Hypercapnic duty cycle is an intermediate physiological phenotype linked to mouse chromosome 5

We hypothesized that upper airway obstruction (UAO) leads to a compensatory increase in the duty cycle [ ratio of inspiratory time to respiratory cycle length (TI/TT)], which is determined by genetic factors. We examined the compensatory TI/TT responses to 1) UAO and hypercapnia among normal individuals and 2) hypercapnia in different inbred strains, C3H/HeJ (C3) and C57BL/6J (B6), and their first- and second-generation (F2) offspring. 3) We then used the compensatory TI/TT response in the F2 to determine genetic linkage to the mouse genome. First, normal individuals exhibited a similar increase in the TI/TT during periods of hypercapnia (0.11 +/- 0.07) and UAO (0.09 +/- 0.06) compared with unobstructed breathing (P < 0.01). Second, the F2 offspring of C3 and B6 progenitors showed an average TI/TT response to 3% CO2 (0.42 +/- 0.005%) that was significantly (P < 0.01) greater than that of the two progenitors. Third, with a peak log of the odds ratio score of 4.4, TI/TT responses of F2 offspring are genetically linked to an interval between 58 and 64 centimorgans (cM) on mouse chromosome 5. One gene in the interval, Dagk4 at 57 cM, is polymorphic for C3 and B6 mice. Two other genes, Adrbk2 at 60 cM and Nos1 at 65 cM, have biological plausibility in mechanisms of upper airway patency and chemosensitivity, respectively. In summary, TI/TT may serve as an intermediate physiological phenotype for compensatory neuromuscular response mechanisms for maintaining ventilation in the face of UAO and hypoventilation and to help target specific candidate genes that may play a role in the expression of sleep-disordered breathing.