Genetic architecture of complex traits predisposing to nephropathy: hypertension

Abstract

Blood pressure and hypertension have significant genetic underpinnings that may be age-dependent. The age-dependency, significant contributions from environmental factors such as diet and exercise, and inherent moment-to-moment variability complicate the identification of the genes contributing to the development of hypertension. Although genetic abnormalities may have moderate effects, the physiologic pathways involving these genes have redundant compensating mechanisms to bring the system back into equilibrium. This has the effect of reducing or completely masking the initial genetic defects, one of the hypothesized reasons for the small genetic effects found by the recent genome-wide association studies. This review article discusses the concept of initiators versus compensators in the context of finding genes related to hypertension development. A brief review is provided of some key genes found to be associated with hypertension, including the genes identified from the nine genome-wide association studies published to date.

Figure 1

Transient acute but not chronic sodium retention in the microsomal prostaglandin E synthase-1 knockout (KO) mouse. From: Jia Z, Zhang A, Zhang H, Dong Z, Yang T. Deletion of microsomal prostaglandin E synthase-1 increases sensitivity to salt loading and angiotensin II infusion. Circ Res. 2006 Nov 24;99(11):1243-51.

Figure 2

Effect of dietary sodium on sodium excretion in salt resistant (SR) (○) and salt sensitive (SS) (■) hypertensive Japanese subjects. From: Sanada H, Yatabe J, Midorikawa S, Hashimoto S, Watanabe T, Moore JH, et al. Single-nucleotide polymorphisms for diagnosis of salt-sensitive hypertension. Clin Chem. 2006 Mar;52(3):352-60.

Figure 3

Sodium excretion (lines) in hypertensive subjects classified by rate of renin-angiotensin system suppression (solid bars). Aldosterone (not shown for clarity) was highly correlated with plasma renin activity (PRA). Subjects were in balance on 10 mEq/day Na diets and infused for 6 hours (beginning at time 0) with 0.9% NaCl at 500 ml/hr. Adapted from Tuck ML, et al. Circ Res 1976; 39:711.