Variation in human ventilatory control—genetic influence on the hypoxic ventilatory response
Introduction
Indications of variation in ventilatory control among human subjects were evident in the demonstration in the 1950s of inter-individual differences in the ventilatory response to hypercapnia (Schaeffer, 1958). The subsequent finding that hypercapnic responses in the Enga tribesman of New Guinea were lower than those in Caucasians led to the suggestion of a genetic effect (Beral and Read, 1971). However, studies in mono- and dizygotic twins failed to detect a genetic contribution to the hypercapnic ventilatory response although an influence on ventilatory pattern was suggested (Arkinstall et al., 1974).
Early studies of variation of the ventilatory response to hypoxia showed profound decreases in persons native to high altitude (Severinghaus et al., 1966) which appeared to be acquired during long-term altitude exposure (Weil et al., 1971, Byrne-Quinn et al., 1972). Investigation of more subtle variation among low altitude populations was facilitated by the development of methods for accurate assessment of oxygenation by measurement of end-tidal oxygen tensions or oximetry. The use of continuous progressive hypoxia with gradual reduction of end-tidal oxygen tensions from hyperoxic levels to values near 40 torr with breath-to-breath data acquisition provided a more detailed description of the response than previous approaches. These, together with active real-time maintenance of constant CO2 tensions during hypoxic hyperventilation also improved precision in estimation of the hypoxic ventilatory response. Measurements with these techniques showed that the hypoxic response in normal human subjects showed considerable inter-individual variation spanning a range of 7-fold (Fig. 1, top panel) (Hirshman et al., 1975, Weil and Zwillich, 1976)
It also appeared that these responses were non-randomly distributed within the general population. Low responses were found in athletes, particularly in distance runners (Byrne-Quinn et al., 1971, Schoene et al., 1981, Bjurstrom and Schoene, 1987, Ohyabu et al., 1990). It was found that these decreases in hypoxic response could not be induced in unconditioned subjects by athletic training (Levine et al., 1992, Markov et al., 1996), although clearly no studies were able to duplicate the kind of very long term training of the conditioned serious athlete. Conversely, high hypoxic responses were found in mountain climbers capable of unusually high altitude climbs (Schoene, 1982, Masuyama et al., 1986) and low responses in subjects who adapt poorly to altitude (Moore et al., 1986, Matsuzawa et al., 1989).
Section snippets
Family studies
Clues to inter-individual linkage of the magnitude of the hypoxic ventilatory response came from observations in patients with unexplained hypoventilation. In the early 1970s D.W. Hudgel, during his Fellowship in Pulmonary Disease observed an asthmatic patient who had frequent episodes of hypoventilation and severe hypoxemia. His airway obstruction was mild and seemed insufficient to explain these occurrences. Studies of the patient's ventilatory responses during asthmatic remission showed
Studies in twins
Accordingly, studies to explore the role of genetic effects were undertaken to compare responses among healthy mono- and dizygotic twins. The approach was to compare similarity of responses between the two members of a twin pair (within-pair variance) for the two classes of twins. The extent to which there was greater similarity of responses within pairs of monozygotic (identical) twins, measured as within-pair variance, compared to that of dizyogotic (fraternal) twins is taken as an indicator
Studies in animals
Animal studies have found apparent inter-species variation in hypoxic response possibly reflecting genetic effects. Bar-headed geese, a species endowed with capacity to fly to exceptionally high altitudes, have reduced, or left-shifted, ventilatory response to hypoxia compared to the low altitude pekin duck (Black and Tenney, 1980). These inter-species differences were evident in birds born and maintained at low altitude. Differences in hypoxic response are also reported among in-bred rodent
Conclusion
Thus ventilatory responses to hypoxia vary among human subjects with familial clusters, which together with concordance among identical twins points to a genetic influence. This is evident with studies of small sample size suggesting a strong genetic effect, which seems substantially greater for the hypoxic than the hypercapnic response. Selectivity for the hypoxic response and results of rapid reversal of hypoxia point to an effect on peripheral chemosensitivity and studies in animals suggest
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