Identification and chromosomal localization of ecogenetic components of electrolyte excretion

To determine to what extent urinary excretion of blood pressure-modulating electrolytes is genetically determined, and to identify their chromosomal localization.

Twenty-six rat recombinant inbred strains (RIS) originating from reciprocal crosses of normotensive Brown Norway (BN.Lx) and spontaneously hypertensive rats (SHR) were used. A pilot experiment on a subset of strains determined that fasting decreases the impact of environmental noise and increases that of heritability. Twenty-four-hour urinary collections were obtained from fasting rats aged 6-12 weeks (3-8 rats per strain). Sodium (Na), potassium (K) and calcium (Ca) excretions were measured, and the Na/K ratio calculated. These phenotypes served as quantitative traits for the search of quantitative trait loci (QTLs) by scanning the RIS genome that was mapped with 475 polymorphic markers.

Constant Na intake resulted in a low heritability for Na excretion, reflecting the environmental impact (intake = excretion), whereas fasting revealed a gradient among RIS indicative of the genetic component of the traits. In the fasting state, a locus on chromosome 14 was found to be significantly associated with K excretion (Alb, P = 0.00002, r = -0.69, logarithm of the odds score (LOD) 3.9), whereas another locus on chromosome 10 (D10Cebrp97s5, P = 0.0003, r = -0.69, LOD 3.0) and one on chromosome 6 (D6Cebrp97s14, P = 0.0007, r = -0.65, LOD 1.9) were more significantly associated with Na excretion and the Na/K ratio respectively. The observed correlations were all negative for Na, K and Na/K, indicating a higher excretion of Na and K and a greater Na/K ratio in rats bearing BN.Lx alleles at these loci, i.e. salt retention in fasting SHR. These three loci accounted for 47-55% of variance of their associated trait, suggesting that they are the main genetic determinants for these phenotypes in basal fasting conditions. Rats bearing the Y chromosome of SHR origin had significantly higher K excretion that, in turn, led to a significantly lower Na/K ratio. Finally, a locus on chromosome 7 was linked to Ca excretion, explaining 46% of the trait variance (D7Mit10, LOD score 3.0).

RIS enabled us to determine QTLs for environmentally modulated traits such as Na, K and Ca excretions. We demonstrated that whereas urinary electrolytes are determined mainly by intake (environment) in a steady state, their excretion in an adaptive state (fasting) is predominantly genetically determined by distinct QTL on autosomes as well as the Y chromosome. Furthermore, the loci responsible for Na and K excretions act independently of the locus governing the relative excretion of Na/K. Thus, the salt-retaining aspects of some hypertensives may be, in large part, determined by genes responsible for renal excretion, the impact of which is predominant over the environment under acute challenge.