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The fa leptin receptor mutation and the heritability of respiratory frequency in a Brown Norway and Zucker intercross

¹Department of Epidemiology and Biostatistics, and ²Department of Ophthalmology, Case Western Reserve University, and ³Department of Medicine, Louis Stokes Veterans Affairs Medical Center, Case Western Reserve University, Cleveland, Ohio 44106

Submitted 5 November 2003 ; accepted in final form 15 March 2004

We sought to determine whether the fa (leptin receptor) mutation was a major determinant of the putative obesity effects on respiratory frequency in an intercross between the Brown Norway (low breathing frequency, nonobese strain) and the Zucker (moderately high breathing frequency, with the fa mutation) strains. The hypothesis was that rats bearing one (heterozygote) or two (homozygote) alleles of the Glu296Pro point mutation (fa) would have a uniformly high respiratory frequency in the second filial (F2) generation, compared with wild-type animals. In addition to breathing frequency, tidal volume and minute ventilation were assessed during baseline, acute hypoxic (10% O₂-0% CO₂-balance nitrogen), hypercapnic (93% O₂-7% CO₂), hyperoxic (100% O₂-0% CO₂), and combined (10% O₂-3% CO₂-balance nitrogen) challenges in fa homozygote (fa/fa; n = 24), fa heterozygote (fa/wt; n = 33), and wild-type (wt/wt; n = 19) animals. Phenotypes were adjusted with stepwise regression analyses for the effects of age, sex, length, and litter size. Broad-sense heritability was estimated by examining the variance of the traits in first filial and F2 generations. ANOVAs were used to determine the mode of inheritance of the fa allele in the F2 generation. As anticipated, weight demonstrated the greatest overall broad-sense heritability (77%) and was the result of the recessive mutation. Breathing parameters during the hypoxic, hypercapnic, and combined challenges demonstrated a wide range of heritability from 5 to 96%, with a very nonuniform proportion of heritability explained by the leptin receptor. At best, for frequency 4.5 min into the hypercapnic hypoxic challenge, 20% of the total heritability (67%) could be attributed to an effect of the leptin receptor mutation. We conclude that, unlike its major effect on weight, the effect of the fa allele is not a major gene involved in the regulation of breathing frequency.

minute ventilation; tidal volume; respiratory quotient; Glu296Pro mutation