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Genotype-phenotype correlations (II): assessing the influence of sequence variants on the clinical phenotype in multifactorial disorders.

Several recent articles in Clinical Chemistry have described the use of single-nucleotide polymorphisms (SNPs) as markers in genetic linkage studies (1, 2). These markers can be used to identify loci associated with specific disease phenotypes in a general or specific manner. The general approach, commonly called "genome-wide scanning", uses hundreds to thousands of polymorphic markers (most often SNPs) to look for genetic associations in individuals with a specific phenotype. Alternatively, when SNPs in specific candidate genes have been identified and selected, these genes are usually associated with biochemical or physiologic pathways believed to be involved in the disease pathogenesis.

Even in the so-called "single gene" disorders (e.g., cystic fibrosis), where we previously thought pathways were relatively straightforward, there are often complicating factors, such as modifier genes. To help define modifier genes, it is important to precisely define clinical phenotypes (3). In the case of multifactorial disorders, where multiple biochemical and physiologic pathways may be involved, the need for "carefully generated distinct phenotypes" becomes even more critical. A case in point is found in this issue of Clinical Chemistry, where Hsieh et al. (4) describe a study looking for such genetic modifiers in patients with ischemic cerebrovascular events, commonly called strokes. This study affects our understanding of the complex multifactorial nature of hypertension, the major risk factor of stroke.

Hypertension is the leading cause of morbidity and mortality in industrialized countries worldwide (5), and most hypertension is "essential", meaning that no obvious cause is known. Approximately 50 million Americans age 6 and older have high blood pressure. Of those with high blood pressure, 32% are unaware they have it, and 54% are on medication; blood pressure is adequately controlled in only one-half of those who are treated. High blood pressure directly increases the risk of coronary heart disease, heart attack, and stroke, especially when other risk factors, such as diabetes, are present. Proper diagnosis and treatment of hypertension can reduce heart failure by 55% and stroke by 37% (6).

Essential hypertension (EH) is a complex disease that has both environmental and genetic determinants (7) and a heritability that ranges from 30% to 90%. Because of the variable extent of heritability, EH probably results from the effects of multiple genes, not all of which are responsible, in any given individual, for the high blood pressure that is characteristic of the disease. This contribution of multiple genes is supported by studies in animals and humans, in which peripheral blood pressure follows a single monotonic distribution that is not bimodally distributed (8). In addition, EH probably is a result of the combination (via unknown interactions) of genetic alterations in selected metabolic pathways with other genetic variants in less well characterized pathways that are susceptible to changes in each persons environment (e.g., diet, stress, and exposure to xenobiotics). Thus, the trait of increased blood pressure observed in EH is likely the result of chronic interaction(s) between several minor genetically induced alterations in metabolic pathways that are coupled to other genetically altered changes in pathways; together, these genetic features determine an individual's susceptibility to inputs from environmental stressors (e.g., diet, abuse of nicotine, salt intake, and lifestyle).

The search for genetic components that contribute to EH began with the concept of a single candidate gene being responsible for the trait of increased blood pressure that is observed in EH patients. Investigators have searched for the presence of a defect (or defects) in multiple pathways, including those of the renal kallikrein system, sodium epithelial transport system, renin-angiotensinogen-aldosterone pathway, and the catecholaminergic-adrenergic pathway; gene changes have also been searched for in genes for [alpha]-adducin and, more recently, G protein [beta] 3, nitric oxide (NOS), and G-protein-related kinase subtype 4 (GRK4) (9, 10). Although studies of these genes or collections of genes have shown some weak associations, to date no significant gene defect in a single gene (e.g., similar to [DELTA]F508 in the CFTR gene associated with cystic fibrosis) has been identified for EH. The results of these and other genetic studies of EH have led to the conclusion that EH is a multifactorial disease of delayed penetrance, with a substantial environmental influence. One gene system that does seem to play a role in EH is the G-protein-related kinases. SNPs in the GRK4 genes, in combination with several other SNPs, appear to be correlated with EH, both in rats and in human studies (11). Thus, the conclusion is that multiple SNPs will likely need to be evaluated for characterizing and detecting hypertension.

