Model-fitting and linkage analysis of sodium–lithium countertransport

Abstract

Increased sodium -lithium countertransport activity (SLC) associates with hypertension and is highly heritable, yet the underlying genes remain unknown. SLC, measured on 1113 and remeasured 2-3 years later on 675 adult members of 48 Utah pedigrees, was tested for candidate gene association, major locus inheritance, and linkage to genome scan markers using a bivariate model with genotype-specific effects of age, body mass index (BMI), and triglycerides level (TG). No effect of the a-adducin Gly460Trp polymorphism on SLC was found. In contrast, SLC increased with age in carriers of apolipoproteinE e2 (85 individuals; 8.7% of the sample) and decreased in noncarriers. Model-fitting analyses inferred two additional loci with genotype-specific responses to BMI and TG. Using the inferred model, lod scores 42 were obtained for D3S3038, D11S4464, and D10S677 for the BMI-responsive locus, and for D8S1048 for the TG-responsive locus.

Regional Association-based Fine-mapping for Sodium-Lithium Countertransport on Chromosome 10

“…[3][4][5][6][7] These include four genome-wide analyses of SLC in humans. [8][9][10][11] In the Rochester Family Heart Study, we observed consistent evidence of linkage (LOD > 2) for SLC on chromosome 10 in two independent samples of non-Hispanic white families. 11 The overlap of the 1-LOD confidence intervals for the observed linkage between the two samples defined a genomic region of interest on chromosome 10 between 26 and 56 Mb on the physical map (NCBI Build 34).…”

“…No adjustment for multiple comparisons was made within this study, given the consistent published evidence 11 of the existence of a gene that influences SLC and/or blood pressure in this region of chromosome 10, and also the evidence that variations in multiple genes may contribute to SLC. 10 In the Rochester Family Heart Study, this region of chromosome 10 was identified by evidence of linkage with SLC. 11 Therefore, for each individual SNP that was significantly associated with SLC in the variance-components model, we evaluated the decrease in the LOD score from the peak LOD of 2.27 at 55 cM, originally observed in the Phase 2 pedigrees.…”

Sodium-Lithium Countertransport Activity in Healthy, Dyslipidemic, and Hypertensive Individuals

“…It has been suggested that the distribution of Na + /Li + CT is bimodal, composed of 2 overlapping normally distributed subpopulations, indicating that there is a large genetic contribution of Na + /Li + CT. 44,45 Most genetic analyses support a high heritability for Na + /Li + CT, reportedly in the range of 60% to 80%, 9 characterized by a polygenic mode of inheritance. 46 Indeed, a possible explanation for the higher Na + /Li + CT activity levels observed in the D/NT group in comparison with the D/HPT patients, who had significantly higher plasma TG levels compared to D/NT patients, may lie in the different genetic profile of those patients and in particular in the presence or absence of the apolipoprotein E2 (apoE) allele. The apoE phenotype has been reported to modulate Na + /Li + CT activity, and the presence of an apoE2 allele phenotype has been associated with lower Na + /Li + CT activity.…”

An association study of sodium-lithium countertransport activity with glutathione S transferase (GST) T1 and GST M1 null polymorphisms in Greek dyslipidaemic patients and controls

“…Despite its obvious significance as a quantitative risk factor for the above conditions, Na/Li CT has eluded, as yet, precise structural and genetic characterisation. While Zerbini et al (4) have recently produced compelling evidence suggesting a functional association with an amiloride-insensitive splice variant of the ubiquitous first isoform of the Na-H exchanger (NHE-1), genomic linkage studies have produced a number of chromosomal regions as candidate loci for the highly inheritable component of interindividual variability of Na/Li CT activity (5)(6)(7). In one of these studies, performed with immortalised lymphoblasts from pedigrees of the Centre d'Etude du Polymorphisme Humain (CEPH), as to shield away the environmental component of variation, Schork et al (5) have succeeded in identifying genetic markers associated with Na/Li CT activity, a number of which are positioned in close vicinity to various glutathione S transferase (GST) genes.…”