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Small Genetic Differences, Huge Health Problems

Genomics takes the first step toward curing the toughest diseases.

By Dr Robert W Lash
Oct 3, 2007 5:00 AMNov 12, 2019 4:10 AM


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When you get right down to it—and by "right down to it," I mean at the DNA level—we are far more like one another than most of us would care to admit. It is estimated that we are 99 percent genetically identical, with that varying 1 percent causing quite a lot of variance. (The 1 percent explains, for instance, why I'm writing this column instead of sprinting in the Olympics or starring as the next James Bond.) An ever-growing body of research is also demonstrating how some of these differences put us at risk for a variety of diseases, including cancer, Alzheimer’s, and disorders that affect the immune system. Many of these differences are as small as one can imagine: a single change in the order of our DNA.

As I learned in college, and children now learn in elementary school, DNA is made up of four letters, or nucleotides: adenosine (A), guanine (G), cytosine (C), and thymidine (T). At certain points in our genes, we have variations in these letters, called polymorphisms. For example, where one part of the population may have a C, the rest of the population will have a T. These single nucleotide polymorphisms are known in the field as SNPs (pronounced "snips").

In a recent paper in the New England Journal of Medicine, a group of investigators looked at SNPs from over 2,500 patients with two rheumatologic disorders—lupus and rheumatoid arthritis—and compared their DNA with that of over 2,000 normal patients. The scientists concentrated their efforts on 13 different genes on a part of chromosome 2 that had previously been identified as containing genes related to these disorders. Patients with a particular SNP in a gene called STAT4 were 32 percent more likely to have rheumatoid arthritis and 55 percent more likely to have lupus. If you had two copies of this particular SNP (one from each of your parents), then your risk for either disorder was even higher.

Looking for SNPs has turned out to be a powerful tool to identify genes that may put us at risk for disease. The idea is simple, although the execution is not. Investigators pick a region of DNA that they suspect has genes related to a specific disease. Then they compare the SNPs in this region from thousands of people who have the disease with the SNPs of thousands more who don’t. If they find a SNP that separates the two groups, that’s a good candidate for an important gene. If that gene turns out to do something related to the disease being studied, that’s an even bigger payoff. What makes this discovery particularly exciting is that STAT4 is a gene that plays an important role in activating the immune system and may be associated with several autoimmune diseases.

But while a particular SNP in STAT4 may put someone at greater risk for a rheumatologic disease, the vast majority of people with this polymorphism will never get lupus or rheumatoid arthritis. STAT4 is only one part of a very complex story and may not even be the most important part. What this study does demonstrate is the power of genomic medicine in helping us to understand diseases at the most basic level. In the future, we can expect these advances to help us identify people at risk for certain disorders and even help us pick the best medicines to treat them. Genomic medicine will give "getting a blood test" a whole new meaning.

Robert W. Lash, M.D. is an associate professor of internal medicine at the University of Michigan Medical School. His clinical interests include thyroid disease, diabetes, endocrine disorders in pregnancy, osteoporosis and metabolic bone disease, and medical education. A member of the LLuminari team of experts, a board certified internist and endocrinologist, Dr. Lash has an active clinical practice and is a hospitalist at the University of Michigan.

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