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Stanford Team Identifies SNP Linked to Adverse Events in Two Antidepressants

Researchers at Stanford University Medical Center claim to have identified a genetic marker linking the use of certain common antidepressants and side effects.

Greer Murphy, associate professor of psychiatry and behavioral sciences, and Alan Schatzberg, professor of psychiatry and behavioral sciences, sought to find proteomic and genomic variations among patients undergoing therapy with antidepressants.

“Good candidate” proteins linked to antidepressant response include the neurological receptors with which the drug interacts, and the hepatic enzymes that metabolize the drugs. In their eight-week study, Murphy and Schatzberg analyzed DNA samples from 246 depressed patients randomly assigned either paroxetine, marketed as Paxil by SmithKline Beecham, or mirtazapine, marketed as Remeron by Organon.

The two drugs “work in completely different ways,” though both affect serotonin, the authors explained. This led them to study one type of serotonin receptor, 5HT2A, which is implicated in antidepressant-related side effects. Since Remeron “completely blocks” this receptor, Murphy and Schatzberg predicted that variations in the 5HT2A gene would not influence the drug’s side effects. Paxil, by contrast, is a selective serotonin re-uptake inhibitor and works by allowing more serotonin to remain in the brain. The drug “does not directly interact” with serotonin receptors, “so they remain functional, which can lead to unwanted side effects” such as dyspepsia, dizziness, insomnia, and agitation.

The researchers determined that genotype for the 102 T/C SNPs in the serotonin 5-HT2A locus “is thought to affect the amount of the receptor on nerve cells,” they explained in their study, which appears in the October issue of the American Journal of Psychiatry. (The team said that this locus was previously associated with outcomes of psychotropic treatment.) When Murphy and Schatzberg compared the version of this gene with a patient’s experience taking the drug, the differences generated by the mutation “were striking,” the researchers said. “People with the one version of the gene were much more likely to discontinue therapy due to intolerable side effects when compared to the two other versions,” the team said, adding that 46 percent of patients sought to end their therapy compared with 16 percent who did not.

Among patients given Remeron, however, the researchers saw “no effect” linked to the SNP — an outcome they predicted. The ability of both drugs to work as an antidepressant “was unrelated” to the patients’ genetic component, the researchers stressed.

Murhpy told SNPtech Reporter that Duke has offered to license an assay based on these findings to drug and diagnostic makers, but has had no takers yet.

Procter & Gamble Exploring Developing Molecular Dx for Toxic Shock Syndrome

Procter & Gamble is considering creating a molecular diagnostic test to determine whether certain women are at an increased risk for developing toxic shock syndrome, a company official told SNPtech Reporter.

A spokesman for P&G, the maker of Tampax tampons — which are linked, like all other tampons, with toxic shock syndrome — said the company has no timeline within which it would create the diagnostic, and has not yet decided what steps it would take. However, the spokesman, Jay Gooch, said one way might be to link up with a SNP-database company or molecular diagnostics company to start looking for relevant mutations.

Toxic shock syndrome, or TSS, is a rare illness that occurs mostly in menstruating women who use high-absorbency tampons. Non-menstrual TSS risk is increased for women who use vaginal barrier-contraceptive methods, although the incidence is much lower, according to the University of Illinois at Urbana-Champaign, which tracks data on TSS and maintains a patient-support web site.

TSS is caused by a certain strain of Staphylococcus Aureus, and hyperabsorbent tampons “may facilitate” the infection because their prolonged intra-vaginal use enhances the bacterial growth, the university said.

Gooch said P&G’s decision to pursue a molecular diagnostic for the condition follows a study the company sponsored that found a link between TSS and a low-serum concentrate of 30 proteins called complement. Complement is believed to play a “pivotal role” in the body’s immune response to infections.

In their study, the researchers analyzed the levels of complement in sera taken from women during TSS as well as after they had fully recovered. They then compared these levels to levels found in age-matched healthy women who carried S. Aureus, which makes TSST1, the staphylococcal toxin associated with TSS. Complement levels were “significantly higher” in healthy women than in women who had been diagnosed with TSS, including even after they recovered, the researchers found.

Most women have antibodies to the toxin, though the lack of antibodies “may not be the only explanation as to why some women get” TSS, P&G said.

UCSD Team Identifies gene variant That May Suppress Retrovirus-Insertion Mutations

A team of researchers from the University of California, San Diego has identified a variation in an “essential” gene that appears to suppress gene mutations caused by retroviruses.

Working with mice, the researchers identified a novel change in the mRNA nuclear export factor 1 gene, which in its normal state ensures that only properly functioning genes are expressed within cells.

The team demonstrated that the Nxf1 variation “restored function to mutated genes” by increasing the amount of normal product made by the mutated gene, and “alleviated abnormalities” in two mouse mutations.

“The properties of this gene could be used to engineer a system for controlling some mutations caused by retroviruses,” according to Bruce Hamilton, UCSD assistant professor of medicine and a study co-author. “This could be particularly useful for creating mouse models of human disorders where loss of gene expression is a target of therapeutic efforts, but the dose-responsiveness required for functional recovery is unknown, such as in Fragile X syndrome and certain cancers.”

When a retrovirus enters a cell, it can insert a copy of itself into a gene. “As a result, the host gene may be poorly expressed, and depending upon the gene and how it is affected, this can cause disease,” the team said. According to a UCSD statement, the researchers were surprised that a protein required for a late step in gene expression “appears to influence earlier steps in gene expression, processing of the pre-mRNA.” As a result, the group’s findings are believed to be the first to identify suppression at a later stage, “when the mutated gene has been activated, but before it can do damage.”

To arrive at their conclusions, which appear in the Sept. 28 online edition of Nature Genetics, the UCSD team began investigating the murine Modifier-of-vibrator-1 gene, which is known to reduce the sequalae of a neurological gene mutation called vibrator. The vibrator mutation — which causes severe tremors, progressive degeneration of the brain stem and spinal cord, and premature death — is in turn caused by insertion of a mouse retrovirus called IAP.

The team found that vibrator mice carrying the Mvb1 genes showed “reduced” tremor severity and managed to survive to adulthood. The researchers also showed that the Mvb1 genes were able to do this by increasing the amount of normal RNA made from the mutant vibrator gene. Later, the team showed that Mbv1 also modifies an Eya1 mutation, which is a murine model of human branchio-otorenal syndrome — also caused by an IAP retrovirus. The Eya1 gene helps develop the inner ear and other structures. Mutations are characterized by hearing impairment, ear malformation, and, in some cases, kidney malfunction. “Again, Mbv1 modified several of the Eya1 characteristics by increasing the expression of normal RNA made from the mutant gene,” the researchers said.

Next, the team relied on positional complementation to identify Mvb1, and to “determine that it is part of the mRNA nuclear export factor Nxfl.” The researchers also showed that the Nxf1 variation that enables the suppression of retrovirus mutations “is present in a large population of wild mice,” and that this variant form of the gene has “evolved, under natural selection, to increase its frequency in the population.” — KL

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