, suggesting a genetic component to susceptibility. As the vasodilator bradykinin may be involved in acclimatization to altitude, we hypothesized that variants in genes encoding components of this pathway might play a role in AMS susceptibility. We tested this by looking for associations between two functional polymorphisms (the in/del polymorphism +9/-9 [rs5810761] and the single-nucleotide polymorphism C--58T [rs1799722]) of BDKRB2 (the gene encoding the bradykinin receptor B2) and susceptibility to AMS in an altitude-exposed Nepalese population. Lowland attendees (n = 233) at a religious festival at 4380 m in the Nepalese Himalaya were recruited and assessed for AMS by clinical evaluation and Lake Louise score (LLS). Those with a clinical diagnosis of AMS and an LLS >or=3 were designated AMS+ (n = 100) and those without a diagnosis of AMS and with an LLS <3 were categorized as AMS- (n = 117). DNA was prepared from buccal cells, genotyped for the two polymorphisms and allele frequencies compared between the two cohorts. No association was found between alleles at either polymorphism and susceptibility to AMS (P > 0.50), although C - 58T heterozygotes were significantly more common (P < 0.001, chi(2) = 49.6) in the subjects than would be predicted if the population was in Hardy-Weinberg equilibrium. The results of our association study do not support the hypothesis that variants in BDKRB2 influence altitude tolerance in a lowland Nepalese population; however, the deviation from Hardy-Weinberg equilibrium observed for the C - 58T polymorphism could be explained by self-selection for altitude tolerance in the festival attendees.

A variant of the endothelial nitric oxide synthase gene (NOS3) associated with AMS susceptibility is less common in the Quechua, a high altitude Native population.

Endothelial nitric oxide synthase (eNOS) is a vascular enzyme that produces nitric oxide, a transient signaling molecule that by vasodilatation regulates blood flow and pressure. Nitric oxide is believed to play roles in both short-term acclimatization and long-term evolutionary adaptation to environmental hypoxia. Several laboratories, including ours, have shown that variants in NOS3 (the gene encoding eNOS) are overrepresented in individuals with altitude-related illnesses such as high altitude pulmonary edema (HAPE) and acute mountain sickness (AMS), suggesting that NOS3 genotypes contribute to altitude tolerance. To further test our hypothesis that the G allele at the G894T polymorphism in NOS3 (dbSNP number: rs1799983; protein polymorphism Glu298Asp) is beneficial in hypoxic environments, we compared frequencies of this allele in an altitude-adapted Amerindian population, Quechua of the Andean altiplano, with those in a lowland Amerindian population, Maya of the Yucatan Peninsula. While common in both populations, the G allele was significantly more frequent in the highlanders. Taken together, our data suggest that this variant in NOS3, which has been previously associated with higher levels of nitric oxide, contributes to both acclimatization and adaptation to altitude.

Genotype at the missense G894T polymorphism (Glu298Asp) in the NOS3 gene is associated with susceptibility to acute mountain sickness.

Acute mountain sickness (AMS) is a potentially serious affliction that frequently occurs in travelers to altitudes above 2500 m. The probability of developing AMS depends on environmental factors such as rate of ascent and altitude attained; however, familial clustering and recurrence rates suggest that there may be a genetic contribution to the etiology of the condition. The underlying pathophysiology of AMS is unknown, but it may involve vasogenic edema secondary to hypoxia-induced sympathetic response and endothelial dysfunction. Nitric oxide is a potent vasomodulator, and variants in the gene that encodes endothelial nitric oxide synthase (NOS3) have been shown to affect blood pressure. We tested the hypothesis that haplotypes, as determined by tagSNPs, in NOS3 would be differentially represented in individuals with and without AMS sampled at the Janai Purnima Festival at Lake Gosain Kunda, Nepal, at 4380 m. Seven SNPs were tested, and a highly significant association (p = 0.004) was found for genotypes of the commonly studied missense polymorphism Glu298Asp (rs 1799983; G/T transversion at base 894). The T allele, which previously has been associated with hypertension, was overrepresented in individuals with AMS (0.30 vs. 0.10), but not significantly when the data were corrected for multiple testing (p = 0.024). These data suggest that a variant in a gene involved in nitric oxide synthesis is a risk factor for developing AMS.

