Toward an understanding of hypertension resistance

PHYSIOLOGISTS HAVE LONG APPRECIATED the central role of renal salt excretion in the control of blood pressure (4). Maintenance of a constant intravascular fluid volume and blood pressure depends on the ability of the kidneys to regulate urinary sodium excretion through the concerted action of several parallel sodium transport mechanisms. While abnormal function of any one transport process can usually be compensated for, there is a price. That is, a greater than normal change in arterial blood pressure must occur for natriuresis to be brought into balance with an increased Na intake. This concept has been reinforced though the study of rare Mendelian diseases of hypertension or hypotension, since all of the monogenic blood pressure syndromes characterized to date are caused by mutations in genes that influence sodium homeostasis (8). Individuals with these disorders often develop dramatic phenotypes of hypertension or salt wasting, usually through the inheritance of alleles harboring single nucleotide mutations. In recent years, considerable effort has been directed toward understanding whether these genes or others contribute substantially to blood pressure variation in the population as a whole. The approach for a number of these analyses has involved the unbiased search for associations between common genetic polymorphisms and blood pressure through genomewide association (GWA) studies. In some cases, GWA scans have confirmed the involvement of signaling pathways known to regulate renal salt excretion (10), or uncovered novel potential targets for antihypertensive therapy (6). In other examples, however, they have failed to identify common variants that reach genome-wide statistical significance (7, 11). More recent efforts by large-scale consortia have yielded success at identifying new associations (6). However, questions remain regarding the effect size of individual variants (3), and, in general, GWA studies have only identified a fraction of the total predicted genetic component for a variety of complex disease traits. Thus a shift in attention away from common polymorphisms, and toward the analysis of rare variants has been called for, so that their relative contributions may be assessed (3). In a genetic tour-de-force, Ji et al. (5) recently took such an approach, testing whether rare mutations in kidney salt transport genes might contribute substantially to blood pressure variation in the general population. The authors recognized that the heterozygous carrier state for Bartter’s and Gitelman’s syndromes, two Mendelian salt-wasting disorders, should be prevalent in at least 1% of individuals worldwide. Thus they asked whether rare coding variants in genes mutated in these disorders affect blood pressure in a large study population, the Framingham Offspring Cohort. They chose to sequence the exons of three candidates that affect renal sodium transport: SLC12A1 [Na-K-Cl cotransporter (NKCC2), mutated in type 1 Bartter’s syndrome], KCNJ1 (ROMK, mutated in type 2 Bartter’s syndrome), and SLC12A3 [Na-Cl cotransporter (NCC), mutated in Gitelman’s syndrome]. To select for relevant coding variants, Ji et al. first identified carriers for mutations in NKCC2, ROMK, and NCC already proven previously to cause hereditary salt wasting. As a second strategy, the authors applied stringent criteria to identify additional variants that could be inferred with confidence to lead to loss of function. To make the cutoff, a variant had to change an evolutionarily conserved residue and be present in the study population at a low frequency (to favor alleles under purifying selection). This approach identified 30 mutations across 49 subjects in 3,000 individuals. The authors found that carriers for one of the proven or inferred mutations in NKCC2, NCC, or ROMK had