(Hypertension. 2001;38:e35.)
© 2001 American Heart Association, Inc.
Letters to the Editor |
Sodium-Lithium Countertransport Activity Is Linked to Chromosome 5 in Baboons
Niche Science & Technology Ltd, London, United Kingdom
Cardiovascular Medicine, Aberdeen University, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, United Kingdom
To the Editor:
We read with interest the elegant work of Kammerer et al1 on sodium-lithium countertransport (SLC) activity in baboons. Their findings were particularly interesting because they apply the exciting field of genetic characterization to that of SLC research some 20 years after a genetic linkage between SLC expression and hypertension was first proposed.2 SLC has since been shown to be highly heritable, but the genetic contribution has been difficult to isolate and identify despite work in special populations such as large family groups and identical twins.3,4
However, it was unfortunate that the authors chose to shackle a 20-year-old method to their cutting-edge genetic technology. In doing little more than measuring lithium efflux from red cells, the method used by Kammerer et al1 makes little or no concession to advances in SLC methodology made over the past 2 decades.5,6 In 1980, Rutherford et al7 described how hypertension may be related to a specific characteristic of the countertransporter, namely a measure of its affinity for sodium. This was achieved by undertaking a kinetic characterization of the transporter. Since its first clinical application, kinetic characterization has revealed a great deal about the behavior of the countertransporter in health and disease.6 Of particular interest with respect to the present work is the possibility that affinity of the transporter for its substrate may be genetically determined, whereas its maximal rate of turnover may be dictated by it lipid environment, itself under genetic and environmental control.5,8,9
Kammerer et al1 appear to have discovered at least 1 genetic loci determining the expression of SLC. If they had performed kinetic analysis, they may have been able to provide data to confirm or reject the proposal for specific influences on different kinetic aspects of the countertransporter. Applied in their animal model, this finding would have been of particular value as one assumes that the baboon population was generally homogenous in its nature, with individual animals sharing a relatively similar environment, thus reducing potentially confounding environmental influences.
One issue that did not receive comment was the conformity between SLC in humans and that in baboons: do baboons show the same degree of inter-individual variation seen in humans? SLC has been claimed to have been measured in several different species.10,11 However, the lithium or sodium efflux profiles used to identify the transporter in these species have often shown markedly different characteristics from those seen in humans. Values for SLC in the baboons described here were certainly similar to those reported in humans.4,5 The question arises as to whether or not the countertransporter in baboons is under the same influences and controls as that in humans. Certainly, the authors report a quiet significant relationship between expression of SLC activity and age, a relationship that is not repeated in humans.12
In conclusion, we cannot fault the reasoning of Kammerer et al1 and agree wholeheartedly with their assessment that the link between hypertension and elevated SLC activity reflect an aspect of the membrane that may cause or be caused by disease. We can only feel, however, that by applying redundant methodology to characterize the countertransporter a unique opportunity to provide new insights has been missed.
References
1.
Kammerer CM, Cox LA, Mahaney MC, Rogers J, Shade RE. Sodium-lithium countertransport activity is linked to chromosome 5 in baboons. Hypertension. 2001; 37: 398–402.
2. Canessa M, Adragna N, Solomon HS, Connolly TM, Tosteson DC. Increased sodium-lithium countertransport in red cells of patients with essential hypertension. New Eng J Med. 1980; 302: 772–776.[Abstract]
3.
Hunt SC, Stephenson SH, Hopkins PN, Hasstedt SJ, Williams RR. A prospective study of sodium-lithium countertransport and hypertension in Utah. Hypertension. 1991; 17: 1–7.
4. Hardman TC, Dubrey SW, Leslie RDG, Hafiz M, Noble MI, Lant AF. Erythrocyte sodium-lithium countertransport and blood pressure in identical twin pairs discordant for insulin-dependent diabetes. BMJ. 1992; 305: 215–219.
5. Rutherford PA, Thomas TH, Wilkinson R. Erythrocyte sodium-lithium countertransport: clinically useful, pathophysiologically instructive or just phenomenology? Clin Sci. 1992; 82: 341–52.[Medline] [Order article via Infotrieve]
6. Hardman TC, Lant AF. Controversies surrounding erythrocyte sodium-lithium countertransport. J Hypertens. 1996; 14: 695–703.[Medline] [Order article via Infotrieve]
7. Rutherford PA, Thomas TH, Wilkinson R. Increased erythrocyte sodium-lithium countertransport activity in essential hypertension is due to an increased affinity for extracellular sodium. Clin Sci. 1990; 79: 365–369.[Medline] [Order article via Infotrieve]
8. Rutherford PA, Thomas TH, Wilkinson R. Familial association of the kinetic determinants of erythrocyte sodium-lithium countertransport activity in essential hypertension. J Hypertens. 1993; 11: 1147.
