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