Tuesday, October 24, 2006

The Genetics of Health

Conventional wisdom suggests that the prospect of developing effective therapies for disease lies with advances in disease genetics. That is, the more we learn about the role certain genes play in the development of disease the better positioned we will be for developing therapeutic interventions that prevent or possibly even cure the wide range of diseases that humans are susceptible to.

Well, the title of my blog suggests that we should be always be willing to question conventional wisdom. And so it was with much interest that I read an interesting article in this month's issue of Nature Genetics (subscription needed) that challenges this conventional wisdom in genetics. In "The Genetics of Health" Joseph Nadeau and Eric Topol argue that the current emphasis on the discovery of disease genes means that the genetics of health is often neglected. They argue that "occurrence of long-lived healthy individuals, despite presence of genetic and environmental risks, raises the possibility that naturally occurring modifier genes and protective alleles maintain health. These 'healthy' genes are a powerful alternative approach for discovering drugs to treat and perhaps prevent disease effectively and safely".

Here are a few excerpts from this interesting article (along with some important definitions):

Research programs in human genetics typically start with a collection of individuals affected with a particular disease. With identification of susceptibility genes, pathogenic mechanisms are studied to discover treatment modalities. Tests are then undertaken to determine whether these modalities restore health in an effective and safe manner. This logical but circuitous path has not yet been as successful as hoped. Development of new drugs is risky because candidates too often show limited effectiveness and adverse side effects. The key problem is designing exogenous agents that interact with endogenous molecules to restore health to dysfunctional biological systems.

....An alternative approach based on the genetics of health provides exciting opportunities to accelerate discovery of genetically based modalities to suppress disease. The tendency for health to persist despite the presence of susceptibility genes has several explanations, including modifier genes and protective alleles that confer genetic resistance to disease1. Resistance genes provide insight into homeostasis that maintains health, whereas susceptibility genes provide insight into the pathogenic mechanisms that lead to dysfunction and disease. A remarkable but often neglected observation in many families and populations is the occurrence of elderly individuals who inherit disease genes but who nevertheless remain healthy. Elderly at-risk but unaffected individuals may be nature's signal for a solution to the problem of inherited disease. Although the strongest evidence involves single-gene disorders in which unaffected individuals are readily identified, several recent studies report evidence for modifiers in multigenic models of human disease. In this Commentary, we review the relevant characteristics of modifier genes and protective alleles, discuss the attributes that make them compelling candidates as therapeutic targets and propose initiatives to test the feasibility of the 'healthy gene' paradigm.

[Some useful definitions from the article]

Modifier genes. Modifiers are variants of one gene that modulate the phenotypic expression of another ('target') gene. Perhaps the most important generalization from studies of genetically engineered mice is that their phenotypic expression depends heavily on modifier genes in the genetic background. A classic example of a modifier effect involves a genetic variant on chromosome 7 in mice and 19q in humans that controls the association of meconium ileus with cystic fibrosis, which results from mutations in the CFTR gene (on 7q31 in humans, with a homolog on chromosome 6 in mice). The variable association of this serious complication with cystic fibrosis is therefore controlled by a genetic variant that is unlinked to the CFTR target gene.

Protective alleles. Three classes of variants can occur at a given gene: an allele might increase disease risk in carriers (a susceptibility allele), another might neither increase nor reduce risk (a neutral allele) and finally an allele might reduce risk (a protective allele). A classic example of these three allelic classes involves the APOE gene that modulates Alzheimer disease susceptibility. The APOE4 variant allele increases risk for Alzheimer disease and associated comorbidities, whereas the APOE2 variant is protective and APOE3 neutral.