Jan. 22, 2013 Scientists have identified genetic circumstances under which common mutations on two genes interact in the presence of cocaine to produce a nearly eight-fold increased risk of death as a result of abusing the drug.

An estimated one in three whites who died of cocaine exposure is a carrier of variants that make cocaine abuse particularly deadly.

The variants are found in two genes that affect how dopamine modulates brain activity. Dopamine is a chemical messenger vital to the regular function of the central nervous system, and cocaine is known to block transporters in the brain from absorbing dopamine after its release.

The same dopamine genes are also targeted by medications for a number of psychiatric disorders. The researchers say that these findings could help determine how patients will respond to certain drugs based on whether they, too, have mutations that interact in ways that affect dopamine flow and signaling.

The scientists had previously identified a total of seven mutations on two dopamine-related genes, some of which were linked to the risk for cocaine abuse death. Years of molecular genetics studies showed that the mutations had specific functions -- a single variant alone was associated with an almost three-fold increase in risk of dying of cocaine abuse -- and led researchers to hypothesize that the variants probably interacted because the genes themselves relied on each other for proper function.

A statistical analysis that dissected the complex interactions among the variants combined with cocaine exposure revealed gene-gene-environment interactions that would dramatically increase the risk of death from cocaine abuse.

"Finding an impact factor of 8 just blew us away," said Wolfgang Sadee, professor of pharmacology and director of the Program in Pharmacogenomics at Ohio State University and senior author of the study. "Beyond that, this represents a new paradigm. Going forward, we can ask whether such interactions do exist between variants that may be a normal variation in the population. These kinds of interactions may underlie the genetics of behavior."

These specific findings apply primarily to whites. The researchers found that a different combination of variants affect the risk of cocaine abuse death in African Americans, and that in this population, some of the variants had protective properties.

The research is published in the online journal Translational Psychiatry.

The mutations are mostly single-nucleotide polymorphisms, or SNPs (pronounced "snips"). Each gene contains two alternative forms -- called alleles -- that are functionally identical in most people. However, in some cases, the activity level, or expression, of an allele can differ from its partner allele in a single gene.

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Gene interactions make cocaine abuse death eight times more likely

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