Hsieh et al. (4) have taken another approach in using a downstream phenotype and surveying candidate genes for hypertension associated with stroke. The necessity for carefully generated distinct phenotypes now becomes doubly important, because some stroke patients may have etiologies other than hypertension. To exclude these phenocopies (stroke attributable to other etiologies), the authors were able to exclude stroke patients with other etiologies, leaving 1399 patients (of 3516 original stroke patients). Control individuals had no personal or family history of stroke. After adjustment for age and hypertension risk factors, a statistically significant association was observed between the Trp493Arg polymorphism in the gene (SCNN1A) for the [alpha] subunit of the amiloride-sensitive epithelial sodium channel (aENaC) and the stroke patient group.

Why ENaC? Each ENaC subunit ([alpha], [beta], and [gamma]) is coded by a different gene. Mutations in the genes coding for the [beta] and [gamma] subunits of ENaC have been implicated in Liddle syndrome (pseudohyperaldosteronism), an autosomal-dominantly inherited single-gene disorder in which increased reabsorption of sodium and water in the renal tubule leads to hypertension (12). However, although genetic associations between the (3 and y subunits of ENaC and EH have been studied, the results are mixed. Therefore, these findings involving the a subunit are intriguing.

References

(1.) Silverman LM, Mahadevan MS. Genotype-phenotype correlations: assessing the influence of sequence variants on the clinical phenotype [Editorial]. Clin Chem 2005;51:8.

(2.) Stephens JW, Sozen MM, Whitall RA, Caslake MJ Bedford D, Acharya J, et al. Three novel mutations in the apolipoprotein E gene in a sample of individuals with type 2 diabetes mellitus. Clin Chem 2005;51:119-24.

(3.) Friedman KJ, Silverman LM, Genetic modifiers and the cystic fibrosis syndrome. In: Bruns DE, Lo YMD, Wittwer CT, eds. Molecular testing in laboratory medicine. Washington: AACC Press, 2002;236-7.

(4.) Hsieh K, Lalouschek W, Schillinger M, Endler G, Reisinger M, Janisiw M, et al. Impact of aENaC polymorphisms on the risk of ischemic cerebrovascular events: a multicenter case-control study. Clin Chem 2005;51:952-6.

(5.) American Heart Association. Heart disease and stroke statistics-1998 update. Dallas, TX: American Heart Association, 1998.

(6.) Lenfant C. Reflections on hypertension control rates. Arch Intern Med 2002;162:131-2.

(7.) Timberlake DS, O'Connor DT, Parmer RJ. Molecular genetics of essential hypertension: recent results and emerging strategies. Curr Opin Nephrol Hypertens 2001;10:71-9.

(8.) Hunt S, Williams R. Genetic factors, family history, and blood pressure. Dallas, TX: Texas American Heart Association, 1993.

(9.) Luft FC. Molecular genetics of human hypertension. J Hypertens 1998;16: 1871-8.

(10.) Felder RA, Sanada H, Xu J, Yu PY, Wang Z, Watanabe H, et al. G protein-coupled receptor kinase 4 gene variants in human essential hypertension. Proc Natl Acad Sci U S A 2002;99:3872-7.

(11.) Bengra C, Mifflin TE, Khripin Y, Manunta P, Williams SM, Jose PA, et al. Genotyping of essential hypertension single-nucleotide polymorphisms by a homogeneous PCR method with universal energy transfer primers. Clin Chem 2002;48:2131-40.

(12.) Tanira MOM, AI Balushi KA, Genetic variations related to hypertension: a review. J Hum Hypertens 2005;19:7-19.

Lawrence M. Silverman *

Theodore M. Mifflin

University of Virginia Health Sciences Center

Charlottesville, VA

* Address correspondence to this author at: University of Virginia Health Sciences Center, Box 800168, Charlottesville, VA 22908. E-mail Lms7r@virginia.edu.

DOI: 10.1373/clinchem.2005.050179
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Title Annotation:Editorial
Author:Silverman, Lawrence M.; Mifflin, Theodore M.
Publication:Clinical Chemistry
Date:Jun 1, 2005
Words:1300
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