How Genes Lead to Disease

WHAT IS A GENE MUTATION?
Each gene is a piece of DNA that tells our cells to manufacture a protein designed for a functional role in the cells that comprise our organs. Our personal genetic characteristics are based on our individual DNA sequence, our own “genetic code.”

Of course, many portions of one person’s genetic code are identical to the same parts of every human’s DNA sequence. However, in some places in each individual the letters of the code may differ from the typical human DNA sequence. A different letter may appear or a portion of the code may be deleted or duplicated. Remarkably, most of these sequence variations are “neutral” with respect to cellular metabolism and overall body function; they have no effect. The changes that do lead to altered function are called “mutations.”

Many mutations alter body chemistry in ways that lead to disease. A mutated gene may alter the structure of its protein product, which can modify, reduce or eliminate its function. In some cases, a single mutated gene will inevitably cause disease – everyone who carries a Huntington gene mutation eventually develops symptoms derived from the changes this mutation causes in the brain. For phenylketonuria (PKU), on the other hand, children with two mutated genes – from both parents – develop the most incapacitating symptoms only if they are exposed to the common amino acid, phenylalanine. Severe dietary restriction enables affected children to lead otherwise normal lives.

LEADING TO A CURE
Once we know genetic mutations cause or predispose to a disease, the first step is to identify the specific genes involved. After this step the chain of events, from the mutation to the disorder, can be analyzed with already available clinical and laboratory methods. This research will lead to new ways to prevent or treat the disorder. Knowing that mutations in a specific gene lead to a serious illness means that scientist can develop genetic tests to identify those who are at substantial risk of developing this disorder. Such identification can be valuable immediately if available data suggest ways to prevent or modify the illness.

Genetic Testing

Genetic tests may be used in ways comparable to the medical use of bacterial cultures. For example, while it is possible to treat pneumonia generically, knowing the precise bacterium that caused it will tells us which antibiotic most likely will cure it. Similarly, testing for gene mutations will be valuable for individuals with the disease and their families. Although the total human genetic code may consist of ten or thirty million bases, it is possible to detect changes in individual genes if one knows what to look for.

Genetic tests are already available for numerous gene mutations. Testing helps patients identify a predisposition to various illnesses, thus empowering them to treat or combat the disease, often before symptoms appear. For example, detection of the A-T mutation that causes breast cancer will enable women to take full advantage of preventative treatments. Finding a WS mutation can guide therapy for an ill individual and alert the family that others may be predisposed to similar disorders, including the possibility of suicide. Prevention and cost-effective treatment, two key benefits that genetic testing can provide, will be recognized by “smart healthcare shoppers” and insurance carriers alike.

Other Breast Cancer Genes: BRCA1 AND BRCA2

Mutations in these genes have been found almost exclusively in women with a striking family history of early onset breast cancer. Many women know about genetic testing for BRCA1/2 mutations because it is offered commercially through genetic counseling clinics. Scientific studies and clinical experience have found BRCA1/2 mutations in 1-2% of breast cancer patients.

Benefits of Knowledge

WHAT CAN BE DONE TO PREVENT OR MORE EFFECTIVELY TREAT THE DISEASES RELATED TO MUTATIONS IN DISEASE GENES?
The steps to prevent or more effectively treat a specific common disease once an important predisposing gene is identified depend on how the gene interacts with other factors to produce clinical manifestations. At the minimum, awareness of disease predisposition can alert a mutation carrier to the need for monitoring to assure early diagnosis, leading to a more successful treatment. As discussed in the Gene Mutation section, mutations in a gene predisposing individuals to a common disease do not invariably lead to the disease. While this has made the task of finding these genes more difficult, it is a cause for optimism when it comes to prevention and treatment, because it indicates that other factors must be involved.

External factors, such as phenylalanine in the diet of PKU patients, can be reduced or eliminated to prevent or control the disease. Drugs may be discovered that interfere with the disease-causing mutant allele, but not the normal allele, to prevent the disease from developing. For those who have already developed the disease, new drugs designed to target the metabolic error determined by the predisposing mutation may provide the most effective treatment.

Our Method

The challenge comes from the fact that mutations in genes associated with common diseases are not invariably expressed as disease. More than $1 billion has been ineffectively spent using older genetic methods such as linkage analysis, SNPs or Populations studies, to find genes involved in common illnesses. Sadly, many times these methods do not work or yield inconclusive evidence.

The Index-Test Method1,2 is a proven, effective way of identifying the genes that underlie common illnesses. The study design exploits the basic characteristics of human inheritance in a simple way that leaves no room for controversial interpretations. It reliably detects an association between a specific gene and a common disease even when, as there usually are, other genetic or environmental factors that predispose to the same disease. The statistical power is high, so that the number of study subjects needed for a definitive study is both predictable and as small as possible.

THESE ARE BOLD CLAIMS – HOW DOES THE METHOD WORK?
This method relies on the high proportion of their genes that close blood relatives share. For each degree of relationship, this proportion is known from the simple rules of Mendelian inheritance. The “test” individuals are cases of the disease of interest, while each “index” individual is a close relative of the test case. The presentation Ataxia-Telangiectasia (A-T) Gene and Cancer demonstrates how the Index Test Method linked the A-T gene with cancer.

SUMMARY
Overall, the index-test method has advantageous characteristics for finding which genes are frequently associated with common diseases, including cancer and psychiatric illness. It does not depend on arbitrary and frequently changing diagnostic criteria; indeed, it will define the phenotypes associated with mutations in a specific gene. No confounder can affect its results because each individual’s genotype is fixed at the time of conception. Unintended bias is unlikely because the cases are selected before laboratory genotyping by explicit objective criteria. This method leads to robust conclusions even though there are many other genetic and environmental factors responsible for common illness in the population.