What follows is from the National Center for Biotechnology Information. I think it’s one of the best descriptions of a SNP. It’s important to remember that when considering SNPs in the context of pharmacogenetics, the actual SNP may not be the cause of a particular response (as, for example, the SNP associated with the ultrametabolizer form of cytochrome P450 (CYP2D6). Some SNPs probably are causes, while others are best considered markers.

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A Single Nucleotide Polymorphism, or SNP (pronounced “snip”), is a small genetic change, or variation, that can occur within a person’s DNA sequence. The genetic code is specified by the four nucleotide “letters” A (adenine), C (cytosine), T (thymine), and G (guanine). SNP variation occurs when a single nucleotide, such as an A, replaces one of the other three nucleotide letters—C, G, or T.

An example of a SNP is the alteration of the DNA segment AAGGTTA to ATGGTTA, where the second “A” in the first snippet is replaced with a “T”. On average, SNPs occur in the human population more than 1 percent of the time. Because only about 3 to 5 percent of a person’s DNA sequence codes for the production of proteins, most SNPs are found outside of “coding sequences”. SNPs found within a coding sequence are of particular interest to researchers because they are more likely to alter the biological function of a protein. Because of the recent advances in technology, coupled with the unique ability of these genetic variations to facilitate gene identification, there has been a recent flurry of SNP discovery and detection.

Technorati Tags: pharmacogenetics, DNA, SNP

If you’re actively engaged in genetic research, you surely know of the National Center for Biotechnology Information, a Division of the NIH’s National Library of Medicine. If you’re not familiar with NCBI, I suggest going to their site right now. Get a cup of coffee and set aside some time. You won’t be disappointed.

NCBI maintains several genetics databases, including the world’s largest repository of DNA sequencing data. In 2005, in collaboration with GenBank (Bethesda, Maryland USA), European Molecular Biology Laboratory’s European Bioinformatics Institute (EMBL-Bank in Hinxton, UK), and the DNA Data Bank of Japan (Mishima, Japan), the DNA sequence database topped 100 gigabases (100,000,000,000).

The site also has a set of map viewers that allow readers to compare physical chromosome maps with linkage and sequencing maps.

But for me, your basic general internist, the best feature of the site are its primers on pharmacogenomics and on Clinically important genetic diseases. I was also pleased to see that this site repeats the mantra of this blog: with respect to medications, one size does not fit all!

Here the introduction to their pharmacogenetics page:

Right now, in doctors’ offices all over the world, patients are given medications that either don’t work or have bad side effects. Often, a patient must return to their doctor over and over again until the doctor can find a drug that is right for them. Pharmacogenomics offers a very appealing alternative. Imagine a day when you go into your doctor’s office and, after a simple and rapid test of your DNA, your doctor changes her/his mind about a drug considered for you because your genetic test indicates that you could suffer a severe negative reaction to the medication. However, upon further examination of your test results, your doctor finds that you would benefit greatly from a new drug on the market, and that there would be little likelihood that you would react negatively to it. A day like this will be coming to your doctor’s office soon, brought to you by pharmacogenomics.

Technorati Tags: DNA databases, pharmacogenetics, pharmacogenomics, genetic diseases

It was nine years ago, the significance of which will shortly be revealed. I was attending on the medicine ward service. Our team—myself, a resident and two interns—was on-call every fourth night. If we were lucky, we would manage to squeeze in a few hours of sleep between admissions and pages from the various wards.

At morning report, the interns would present the cases and I would offer comments and a critique. After that, we’d go down to radiology to review any x-rays that accompanied our cases and then we’d go up to the wards to visit the patients. From an academic medical point of view, there were no particularly rare or challenging cases that day, but there was one patient who I could never forgot: Mr. Johnson.

Mr. Johnson was 103 years old, blind and stiff from arthritis, but entirely alert. Mr. Johnson did not have Alzheimer’s. Instead, he was admitted for treatment of a community acquired pneumonia.

When I went to the bedside I felt obliged to draw on my experiences to say something educational both for the housestaff and for the patient, but as we entered Mr. Johnson’s room I was drawing a blank. In the course of this clinical rotation, we’d pretty much discussed pneumonia to the limits of my knowledge. The interns and resident had taken excellent care of Mr. Johnson. He was getting the correct antibiotics and a whiff of oxygen through some nasal prongs. The TV was on, but I could tell he couldn’t see it through his clouded eyes.

“Good morning Mr. Johnson,” I said and I shook his hand. “I’m Doctor Eshleman—one of the doctors who’s taking care of you in the hospital.”

“Hello,” said Mr. Johnson.

