This gene/disease network for hypertension provides a number of deleterious SNPs for association studies. A sample of these is shown in Table 4. All are classified as deleterious to protein function by the sequence profile method and the structure/stability method. The first is R333W in rennin, which results in the loss of salt bridge and thus is likely to cause loss of function. Given rennin's role an up-regulator of blood pressure, this SNP is a candidate for involvement in hypotension. The second SNP, I444T, occurs in the hydrophobic core of angiotensin-converting enzyme (ACE) and causes a large loss of buried hydrophobic area. ACE is in the same pathway as rennin, and has an established role in blood pressure related disease. Mutants of ACE have been associated with monogenic-type hypertension [71], and ACE knockout mice show 'subnormal blood pressure, kidney obstruction and widening and thickening of infrarenal arterial vessels' [72]. The third SNP, H66R, is in chymase (CMA1), and changes a key catalytic residue, as well a breaking a salt bridge. The physiological function of chymase is still controversial [73,74]. A