Keeping pace with ACE: are ACE inhibitors and angiotensin II type 1 receptor antagonists potential doping agents?

In the decade since the angiotensin-converting enzyme (ACE) gene was first proposed to be a 'human gene for physical performance', there have been numerous studies examining the effects of ACE genotype on physical performance phenotypes such as aerobic capacity, muscle function, trainability, and athletic status. While the results are variable and sometimes inconsistent, and corroborating phenotypic data limited, carriers of the ACE 'insertion' allele (the presence of an alu repeat element in intron 16 of the gene) have been reported to have higher maximum oxygen uptake (VO2max), greater response to training, and increased muscle efficiency when compared with individuals carrying the 'deletion' allele (absence of the alu repeat). Furthermore, the insertion allele has been reported to be over-represented in elite athletes from a variety of populations representing a number of endurance sports. The mechanism by which the ACE insertion genotype could potentiate physical performance is unknown. The presence of the ACE insertion allele has been associated with lower ACE activity (ACEplasma) in number of studies, suggesting that individuals with an innate tendency to have lower ACE levels respond better to training and are at an advantage in endurance sporting events. This could be due to lower levels of angiotensin II (the vasoconstrictor converted to active form by ACE), higher levels of bradykinin (a vasodilator degraded by ACE) or some combination of the two phenotypes. Observations that individuals carrying the ACE insertion allele (and presumably lower ACEplasma) have an enhanced response to training or are over-represented amongst elite athletes raises the intriguing question: would individuals with artificially lowered ACEplasma have similar training or performance potential? As there are a number of drugs (i.e. ACE inhibitors and angiotensin II type 1 receptor antagonists [angiotensin receptor blockers--ARBs]) that have the ability to either reduce ACEplasma activity or block the action of angiotensin II, the question is relevant to the study of ergogenic agents and to the efforts to rid sports of 'doping'. This article discusses the possibility that ACE inhibitors and ARBs, by virtue of their effects on ACE or angiotensin II function, respectively, have performance-enhancing capabilities; it also reviews the data on the effects of these medications on VO2max, muscle composition and endurance capacity in patient and non-patient populations. We conclude that, while the direct evidence supporting the hypothesis that ACE-related medications are potential doping agents is not compelling, there are insufficient data on young, athletic populations to exclude the possibility, and there is ample, albeit indirect, support from genetic studies to suggest that they should be. Unfortunately, given the history of drug experimentation in athletes and the rapid appropriation of therapeutic agents into the doping arsenal, this indirect evidence, coupled with the availability of ACE-inhibiting and ACE-receptor blocking medications may be sufficiently tempting to unscrupulous competitors looking for a shortcut to the finish line.

Genomics and environmental hypoxia: what (and how) we can learn from the transcriptome.

Recent developments in molecular biology have shown that the classic "one gene, one RNA, one protein" model is inadequate to account for the transcriptional complexity apparent in higher organisms. Current understanding of the transcriptome (the -ome term for the entire complement of transcripts in a cell, tissue, or organism) suggests that genes can produce many different transcripts due to variable start and termination sites and alternate splicing, and that much of the extragenic (the region believed to lay outside genes) genome is also transcribed, producing a bewildering array of noncoding RNAs (ncRNA), including antisense transcripts and microRNAs that are thought to be involved in the posttranscriptional regulation of gene expression. As part of the attempt to understand this plethora of biological information, researchers have developed new technologies that permit the assessment of thousands of transcripts simultaneously. The resulting transcription profile provides a high-resolution and highly informative snapshot of gene activity in the tissue. The two most common of these methodological strategies are microarrays, which are based on hybridization technology, and serial (or cap) analysis of gene expression (SAGE or CAGE), which is based on DNA sequencing. This paper reviews the basic principles underlying these technologies and describes how they have been applied to understanding the molecular events that underlie the response to environmental hypoxia.

Inhaled salbutamol and doping control: effects of dose on urine concentrations.