“Mr. Johnson, we don’t get many patients as old as you. In fact, I think you’re the oldest patient I’ve ever had. Can I ask you a few questions?” Read the rest of this entry »

We’ll get to the microarrays in a moment. But first…

It’s Thursday and the latest issue of The New England Journal of Medicine has arrived in my mail. The article that’s getting the most play in the popular press is “The value of medical spending in the United states, 1960-2000.” According to authors David Cutler, Allison Rosen, and Sandeep Vijan, from 1960 through 2000, the life expectancy of a newborn in the USA increased by 6.97 years and lifetime medical spending adjusted for inflation increased by approximately $69,000. That’s an increase, not a total!

The authors use this data to calculate the cost per year of life gained. The numbers are startling. The average cost per year of life gained for a 15-year-old during the period 1960-2000 was more than $31,000. For a 65-year-old, the cost per year of life gained was more than $84,000. Between 1990 and 2000, the costs per year of life gained for a 65-year-old was $145,000!

The authors make a big assumption: that at least half of the gain in life expectancy is due to medical advances, specifically decreases in infant mortality and decreased death rates from cardiovascular disease. Among their conclusions is that the costs of medical care for the elderly are rising more rapidly than did any gains in life expectancy.

That’s not a new conclusion. I recall hearing somewhere that about half of all Medicare funds go to the care of an individual during the last year of his or her life. If someone can give me a cite (or dispute it), feel free.

Reading on in the same issue of the NEJM, I came across a letter commenting on the article Microarray analysis and tumor classification that was published back in the June 8, 2006 issue. That very same article has been sitting in my ever-enlarging pile of things to read. Some of the material at the bottom of the pile is surely out-of-date by now.

Spurred on by the letter, I sat down and read the article. It is a good summary of the techniques being used to identify and interpret patterns of gene expression in cancer cells. There are nice illustrations of microarray analysis and the development of a gene expression matrix. It seems very likely that these techniques will one day augment or replace TNM and other staging systems in choosing therapies or estimating prognosis.

The authors also include a nice summary of all the “-omics” (genomics, metabolomics, proteomics) that are finding their way into the medical literature.

Among the authors’ conclusions are that

“…gene-expression signatures obtained with the use of microarray analysis are difficult to interpret with respect to the biology of the underlying disease. Ultimately, finding genes that can be linked through their mechanism to disease outcome suggest potential therapeutic interventions. But failure to provide a biological interpretation does not diminish the potential clinical usefulness of well-established biomarkers. Many biomarkers, such as prostate-specific antigen and caricinoembryonic antigen, that have unknown functions are useful as diagnostic or prognostic markers for various diseases. It may be useful to consider the lists of genes emerging from classification experiments as sets of biomarkers; insight into biologic mechanism is a bonus.

The Tuesday New York Times section “Science Times” has been doing a nice job of keeping up with advances in pharmacogenetics. This Tuesday’s (August 29, 2006) section includes an interview “Saving lives with Tailor-Made Medication” with Dr. Mary Relling of Memphis’ St. Jude Children’s Research Hospital.

Dr. Relling relates that at her hospital “patients with leukemia [Acute Lymphocytic Leukemia] are now routinely given genetic tests to determine their individual response to a medication. ‘We’ve seen it save lives here. That’s made me a believer’”.

The article doesn’t identify the particular medication to which Dr. Relling refers, but I believe it must be methotrexate

Dr. Relling says what many of us proponents of pharmacogenetics have been saying: that a one-size-fits-all approach to medications can cause problems. “In most cases,” she says, “an average dose of medication is ordered, and then, if the patient suffers side effects, the dosage is adjusted. With gene testing, we can customize the prescription.”

“At the moment, there seems to be a lot of promise for pharmacogenetics in the treatment of arthritis, heart disease, colon cancer and even psychiatric diseases like depression and schizophrenia.”

Article highly recommended. Check it out!

Technorati Tags: pharmacogenetics, oncology, leukemia

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By some estimates, more that 25% of prescription medications are metabolized by a particular form of cytochrome P450 (CYP for short) known as CYP2D6. Some popular medications metabolized with CYP2D6 include Aricept, Strattera, Claritin, Codeine, Elavil, Inderal, Oxycontin, Prozac, Paxil, Zoloft, Vicodin, Effexor, Tofranil.

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Cytochrome P450 takes its name from “pigment at 450 nanometers” because spectrographic analysis shows that the enzyme absorbs light very strongly at that wavelength.

