Sodium-Lithium Countertransport Activity Is Linked to Chromosome 5 in Baboons

Abstract

Abstract-The genes involved in the regulation of cellular sodium transport characteristics, which are correlated with some forms of essential hypertension, have not yet been identified. We are studying the genes and environmental factors that affect red blood cell sodium-lithium countertransport (SLC) activity and intracellular sodium (ICNa) concentration in 634 baboons that comprise 11 pedigrees of 2 and 3 generations each. A lterations in cellular sodium transport characteristics, such as red blood cell (RBC) sodium-lithium countertransport (SLC) activity, are secondary biochemical indices of a primary cell membrane abnormality that is involved in the pathogenesis of some forms of essential hypertension. Ever since the original report by Canessa et al, 1 numerous studies have reported a relationship between hypertension and increased SLC activity and intracellular sodium (ICNa) concentration in several ethnic groups, including whites and Asians. 2,3 In addition to the correlation with essential hypertension, SLC activity and ICNa concentration are highly heritable. Approximately 50% to 80% of the population variation in SLC activity is attributable to additive genetic effects, and several studies have reported evidence that part of this variation is attributable to segregation at a single locus. 4 -6 Furthermore, increased SLC activity can be detected in children and adolescents. 7,8 These studies suggest that sodium transport characteristics could be useful predictors of the risk of developing hypertension. Identification of the genes responsible for these phenotypes will allow better prediction of risk.We are studying genetic and environmental factors that affect cellular sodium transport measures in baboons, a primate model used in hypertension research. 9 -12 In the present study, we report evidence that SLC activity and ICNa concentration are both highly heritable in baboons, as has been shown in humans. We also report evidence of linkage between a quantitative trait locus (QTL) affecting SLC activity and markers on the baboon homologue of human chromosome 4 (baboon chromosome 5). Methods Animal ModelSLC activity and ICNa concentration were measured on 634 noninbred baboons (Papio hamadryas) comprising 11 pedigrees ranging in size from 16 to 99 animals. These 2-and 3-generation pedigrees consisted of 202 founders (29 sires and 173 dams) that were not selected for blood pressure and their 432 offspring. The total 204 males and 430 females had a mean age of 9.4 years and a mean weight of 17.5 kg. All experimental procedures were approved by the Southwest Foundation Institutional Animal Care and Use Committee. RBC Sodium Transport PhenotypesVenous blood (20 to 30 mL) was collected into heparinized Vacutainer tubes and processed within 1 hour. The blood samples were drawn from the femoral vein after baboons were immobilized with ketamine (10 mg/kg). RBCs were separated from plasma and buffy coat by centrifugation for 10 minutes at 1000g. The separated RBCs were washed 3 times with 150 mmol/L choline chlori...

A human Na + /H + antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension

“…Finally, we note that the gene loci of HsNHA1 and HsNHA2 (4q24) lie within a chromosomal region associated with hypertension in numerous linkage studies, including a sib-pair study linking SLC activity to MN blood group (4q28-q31) on chromosome 4 (36). In particular, one study in baboon mapped quantitative trait loci associated with SLC activity to chromosome 5, which is syntenic to human chromosome 4, with a maximum multipoint LOD score of 9.3 near microsatellite marker D4S1645 (37). Taken together, these findings raise the possibility that the previously uncharacterized NHA antiporters contribute to SLC activity and are candidate genes for essential hypertension.…”

Model-fitting and linkage analysis of sodium–lithium countertransport

“…Variance components linkage analysis applied to nuclear family data produced lod ¼ 2.83 on chromosome 15q at marker D15S642 16 and applied to baboon pedigrees produced lod ¼ 9.3 on chromosome 5, in the region homologous to human chromosome 4q near marker D4S1645. 17 Genome-wide association analysis of SLC in immortalized lymphoblasts identified multiple associations, many with markers near genes involved in glutathione metabolism. 18 Herein, we analyzed SLC measured twice at a 2 -3 years interval on members of 48 pedigrees.…”

Lipid lowering: another method of reducing blood pressure?

“…21 Recently, a study in a colony of 634 baboons colony localised the gene behind SLC activity to baboon chromosome 5, a homologue of human chromosome 4. 22 Genetic mapping studies of hypertension in FCH kindreds also show quantitative trait linkage of SLC activity to human chromosome 4p in the region containing a fatty acid hydrolase (CD36) and a-adducin and secondary loci at chromosome 8p near the lipoprotein lipase gene and for diastolic blood pressure chromosome 19 close to the apolipoprotein B locus. 21 Many, but not all, studies, have shown an association between a-adducin polymorphisms and hypertension in cross-sectional studies 23 and a few have implicated the fatty acid hydrolase CD 36.…”