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Clozapine is a highly efficacious drug for the treatment of schizophrenia, but its use is limited, in part due to the side effect of agranulocytosis. In order to reduce the incidence of clozapine-induced agranulocytosis (CIA), patients are required to submit to a blood monitoring program. A genetic component to CIA is suggested by published associations in a number of genes. A genetic test assessing the risk of CIA might allow safer and more broad use of clozapine. We previously conducted a candidate gene-based case-control study to discover genes associated with CIA. Cases were patients with an ANC A replication analysis was performed on an independently collected cohort of 49 cases and 78 controls from Germany. Cases were patients who developed an ANC

Clozapine is a highly efficacious drug for the treatment of schizophrenia, but its use is limited, in part due to the side effect of agranulocytosis. In order to reduce the incidence of clozapine-induced agranulocytosis (CIA), patients are required to submit to a blood monitoring program. There is evidence that there is a genetic component to CIA, with previously published associations in a number of genes, including HLA-DQB1 (Dettling et. al., Arch Gen Psychiatry2001: 59, 93–94) and HLA-C (Dettling et. al., Pharmacogenetics2001: 11, 135–141). If a genetic test for CIA were developed, it is possible that clozapine could become a safer drug and more patients could benefit from its use. As a first step in developing such a test, we have conducted a case-control study to discover genetic markers associated with CIA. Cases were patients with an ANC5000 and ANC Characteristics of the Discovery Cases n=33 Controls n=54 Gender Male 17 33 Female 16 21 Ethnicity American Indian 4 4 Black or African American 1 2 White 28 48 Age Median (range) in years 36 (20–58) 35 (18–54) Nadir ANC Median (range) 237 (0–506) N/A Diagnosis Schizophrenia/Schizoaffective Disorder 32 53 Bipolar Disorder 1 1 Time to CIA Median (range) in months 2.2 (0.5–62.6) N/A Seventy-four candidate genes were sequenced in the exons, intron-exon boundaries, 5′ untranslated region and promoter region for each of the cases and controls. Single nucleotide polymorphisms and small insertion/deletions were scored and a haplotype analysis conducted, comparing the frequency of haplotypes in cases to those in controls using logistic regression with covariates of age, gender and race. Permutation tests were done within each gene and a genetic marker was considered significant with an adjusted p value