Identifying genes for primary hypertension: methodological limitations and gene-environment interactions

Hypertension segregates within families, indicating that genetic factors explain some of the variance in the risk of developing the disease; however, even with major advances in genotyping technologies facilitating the discovery of multiple genetic risk markers for cardiovascular and metabolic diseases, little progress has been made in defining the genetic defects that cause elevations in blood pressure. Several plausible explanations exist for this apparent paradox, one of which is that the risk conveyed by genes involved in the development of hypertension is context dependent. This notion is supported by a growing number of published animal and human studies, although none has yet provided unequivocal evidence that genetic and environmental factors interact to influence the risk of primary hypertension in humans. In this review, an assumption is made that common genetic variation contributes meaningfully to the development of primary hypertension. The review focuses on (i) several methodological limitations of genetic association studies and (ii) the roles that gene environment interactions might play in the development of primary hypertension. The proceeding sections of the review examine the design features necessary for future studies to adequately test the hypothesis that genes for primary hypertension act in a context-dependent manner. Finally, an outline of how knowledge of gene-environment interactions might be used to optimize the prevention or treatment of primary hypertension is provided.