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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...

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM.

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci Lisa de las Fuentes, Yun Ju Sung et al.

Introduction  Monodelphis (Monodelphis domestica) shows 20‐fold differences, that may be under genetic control, in individual responses to a high‐fat challenge diet. Materials and methods Two partially inbred lines of animals were derived by selectively breeding among high responders and low responders and we analysed data from these pedigreed animals and their F1 progeny. A blood sample was taken from each animal while consuming the basal diet (basal sample). Each animal was then fed a high‐fat, high‐cholesterol challenge diet for 8 weeks prior to collection of a second blood sample (challenge sample). Lipoprotein measurements included cholesterol concentrations of high‐density lipoproteins (HDL‐C) and low‐density lipoproteins (non‐HDL‐C) and particle size phenotypes for both. Results Quantitative genetic analyses indicated strong heritabilities (range, 0.382–0.827) for each of the eight traits. We also tested for single genes with large effects on each trait (major genes). Segregation analyses provided evidence of major genes for three traits: basal non‐HDL‐C, challenge non‐HDL‐C, and challenge HDL‐C; no major genes were detected for the lipoprotein size traits. Tests for pleiotropy, using bivariate one‐locus segregation analyses, showed that the major locus for challenge HDL‐C had no effect on the basal HDL‐C and that the major locus for challenge non‐HDL‐C had no effect on basal non‐HDL‐C. However, the major gene for basal non‐HDL‐C did significantly influence challenge non‐HDL‐C. Conclusion We have found evidence for at least three genes influencing lipoprotein phenotypes under two dietary regimes. Identification of these genes may provide valuable insights into lipoprotein metabolism in other species, including man.