Complex Multifactorial Disorders

Single gene (i.e. "Mendelian") disorders follow the patterns of inheritance discussed above under DNA and human diversity. However, many diseases are due to the combination of the inheritance of alleles with suboptimal function with environmental risk factors. These diseases or conditions are termed multifactorial. Each component allelic mutation or polymorphism displays varying degrees of penetrance. Therefore, the contribution of each polymorphism may be subtle and the severity of a trait will depend on the number of genes and alleles involved. Gene polymorphisms associated with altered risk for a disease are termed "susceptibility genes.'' The discovery and characterization of susceptibility genes and alleles for a number of medical conditions has accelerated since the Human Genome Project yielded both a draft sequence of the human genome and a growing compendium of SNPs. These SNPs can be used to screen for potential involvement of a polymorphism in a trait of interest.

Complex traits cluster in families and rarely appear to follow Mendelian patterns of inheritance. However, each component allele does follow a Mendelian pattern of inheritance but the component patterns are difficult to discern when classical genetics approaches (e.g. pedigree analysis) are used to analyze a genetic disorder.5 Multi-factorial traits emerge when genetic and environmental risk factors interact and surpass a critical threshold, resulting in a disease or medical condition defined by specific phenotypic characteristics (e.g. clinical criteria).

The impact of environmental and lifestyle factors on the disease phenotype is complicated and difficult to predict. This complexity arises from the fact that environmental factors interact with individual susceptibility genes in different ways, which influences the contribution of each susceptibility gene to the risk for a trait or disease. In addition, the amount of exposure to environmental factors varies among individuals and is often difficult to quantify accurately, further complicating estimates of risk. Environmental factors may include pathogens, lifestyle factors (e.g. diet, exercise, stress), injury (e.g. surgery, infection), and toxins. Environmental factors can act at the genetic (i.e. DNA-damaging agents), expression (i.e. influencing RNA stability or turnover), and protein levels. Because RNA and proteins act as the molecular machinery of the cell, they mediate cellular phenotype and the balance between health and disease.

Environmental factors can influence biologic processes in a number of ways, including:

• acting as a signal that is transduced through cellular machinery (i.e. receptor-mediated signal transduction);

• by modifying or interacting with a protein that influences the protein's action;

• by modifying the effect of other signals.

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