Submitted on November 5, 2003
Accepted on March 15, 2004
The fa Leptin Receptor Mutation and the Heritability of Respiratory Frequency in a Brown Norway and Zucker Intercross
Sudha K Iyengar1, Catherine M Stein2, Karlie Russo2, Bernadette O Erokwu3, and Kingman P Strohl3*
1 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA; Department of Ophthalmology, Case Western Reserve University, Cleveland, OH, USA; Biostatistics and Epidemiology, MetroHealth Medical Center, Cleveland, OH, USA
2 Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, USA
3 Department of Medicine, Louis Stokes Cleveland DVA Medical Center, Cleveland, OH, USA
* To whom correspondence should be addressed. E-mail: kpstrohl{at}aol.com.
We sought to determine if the fa (leptin receptor) mutation was a major determinant of the putative obesity effects on respiratory frequency in an intercross between the Brown Norway (BN; low breathing frequency, non-obese strain) and the Zucker (Z; moderately high breathing frequency, with the fa mutation) strains. The hypothesis was that rats bearing one (heterozygote) or two alleles (homozygote) of the Glu296Pro point mutation (fa) would have a uniformly high respiratory frequency in the F2 generation, compared with wild type animals. In addition to breathing frequency (f), tidal volume (VT) and minute ventilation (VE) were assessed during baseline, acute hypoxic (10% O2, 0% CO2), hypercapnic (93% O2, 7% CO2), hyperoxic (100% O2, 0% CO2), and combined (10% O2, 3% CO2) challenges in fa homozygotes (fa/fa; n=24), fa heterozygotes fa/wt; n=33) and wild type (wt/wt; n=19) animals. Phenotypes were adjusted using 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 and second (F2) generations. Analyses of variance 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 5-96%, with a very non-uniform proportion of heritability explained by the leptin receptor. At best, heritability for frequency 4.5 minutes 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 leptin receptor fa allele is not a major gene involved in the regulation of frequency.
