AGT M235T Genotype/Anxiety Interaction and Gender in the HyperGEN Study

Sarah S Knox,G Weidner,Scott Williams,Yuqing Zhang,Xinxin Guo,R Curtis Ellison,Alejandro Lucia

doi:10.1371/journal.pone.0013353

Abstract

BackgroundBoth anxiety and elevated heart rate (HR) have been implicated in the development of hypertension. The HyperGen cohort, consisting of siblings with severe and mild hypertension, an age-matched random sample of persons from the same base populations, and unmedicated adult offspring of the hypertensive siblings (N = 1,002 men and 987 women), was analyzed for an association of the angiotenisinogen AGTM235T genotype (TT, MT, MM) with an endophenotype, heart rate (HR) in high and low anxious groups.MethodologyThe interaction of AGTM genotype with anxiety, which has been independently associated with hypertension, was investigated adjusting for age, hypertension status, smoking, alcohol consumption, beta blocker medication, body mass index, physical activity and hours of television viewing (sedentary life style).Principal FindingsAlthough there was no main effect of genotype on HR in men or women, high anxious men with the TT genotype had high HR, whereas high anxious men with the MM genotype had low HR. In women, HR was inversely associated with anxiety but there was no interaction with genotype.Conclusion/SignificanceThe results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men. This type of gene x environment interaction may be one reason why genome wide association studies sometimes fail to replicate. The locus may be important only in combination with certain environmental factors.

Highlights

Despite a great deal of research on the genetic basis of hypertension, the results have been disappointing
Conclusion/Significance: The results suggest that high anxiety in men with the TT genotype may increase risk for hypertension whereas the MM genotype may be protective in high anxious men
An advantage of using endophenotypes is that they help to unravel the comoplexity of chronic disease by specifying intermediate gene x environment interactions that contribute to clinical endpoints

Summary

Introduction

Despite a great deal of research on the genetic basis of hypertension, the results have been disappointing. The factors that increase or decrease disease risk of one genotype (e.g. angiotensinogen), may differ from those affecting another (e.g., the beta adrenergic receptor Arg38Gly polymorphism) If this is the case, interactions may be one reason why relatively few genetic variants have been consistently found to contribute to complex diseases at a population level and why replication of significant findings has been difficult [2]. Contributions of specific genes may be related to different points in multiple underlying causal pathways, confounding differentiation at the phenotypic level (e.g., blood pressure) These issues have led investigators to begin examining the genetic factors associated with endophenotypic precursors to the overtsymptoms of disease [2].

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