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  • Diagnostic Testing: Hypertension
  • Diagnostic Testing: Prior to the Establishment of Hypertension
  • Diagnostic Testing: Salt Sensitivity
  • The Genetic Basis for Hypertension and Salt Sensitivity
  • Salt Sensitivity and Plasma Renin Activity
  • The Importance of Ethnic Background on the Diagnosis of Salt Sensitivity
  • Significance of the Hypogen Test
  • What is the procedure for sample processing?
  • How are the laboratory results reported?
  • Bibliography

Diagnostic Testing: Hypertension: Brachial artery sphygmomanometry is the recommended method to measure blood pressure as recommended by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure 7 (JNC 7) and other recognized health-related organizations (e.g., World Health Organization). JNC 7 definitions of blood pressure levels (mm Hg) are: Normal = <120 systolic and <80 diastolic; Prehypertension = 120-139 systolic or 80-89 diastolic; Stage 1 hypertension = 140-159 systolic or 90-99 diastolic; Stage 2 hypertension≥160 systolic or ≥100 diastolic (2, 3) . However, the blood pressure cuff only tells part of the story. Blood pressure is notorious for being variable throughout the day and for giving false positive readings, in the presence of a physician or nurse (i.e., white coat syndrome). There is a 20% false positive rate for blood pressure readings in physicians’ offices. Furthermore, elevated blood pressure does not often manifest itself until later in life increasing from 30.1% at 40-59 years to 65.4% in Americans 60 years and older (2-4) . Pre-hypertension can lead to significant morbidity before hypertension is established (2, 4) . Even the routine use of home blood pressure monitoring devices can lead to erroneous results (both false positive and false negative results) since naive users get erroneous results more often than trained users and many automated blood pressure equipments may not give reliable readings (5) .

Diagnostic Testing: Prior to the Establishment of Hypertension: The best way to diagnose established hypertension is by the proper use of a sphygmomanometer; however, there are no methods to predict the eventual development of hypertension. Moreover, individuals with normal blood pressure can experience episodes of hypertension after high salt intake that can only be detected with ambulatory 24 hour blood pressure monitoring. A positive genetic test would indicate a need for careful home monitoring of blood pressure, with follow up by the primary care physician. Hypertension may manifest itself later in life, especially in individuals with normal blood pressures whose blood pressures increase (but not to the hypertensive range) with increased salt intake (salt sensitive normotensives) (6) . Therefore, there continues to be a strong demand for better methods of diagnosis (and ultimately more effective therapies). Those with a higher likelihood for developing hypertension and/or salt sensitivity could benefit from a test that would determine if there was an impairment of renal tubular sodium handling. The Hypogen Test currently provides the best predictive value for hypertension and salt sensitivity as compared to any test on the market.

Diagnostic Testing: Salt Sensitivity: The diagnosis of salt sensitivity encompasses two groups; salt sensitive hypertensives and salt sensitive normotensives (Figure 1) (7) . Salt sensitivity is most reliably diagnosed by the increase in blood pressure (>10%) following an increased sodium diet (usually administered in a clinical setting) (8-11) . In the only reliable method, patients are subjected to a rigorous (and expensive) standard protocol for testing salt sensitivity which involves a 153 mmol sodium and 50 mmol potassium/day diet for five-seven days, followed by a reduction of sodium to 51 mmol sodium/day for five-seven days, followed by a high-sodium diet of (340 mmol/day) for five-seven days and then, finally, 153 mmol sodium/day for an additional five-seven days (8) } (10, 12) . The entire protocol requires almost a month of careful diet control and blood pressure measurements. Although a shorter two week protocol has been suggested, the correlation in blood pressure obtained in the shorter protocol (13) and the definitive method of strict dietary regimen (8, 10, 12) is only 0.69. Other protocols, including the effect of diuretics on blood pressure, suffer from a lack of standardization, variability in patient compliance, and dietary salt intake due to the large amounts of “hidden salt” in diets of industrialized societies (12, 14, 15) . The variability in blood pressure response to increased sodium intake has been claimed to reduce the usefulness of blood pressure sensitivity to salt intake as an intermediate phenotype (15) . However, the report of Hurwitz et al (15) is limited by the fact that the Hypogen Test for GRK4 SNPs were not included in their studies.

The Genetic Basis for Hypertension and Salt Sensitivity: The Gaussian distribution and the lack of a definable bimodal distribution of blood pressure suggest that blood pressure is regulated by a complex group of interacting genes. More than one gene locus is undoubtedly involved since Mendelian dominant and recessive traits are not readily discernable in hypertensives. Approximately 30%-50% of hypertension is genetically inherited and the remainder is due to environmental factors, such as consumption of excess salt (7, 16) . However, some environmental factors may also have genetic components. Thus, salt sensitivity is thought to be inherited (7) . Numerous studies have demonstrated linkage between chromosomal regions and hypertension (17) . In these studies, the best linkage signals for hypertension were found on chromosomes 1 and 6 near regions associated with familial combined hyperlipidemia, while other strong linkage signals were also found on chromosomes 4 (18-20) . Many of these studies are not consistent when applied to different ethnic populations. Furthermore, the method of associating chromosomal locations with disease (called linkage disequilibria) cannot be used to predict the probability that a single individual is salt sensitive or will develop salt sensitive hypertension.

