Strategies to improve detection of hypertension genes

The identification of genes that are associated with hypertension has been a slower process than for other diseases, despite a similar heritability in many cases. This is, in part, likely to be a result of a great number of genes being involved with the blood pressure control pathways and their accompanying small effects on the phenotypes that are being measured. With blood pressure fluctuating so acutely with changes in posture, stress, activity level, and even while talking, strong responses to these fluctuations are required to keep blood pressure appropriate for tissue perfusion and cellular function. Because of the importance of blood pressure control, there are redundant compensatory pathways for this pressure normalization. Therefore, a gene that may compromise one pathway may not be found to be associated with hypertension because other pathways can adequately compensate and normalize the phenotypes being studied. What might be detected in these situations are associations of a gene with the compensating factors that change to normalize a causal pathway. The altered levels of the compensating factors will likely be smaller than the causal phenotype levels if there were no compensation, and are probably more difficult to detect. Both initiating genes and compensating genes are involved in eventual hypertension development, in line with the strong polygenic nature of hypertension. Recent genome-wide association studies (GWAS) have begun to suggest genes related to hypertension and blood pressure levels [1, 2, 3, 4, 5, 6, 7, 8, 9]. Comparing the results of each GWAS as a whole, there is little overlap of the significant gene associations. When targeted in silico look-ups of association regions are done in other GWAS, a few genes are then replicated because the penalty for multiple corrections is decreased. These few genes, such as SH2B3 or CACNB2, show very small influences on blood pressure in accordance with the theory of large numbers of genes working together in pathways for fine blood pressure control. Interestingly, few of the physiological candidate genes that have been found associated with hypertension over the last 20 years of research have been replicated by GWAS. In light of these difficulties, elucidation of a few concepts suggested by the literature may increase the ability to detect more genes and to verify the genes already suggested for their involvement with hypertension. These include: (1) selecting of subjects with strong family histories of hypertension; (2) identifying age ranges that show the highest heritability of blood pressure in the target population; (3) measuring local tissue-specific electrolyte or hormone concentrations in addition to systemic concentrations; (4) using acute interventions to investigate genetic interactions with environmental factors such as diet, activity and stress; (5) determining the appropriate time window after intervention to identify initiators versus compensators of blood pressure elevation; (6) genotyping subjects involved in large clinical trials to detect intervention interactions with genotype, and (7) increasing the density of SNPs in and around candidate genes for hypertension in genome-wide or candidate gene association studies.