Genetics of Human Primary Hypertension: Focus on Hormonal Mechanisms

Increasingly, primary hypertension is being considered a syndrome and not a disease, with the individual causes (diseases) having a common sign-an elevated blood pressure. To determine these causes, genetic tools are increasingly employed. This review identified 62 proposed genes. However, only 21 of them met our inclusion criteria: (i) primary hypertension, (ii) two or more supporting cohorts from different publications or within a single publication or one supporting cohort with a confirmatory genetically modified animal study, and (iii) 600 or more subjects in the primary cohort; when including our exclusion criteria: (i) meta-analyses or reviews, (ii) secondary and monogenic hypertension, (iii) only hypertensive complications, (iv) genes related to blood pressure but not hypertension per se, (v) nonsupporting studies more common than supporting ones, and (vi) studies that did not perform a Bonferroni or similar multiassessment correction. These 21 genes were organized in a four-tiered structure: distant phenotype (hypertension); intermediate phenotype [salt-sensitive (18) or salt-resistant (0)]; subintermediate phenotypes under salt-sensitive hypertension [normal renin (4), low renin (8), and unclassified renin (6)]; and proximate phenotypes (specific genetically driven hypertensive subgroup). Many proximate hypertensive phenotypes had a substantial endocrine component. In conclusion, primary hypertension is a syndrome; many proposed genes are likely to be false positives; and deep phenotyping will be required to determine the utility of genetics in the treatment of hypertension. However, to date, the positive genes are associated with nearly 50% of primary hypertensives, suggesting that in the near term precise, mechanistically driven treatment and prevention strategies for the specific primary hypertension subgroups are feasible.