9. Rutherford PA, Thomas TH, Laker MF, Wilkinson R. Plasma lipids affect maximum velocity not sodium affinity of human sodium-lithium countertransport: distinction from essential hypertension. Eur J Clin Invest. 1992; 22: 719–724.[Medline] [Order article via Infotrieve]
10. Duhm J, Becker BF. Studies on lithium transport across the red cell membrane. V. On the nature of the Na+-dependent Li+ countertransport system of mammalian erythrocytes. J Memb Biol. 1979; 51: 263–86.[Medline] [Order article via Infotrieve]
11. Kausar S, Phillips JD, Birch NJ. Species differences in lithium-sodium countertransport rate. Biochem Soc Trans. 1991; 19: 408S.[Medline] [Order article via Infotrieve]
12.
Turner ST, Weidman WH, Michels VV, Reed TJ, Ormson CL, Fuller T, Sing CF. Distribution of sodium-lithium countertransport and blood pressure in Caucasians five to eighty-nine years of age. Hypertension. 1989; 13: 378–391.
Response
Southwest Foundation for Biomedical Research, San Antonio, Texas
We agree completely with Drs Hardman and Noble’s comment that genetic analysis of kinetic characteristics of sodium-lithium countertransport (SLC) activity, especially the maximal rate of turnover (Vmax) and the affinity constant for sodium, should be more informative than the simple, but very robust,1 measurement of SLC activity used in our linkage study.2 However, the SLC activity data in baboons were obtained 
10 years ago, from 1990 to 1992, which was before most of the advances made in the kinetic characterization of SLC activity.3,4 Furthermore, we could not perform the genetic linkage analyses of SLC activity until now, because the baboon genetic linkage map was not available until 2000.5 In future studies of SLC activity, we plan to use the best possible methodology.
We do not yet know whether SLC activity in baboons is under the same influences and controls as that in humans. However, the mean and range of SLC activity is similar between both species, and females also have lower activities than males. Certainly more work needs to be done in this area.
Finally, we do not believe that our evidence for a quantitative trait locus (QTL) affecting SLC activity in baboons represents a missed opportunity to gain new insights. In contrast, we believe that detection of a QTL in baboons, in combination with knowledge about kinetic characteristics of the countertransporter obtained from numerous studies in humans, provides us with a unique opportunity to identify and characterize candidate genes for SLC activity. Specifically, information regarding characteristics of the countertransporter will greatly facilitate our search for candidate genes among the hundreds of genes located within the region of linkage. To date, no known genes related to hypertension or SLC activity have been mapped to this region of baboon chromosome 5 (which is homologous to human chromosome 4). If the QTL is encoded by a known gene with a product that has been physiologically and/or kinetically characterized, these data will direct our functional studies for determining mechanisms of SLC phenotypic variation encoded by genetic variation. If the QTL is encoded by a novel gene, existing functional data will help prioritize candidate genes for further study. The identification, and subsequent molecular and physiological characterization, of a gene that affects SLC could provide insights into susceptibility to hypertension.
References
1. West IC, Rutherford PA, Thomas TH. Sodium-lithium countertransport: physiology and function. J Hypertens. 1998; 16: 3–13.[Medline] [Order article via Infotrieve]
2. Kammerer CM, Cox LA, Mahaney MC, Rogers J, Shade RE. Sodium lithium countertransport activity is linked to chromosome 5 in baboons. Hypertension. 2001; 37: 398–402.
3. Rutherford PA, Thomas TH, Wilkinson R. Erythrocyte sodium-lithium countertransport: clinically useful, pathophysiologically instructive or just phenomenology? Clin Sci. 1992; 82: 341–352.
4. Hardman TC, Lant AF. Controversies surrounding erythrocyte sodium lithium countertransport. J Hypertens. 1996; 14: 695–703.
5. Rogers J, Mahaney MC, Witte SM, Nair S, Newman D, Wedel S, Rodriguez LA, Rice KS, Slifer SH, Perelygin A, Slifer M, Palladino-Negro P, Newman T, Chambers K, Joslyn G, Parry P, Morin PA. A genetic linkage map of the baboon (Papio hamadryas) genome based on human microsatellite polymorphisms. Genomics. 2000; 67: 237–247.[Medline] [Order article via Infotrieve]
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