Hypertension Genes Are Genetic Markers for Insulin Sensitivity and Resistance

Abstract

Abstract-Insulin resistance is a determinant of blood pressure variation and risk factor for hypertension. Because insulin resistance and blood pressure cosegregate in Mexican American families, we thus investigated the association between variations in 9 previously reported hypertension genes (ACE, AGT, AGTRI, ADDI, NPPA, ADDRB2, SCNN1A, GNB3, and NOS3) and insulin resistance. Families were ascertained via a coronary artery disease proband in the Mexican American Coronary Artery Disease Project. Individuals from 100 Mexican American families (nϭ656) were genotyped for 14 polymorphisms in the 9 genes and all adult offspring and offspring spouses were phenotyped for insulin sensitivity by hyperinsulinemic euglycemic clamp (nϭ449). AGT M235T and NOS3 A(Ϫ922)G and E298D polymorphisms were significantly associated with insulin sensitivity (Pϭ0.018, 0.036, 0.039) but were not significant after adjusting for body mass index. ADD1 G460W was associated with insulin sensitivity only after adjusting for body mass index. The NPPA T2238C and SCNN1A A663T were associated with decreased fasting insulin levels after adjusting for body mass index (Pϭ0.015 and 0.028). (HTN) is not benign; it is strongly associated with the development of atherosclerosis and left ventricular hypertrophy resulting in congestive heart failure, stroke, and age-related macular degeneration. 1-2 The risk of complications increases with increasing blood pressure (BP), particularly systolic blood pressure (SBP). 3,4 High BP is also a major antecedent for renal failure and, after diabetes, is the second most common cause of chronic renal failure in the adult population. 1,5 Insulin resistance (IR) is a potentially important intermediate phenotype for HTN in certain populations, particularly in Mexican Americans (MAs). Cross-sectional studies have revealed correlations between IR and BP in this and other ethnic groups. 6 -8 Hyperinsulinemia preceded and predicted the development of HTN in an 8-year prospective study of MAs in San Antonio, Texas 6 and has exhibited major gene effects in at least 3 ethnic groups. 9 -11 By path analysis, we have shown that BP and IR cosegregate and have a significant genetic component independent of any relationship to body mass index (BMI). 12 This cosegregation was further confirmed in our genome scan linkage analysis, wherein we identified several regions of coincident linkage of insulin sensitivity and BP. 13 For example, fasting insulin, SBP, and mean arterial blood pressure were all mapped to the same region on chromosome 7 (112 to 128 cM). Considered together, these findings provide strong support for the concept that IR is an intermediate and genetically regulated phenotype for HTN.Although the aforementioned data may suggest that IR is a proximate cause of HTN, an alternative possibility is that both are pleiotropic manifestations of the same underlying susceptibility. In support of this latter hypothesis has been the observation that several large scale clinical trials of pharmacological agents whose targets are t...

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