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SAEC and Duke Partner to ID SNPs Linked to Clozapine-Induced Agranulocytosis

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By Turna Ray

The International Serious Adverse Events Consortium and Duke University's Center for Human Genome Variation will work together to identify rare gene variants linked to a reduced immune response in some schizophrenia patients treated with clozapine.

Clozapine-induced agranulocytosis, or CIA, is a condition that prevents the bone marrow from producing white blood cells, resulting in a severely reduced immune response. Less than 2 percent of clozapine-treated patients experience this adverse event. The US Food and Drug Administration has approved the marketing of the antipsychotic medication under a surveillance system requiring clozapine-treated patients to undergo a weekly white-cell count prior to receiving their weekly supply of the drug.

David Goldstein, professor of molecular genetics and microbiology at Duke, and Anna Need of the department of psychiatry will jointly lead the effort to identify and validate rare gene variants associated with this adverse event via whole-genome sequencing. This is the first time whole-genome sequencing technology will be applied for a SAEC pilot project.

SAEC is a non-profit consortium formed in October 2007 between industry, academia, and the FDA to identify genetic variants associated with serious adverse events. The group last year released initial data on gene variations linked to the drug-related skin condition Stevens-Johnson syndrome and drug-induced liver injury [see PGx Reporter 06-03-2009]. Those studies used microarray-based GWAS.

According to SAEC Chairman Arthur Holden, the research into gene variants associated with CIA is an extension of the consortium's previous work in Stevens-Johnson syndrome and drug-induced liver injury, since the immune system plays a "strong role" in those conditions as well.

"By researching the genetics of drug-induced CIA, we hope to further our understanding into the genetics of immunologically mediated adverse drug responses," Holden said in a statement.

As with all SAEC research efforts, the data from the CIA studies will be made available to researchers through the consortium's website. Whole-genome sequencing has already begun for the project, and initial data from the research is projected for release in mid-2011.

The SAEC/Duke research into CIA is made possible by a donation of research materials and data from Clinical Data's PGxHealth division on a collection of CIA cases. Specifically, PGxHealth last November provided data on candidate gene studies and genome-wide association studies of CIA that it had already completed. The data gave further credence to already published evidence on common gene variations linked to CIA in the HLA region on chromosome 6.

Holden told Pharmacogenomics Reporter this week that due to the rarity of CIA, PGxHealth's data on common variants linked to this adverse event would have no commercial viability in terms of developing a genetic test. However, with whole-genome sequencing, researchers will be able to identify rare variants, which, when combined with common SNPs associated with CIA, may help create a more detailed molecular profile of the condition.

"For many patients clozapine is the most effective drug available, but its use is constrained by the possibility of this serious adverse event requiring intrusive monitoring programs." said Goldstein in a statement. "We hope that understanding the genetics of CIA will not only reduce its occurrence, but also allow wider use of clozapine."

Still a commercial test for CIA is a long way off and would likely need to be spearheaded by a large pharmaceutical firm, Holden said, since validating clinical trials would need to enroll a large number of patients in order to capture enough events. Although Clinical Data did not garner any special commercialization rights for donating their GWAS data on CIA, the company remains interested in the findings of SAEC's efforts.

"As early investigators in this area, we are pleased to be working with the SAEC and Duke to advance important research on clozapine," said Marcia Lewis, VP of biomarker development at PGxHealth. "We look forward to the results of the research, which will continue to inform potential commercialization strategies for diagnostic test development."

Novartis, one of SAEC's industry partners, manufactures clozapine under the brand Clozaril for treatment of recurrent suicidal behavior in schizophrenia patients and for the treatment of severely ill schizophrenic patients who fail to respond to standard antipsychotic drug therapies.

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