Genotype-Phenotype Correlations

Genetics as it applies to evolution, molecular biology, and medical aspects.

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Genotype-Phenotype Correlations

Post by conecticut » Mon Aug 01, 2005 1:42 pm

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 (. 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 person's 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 α-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 ΔF508 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 α subunit of the amiloride-sensitive epithelial sodium channel (αENaC) and the stroke patient group.

Why ENaC? Each ENaC subunit (α, β, and γ) is coded by a different gene. Mutations in the genes coding for the β and γ subunits of ENaC have been implicated in Liddle syndrome (pseudohyperaldosteronism), an autosomaldominantly 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 β and y subunits of ENaC and EH have been studied, the results are mixed. Therefore, these findings involving the a subunit are intriguing. ... index.html

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Joined: Mon Aug 15, 2005 9:54 pm

SNPs report released by The Science Advisory Board

Post by natekarle » Mon Aug 15, 2005 9:55 pm

Does anyone have reactions to the SNPs report released by The Science Advisory Board? ( ... tudyId=117)

Some of the findings include....

"Drug research is another common objective of scientists who use SNPs. While greater than 70% of SNP genotyping is done on samples of human origin, one-fifth of samples are murine-based."

"Overall, 84% of study participants perform at least some of their genotyping in-house, and 59% of all total genotyping experiments are performed in-house. They named Applied Biosystems as the leading supplier of SNP genotyping instrumentation, followed by Affymetrix. In contrast, researchers who outsource their SNP genotyping are more likely to do so to a core facility or a collaborator’s lab rather than to an off-site service provider. These researchers cite convenient service, the fact that they cannot justify purchase of an instrumentation platform at current throughput levels and the expertise provided by their SNP genotyping provider as the three most common reasons why they outsource. These individuals identified Applied Biosystems as the leading commercial provider of outsourcing services, followed by Illumina."

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