OBJECTIVE: The present study was designed to examine the dose-response relationship of inhaled salbutamol and its concentration in the urine while resting at various times after inhalation, and to compare these values against the current World Anti-Doping Code limits. DESIGN: An interventional, repeated-measures design. SETTING: Sport Medicine Clinic, University of British Columbia (Vancouver, Canada). PARTICIPANTS: Eight healthy, nonasthmatic males participated in this study (age = 28 +/- 6 years, height = 179.4 +/- 5.1 cm, and weight = 77.4 +/- 5.4 kg). INTERVENTION: Administration of three different doses of inhaled salbutamol (800, 400, and 200 microg) in a randomized fashion separated by at least 72 hours. MAIN OUTCOME MEASUREMENT: Urine concentration of nonsulphated salbutamol RESULTS: Urine concentrations were highly variable between subjects and increased as dose increased, with a significant difference noted between 800 and 200 microg at 30, 60, and 120 minutes after inhalation. Urine concentrations of salbutamol peaked at 60 minutes for all doses. No samples exceeded the doping criterion of 1000 ng/mL, and the maximum value observed was 904 ng/mL. CONCLUSION: These results indicate that after inhalation of doses up to 800 microg, urinary concentrations of salbutamol are well below the limits used in doping control.

Common haplotypes in the beta-2 adrenergic receptor gene are not associated with acute mountain sickness susceptibility in Nepalese.

Acute Mountain Sickness (AMS), the most common and least serious of the altitude-related illnesses, is frequently experienced by sojourners traveling above 2500 m. Although altitude and rate of ascent are likely the most critical factors in determining whether the condition will develop in a person, interindividual variation and patterns of susceptibility suggest that there may be genetic risk factors as well. We hypothesized that variants in the gene that encodes the beta-2 adrenergic receptor (the principal catecholamine receptor in the lungs) are involved in the etiology of AMS and tested this hypothesis in cohorts of Nepalese individuals who developed or did not develop AMS when attending the Purnima Festival at Lake Gosain Kunda at 4380. Polymorphisms that could serve as markers for the common haplotypes encompassing the gene were chosen using the HapMap database. We found no association between any alleles at the seven highly informative polymorphic loci (tagSNPs) that we assayed and AMS status, suggesting that variants in, or near, the beta-2 adrenergic receptor gene do not contribute to AMS susceptibility in this population. This study is the first application of the HapMap database and associated haplotype mapping tools to the understanding of altitude-related pathologies.

Inspiratory muscle training attenuates the human respiratory muscle metaboreflex.

We hypothesized that inspiratory muscle training (IMT) would attenuate the sympathetically mediated heart rate (HR) and mean arterial pressure (MAP) increases normally observed during fatiguing inspiratory muscle work. An experimental group (Exp, n = 8) performed IMT 6 days per week for 5 weeks at 50% of maximal inspiratory pressure (MIP), while a control group (Sham, n = 8) performed IMT at 10% MIP. Pre- and post-training, subjects underwent a eucapnic resistive breathing task (RBT) (breathing frequency = 15 breaths min(-1), duty cycle = 0.70) while HR and MAP were continuously monitored. Following IMT, MIP increased significantly (P < 0.05) in the Exp group (-125 +/- 10 to -146 +/- 12 cmH(2)O; mean +/- s.e.m.) but not in the Sham group (-141 +/- 11 to -148 +/- 11 cmH(2)O). Prior to IMT, the RBT resulted in significant increases in HR (Sham: 59 +/- 2 to 83 +/- 4 beats min(-1); Exp: 62 +/- 3 to 83 +/- 4 beats min(-1)) and MAP (Sham: 88 +/- 2 to 106 +/- 3 mmHg; Exp: 84 +/- 1 to 99 +/- 3 mmHg) in both groups relative to rest. Following IMT, the Sham group observed similar HR and MAP responses to the RBT while the Exp group failed to increase HR and MAP to the same extent as before (HR: 59 +/- 3 to 74 +/- 2 beats min(-1); MAP: 84 +/- 1 to 89 +/- 2 mmHg). This attenuated cardiovascular response suggests a blunted sympatho-excitation to resistive inspiratory work. We attribute our findings to a reduced activity of chemosensitive afferents within the inspiratory muscles and may provide a mechanism for some of the whole-body exercise endurance improvements associated with IMT.