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It turns out that different forms of CYP2D6 have different levels of activity. It’s also known that genetic variants called Single Nucleotide Polymorphisms (geneticists call these SNPs, pronounced “snips”) are associated with the different forms of CYP2D6. Read the rest of this entry »

It was only through serendipity that I was able to attend the last day of the conference on Genomics, Race, and Health Disparities that I mentioned in my previous posting. My wife heard mention of the conference on a local NPR station while driving home from work. “This sounds like the kind of stuff you’re interested in,” she said. She was right!

The first day’s topics centered on genomics and race, and included a presentation by Dr. Rick Kittles of Ohio State University. Dr. Kittles was the founder of African Ancestry Inc. and currently Associate Professor in the Department of Molecular Virology, Immunology & Medical Genetics at Ohio State University. Dr. Kittles’ current work concentrates on “how DNA sequence variation contributes to susceptibility to common complex diseases…,” specifically prostate cancer, which in the USA has the highest incidence and prevalence rates among African Americans.

In the abstract of his presentation, Dr. Kittles writes “the observed population differences in prostate cancer incidence and mortality can not be explained completely by differences in access to and quality of health care, diet, or other lifestyle characteristics. Whether differences in the distribution of known or undefined genetic risk factors among different populations explain the disparity is unknown. What is known is that many prostate cancer candidate genes exhibit large differences in allele frequencies across different populations. The significance of these patterns has yet to be fully understood.” Read the rest of this entry »

From the University of California, Davis news and information service:

Health experts, researchers and opinion leaders from across the country will meet in Oakland, Calif., Aug. 18-19 for a national conference on genomics, health and race. The goal of the conference is to explore how genomics could potentially be used to customize medical care such as diet plans and medications to improve the health of minorities. Conference attendees will discuss a wide spectrum of related ethical, legal and economic issues.

The conference, titled “A National Dialogue: Genomics, Race, and Health Disparities,” will be held at the Claremont Resort.

The meeting is organized by the National Center for Minority Health and Health Disparities’ (NCMHD) Center of Excellence for Nutritional Genomics, based at the University of California, Davis, and Children’s Hospital Oakland Research Institute (CHORI). Keynote speakers include Nicholas Wade, science writer for the New York Times, and Dr. Jeffrey Drazen, editor of the New England Journal of Medicine and professor at Harvard University. The conference chairman is Dr. Ronald Krauss, senior scientist at CHORI.

“We are moving toward an era in which personalized medicine is a real possibility, but there are real concerns that must be resolved such as safeguards to ensure genetic information will not be used in a discriminatory way,” said Krauss. “We hope this conference will begin a national dialogue to bridge the gap between science and social responsibility.” Leading anthropologists and sociologists will also share their views during the conference.

Two articles in the most recent (August 10) issue of The New England Journal of Medicine are very apropos. The first article–Dr. Adam Wolfberg’s Genes on the Web: Direct to Consumer Marketing of Genetic Testing–contains several references to DNA Direct, the company that sponsors this blog.

Direct to Consumer advertising (DTC) are fighting words to many physicians, due to pharmaceutical companies relentless use of the practice. By now we have all become accustomed to televised images of happy consumers who appear to be constantly on vacation and whose lives have apparently been transformed by prescription sleep aids, anti-depressants, allergy remedies, cholesterol drugs, and, of course the whole family of ED drugs.

The practice is objectionable (among other reasons) because it creates stresses in the doctor-patient relationship when a patient presents demanding the advertised drug and the doctor determines that it is either (1) not indicated or (2) presents no advantage over a lower-priced generic.

DTC genetic testing has to the best of my knowledge yet to be advertised on prime time television, but there are several companies, including DNA Direct, that offer these services through their Web sites. Read the rest of this entry »

Although this blog concentrates on how genomic technology can aid in the correct prescription of therapeutic drugs, it’s also a place where physicians (and others) can share experiences, ask questions, and maybe even let their hair down. What follows is a memory of a trip I took not long ago to Hawaii to attend a CME event.

Twilight spreads over the beach and the blue Pacific. The trade winds carry the scent of the sea mingled with touches of ginger and barbecue smoke. I’m seated in the dining room of an elegant restaurant on the windward side of Kauai, finishing a cocktail and getting ready to spear a crabcake pupu with my chopsticks. Somewhere between the crabcake and the ahi carpaccio, the lights dim and a PowerPoint® presentation begins. Then I notice that jaws are beginning to drop all around our table, and that all of the jaw-droppers are non-physicians

The speaker—a physician from a neighbor isle—is telling us about therapy for irritable bowel syndrome. His talk is peppered with references to “diarrhea, bloating, constipation” and to the various combinations of these conditions.

Our choices of Prime Rib or Mahi Mahi arrive at the table. Read the rest of this entry »