Many different genes have been associated with salt sensitivity and essential hypertension (1, 21-29) It is generally accepted that measuring variations of selective SNP allele frequencies in hypertensives provide useful diagnostic information (21-23) . There are at least 50 ligand/receptors, enzyme/substrates and transporters contributing to blood pressure and salt sensitivity, so there are many candidate genes that could prove useful in a genetic diagnostic test . However, specific salt sensitivity genetic testing panels have not been developed. The candidate gene strategy assumes that a given gene, or a set of genes involved in a specific function, might contribute in blood pressure variation. In order to predict salt sensitivity and the onset of hypertension, specific SNPs will have to be associated with salt sensitivity and salt sensitive hypertension, and then further investigated for their prevalence in given ethnic groups. However, selecting the appropriate genetic markers to provide predictive information has been difficult. For example, hypertension was associated with variations in the angiotensin gene in French and North American subjects (30) . However, no association was found in British or Hispanic subjects (31) . Moreover some variations are associated with hypertension while others are not (32-41) . Up until recently, the lack of studies examining a panel of hypertension related SNPs in different ethnic populations has limited the usefulness of genetic screening.

Proof of the involvement of individual genes in a complex polygenic disease is difficult to obtain (42) . Examining the contribution of one, or several, genes to a polygenic disease, such as salt sensitivity, may not yield fruitful results (32) . However, by focusing our studies and diagnostic test development on the interaction of genes that regulate sodium excretion, such as the renin angiotensin aldosterone system (21-24) } (26, 27, 30, 31) } (34-41) and the D 1 receptor dopaminergic system has yielded positive results (1, 43-55).

In order to overcome these challenges, Glazier et al recently proposed criteria to assign genes that underlie complex traits (56) . The GRK4 SNPs that constitute the Hypogen Test, meets these criteria. The locus of GRK4 gene, chromosome 14 p16.3, is strongly linked to hypertension (18, 19) . GRK4 variants (R65L, A142V, A486V), by themselves or via their interaction with genes of the renin angiotensin aldosterone system, are associated with essential hypertension (43, 55) . GRK4A486V and the interactions of the different GRK4 variants are associated with hypertension in Italians, Japanese, and Australians (1, 45, 46) . In our studies, when the increase of blood pressure with an increase in salt intake is ≥10%, all subjects with three GRK4 SNPs (R65L, A142V, and A486V) were salt sensitive (1) (Figure 2), in agreement with the calculated predictive accuracy for the prediction of salt sensitivity of 94%. GRK4 variants impair the cellular and biochemical function of D 1 receptors in endogenously expressed in renal proximal tubules from hypertensive humans and rats and D 1 receptors exogenously expressed in mammalian cell lines (44) . D 1 receptor dysfunction in renal proximal tubules, present in human essential hypertension, could be related to a defect in the inhibitory function of D 1 receptors on renal proximal sodium transport. D 1 dopamine receptors are important in facilitating sodium excretion under conditions of sodium excess  We have also reported that mice hyper-expressing GRK4A142 are hypertensive (44) .  We have preliminary data while mice hyper-expressing GRK4A486V are salt sensitive (Am Soc Nephrol 2003;14: 362A).  Thus, GRK4 fulfills the criteria of genes causing complex disease advocated by Glazier et al (44, 56) (45, 47, 48) [Sanada and SHR rat] (50-52) . Furthermore, patients with three or more SNPs do not increase urinary sodium excretion in response to docarpamine, a dopamine pro-drug that produces a natriuresis, via D 1-like receptors, in normotensives (1) , (Figure 2). Impaired renal proximal tubular response to D 1-like receptor stimulation is present in salt sensitive hypertensive subjects (50).

The Hypogen Test constitutes the gene polymorphisms that have been used to satisfy the criteria set forth by Glazier, and thus may be prognostic and diagnostic of the hypertensive and salt senstivity phenotype.

Figure 2. Higher number of GRK4 variants resulted in a higher Mean Arterial Pressure (MAP). 3 or more GRK4 SNPs resulted in a 10% or higher increase in MAP, which is the definition of salt sensitivity. Left axis and bars: Relationship between the increases in blood pressure with the increase in salt intake in hypertensive subjects classified according to the number of GRK4 variant alleles (1) . The number of subjects from our study that were salt resistant is the left number in parenthesis, while the number that were salt resistant is the right number., *P<0.05 vs 0-2 alleles, factorial ANOVA, Duncan’s test. Right axis and line with circle symbols: the ability of these subjects to excrete sodium following dopaminergic stimulation. The higher the number of SNPs (X axis) resulted in lower ability to excrete sodium following the drug challenge. (r 2= 0.95), copyright, American Association for Clinical Chemistry (1).

