Showed Evidence For Linkage Research Articles

Linkage of Nedd4, a Regulator of the Epithelial Sodium Channel, to Primary Hypertension in Blacks

40 Salt-sensitive hypertension is common in blacks. A primary renal mechanism may account for the increase in sodium reabsorption since levels of mineralocorticoids, including aldosterone, are often reduced in blacks. Albeit milder, the hypertension in blacks resembles Liddle s syndrome, where mutations in the epithelial sodium channel result in increased numbers of functioning channels and sodium retention. In Liddle s syndrome, molecular mutations in the PY-motif at the COOH-terminus of either the α- or β-subunit prevents binding of Nedd4, an ubiquitin ligase that targets channels for removal from the cell surface. Thus, Nedd4 is a candidate mediator of risk for hypertension in blacks. To evaluate Nedd4 s role, we performed linkage analyses in 86-88 black hypertensive sib pairs. Subjects were genotyped for two highly polymorphic markers, D15S126 and D15S1016, with heterozygosity of 79% and 89%, respectively. Both are within a 5 cM interval of chromosome 15 that contains KIAA0093 or Nedd4. Among the affected sibling pairs, we observed increased allele sharing for D15S126 (π = 0.57; p=0.01) and D15S1016 (π =0.55; p=0.07). Using only hypertensive sibling pairs (n=42-45 pairs) with BMI 2 resulted in greater allele sharing for both D15S126 (π =0.63; p=0.0001) and D15S1016 (π =0.57; p=0.06). In summary, we show evidence for linkage of hypertension to a region on chromosome 15 containing the gene for Nedd4. While these results need to be confirmed in other samples, they suggest that variability in Nedd4 or a nearby gene(s) confers a strong influence on differences in sodium homeostasis and blood pressure in blacks.

Blood Pressure and Insulin Resistance Cosegregate at Two Distinct Regions on Chromosome 7

P137 Purpose: Insulin resistance (IR) and hyperinsulinemia precede hypertension in Mexican Americans and may be a preclinical phenotype for hypertension. We tested the hypothesis that IR and blood pressure (BP) share genetic regulation by conducting a genome scan in healthy adult offspring of hypertensive probands, chosen so that the traits would not have been influenced by either the disease process or treatment. Methods: A total of 390 Mexican-Americans in 77 nuclear hypertension families were genotyped with 386 microsatellite markers. We performed two-point (by SIBPAL) and multipoint linkage analysis (by SOLAR) for BP, IR, and related traits. Results: In direct support of our hypothesis, we observed evidence for two loci on chromosome 7 that influenced both IR and BP. Two-point analysis showed evidence for linkage of a locus on 7p (∼18cM) with diastolic BP (DBP), systolic BP (SBP), mean arterial pressure (MAP), and two-hour insulin (p=0.01-0.05), with a LOD of 1.44 for SBP. More impressively, the locus on 7q (∼133cM) showed lod scores of 1.78 for SBP, and 2.97 for fasting insulin. Additional quantitative traits mapping to the 7q locus are plasma levels for leptin (LOD=1.5) and apoAII (LOD=2.0). This region overlaps with the diabesity locus reported in the Pima (Hanson et al. 1998). Two candidate genes exist in the region: PPP1R3 (∼135cM), which regulates skeletal muscle glycogenesis and has a role in type 2 diabetes (Xia et al. 1998), and leptin (∼126cM). Of particular interest, it appears that the two loci interact. Thus, the 7p locus lod score for MAP increases from 0.90 to 2.37 when an interaction with 7q is introduced Conclusions: 1) The coincident mapping of loci for BP and insulin supports the role of IR in the pathogenesis of hypertension in this population. 2) There appear to be at least two different genes on chromosome 7 responsible for BP and IR. 3) There is an interaction of these two genes, suggesting they are part of a common pathway for the IR-BP syndrome.