Salt Sensitivity and Plasma Renin Activity: Low plasma renin activity (PRA) is associated with salt sensitive hypertension and is used by some to diagnose salt sensitive hypertension (15, 26, 57-59) . However, PRA levels may not predict the salt sensitive phenotype and therefore, cannot be used to diagnose salt sensitivity (60, 61) . In a group of subjects studied at the Fukushima Medical School were grouped according to the blood pressure response to the chronic salt loading protocol (8, 10, 12) , 8% of the salt sensitive subjects had normal PRA while 92% had low PRA. In contrast, 33% of salt resistant subjects had low PRA while 67% had normal PRA (1) . Thus, PRA has low specificity (true positives/false positives) for predicting salt resistance or sensitivity, in agreement with other reports (60, 61) . Indeed, Dr. Sanada found that the genetic make up of hypertensive subjects with low PRA (GRK4A142V and CYP11B2 -344C>T predicted the hypertensive phenotype with an 84% accuracy) is different from that noted in salt sensitive (GRK4R65L, A142V, A486V) subjects. The association of CYP11B2 and other genes and low renin hypertension has been reported by others (25, 27).

The Importance of Ethnic Background on the Diagnosis of Salt Sensitivity: The incidence of salt sensitivity independent of hypertension, salt sensitive hypertension, and hypertension varies among ethnic groups (16, 62) . Frequencies of linkage disequilibrium between the GRK4 SNPs varied substantially among populations (African-Americans, Chinese-Americans, Hispanic Americans, white Americans) (63) . Thus, any diagnostic test must take into account ethnic variability in order to provide clinically useful information. The National Heart, Lung, and Blood Institute has suggested that reduction in sodium in the diet is a national priority and that new measures are necessary to make the general population, and particularly ethnic minorities, aware of the consequences of uncontrolled elevated blood pressure (62) . Hypogen is continually seeking new SNPs that have been reported to provide an indication of the homogeneity of an ethnic population and factor this genetic information into our studies. However, we are cognizant that these SNPs may not be definitive, and provide interpretive complications in individuals of mixed ethnicity.

Significance of the Hypogen Test: Preliminary studies suggest that the Hypogen Test predicts hypertension, salt sensitive hypertension, and salt sensitivity in normotensives in Ghanaian, Japanese, and Italian population (43, 45, 55) . As stated earlier, our current test offers a 70% predictive value for hypertension in Ghanaians (43) , and 94% predictive value for salt sensitivity in Japanese (1) a 57% accuracy in white Americans (unpublished data). GRK4 variants appear to be important in the pathogenesis of salt-sensitivity. With aging (15) or when GRK4 gene variants act alone or interact with gene variants that regulate the renin-angiotensin-aldosterone axis, hypertension and or salt sensitivity then develops. The interactions of these gene variants in other populations need to be studied. We propose that a genetic diagnostic test would be useful to raise individual and general awareness of the more universally understood condition of hypertension, as well as the virtually unknown condition called “salt sensitivity”. The use of a follow-up cell based assay based on freshly voided proximal tubular cells in urine may lead to an important method to determine if subjects with a genetic predisposition for salt sensitivity and/or hypertension are actually expressing the disease phenotype. Individuals with elevated blood pressure, and/or salt sensitivity are at an increased risk for cardiovascular disease. Given the generally accepted positive benefits of lifestyle modification on delaying or preventing the development of hypertension, there is a strong need for effective clinical and public health strategies that lead to the initiation and continuation of lifestyle modifications (64) . Through the use of predictive genetic diagnostics, there is a growing trend of changing medicine from an episode-based practice to a service that provides consumers with tools that emphasize wellness. Genetic testing has been demonstrated to increase personal awareness of the potential for disease and to result in motivation to initiate healthy lifestyle changes (65) . Furthermore, recent data from The Harris Poll ® demonstrate that 81% of individuals over the age of 18 would favor being tested for a genetic disease if an effective treatment existed ( ). Substantial social and economic benefits to public health can be achieved by encouraging individuals to adopt personal behaviors and related strategies that can improve their cardiovascular health. In the future, and possibly a derivative benefit of these studies, drug treatment based on genetics may result in increase the drug efficacy and decrease unwarranted drug side effects.

What is the procedure for sample processing?

1. Obtain a Hypogen™ Kit from Hypogen by ordering on-line and review the testing procedure.
2. Obtain informed consent from your patient if required by your state.
3. Fill out the forms that were enclosed with the test.
4. Draw the necessary blood using the tube supplied in your kit or collect the specimen from the mouth by using a buccal swab.
5. Ship the samples and forms using the prepaid envelope that was supplied in the kit. The kit should be stored at room temperature.

How are the laboratory results reported?

  • Results will be mailed to the physician
  • The test sensitivity and specificity of Hypogen AGT for M235T genotyping are greater than 99%.
  • It takes approximately two weeks to report the results of the test.
  • There are three possible results from the test:
    1. T235 variant not identified (MM)
    2. Homozygous T235 identified (TT)
    3. Heterozygous T235 identified (TM)
  • Patients carrying the T235 variant (TT or TM) may be at increased risk for CHD and or certain forms of hypertension and might benefit from targeted interventions.


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