Genetic Susceptibility to Clozapine-Induced Agranulocytosis/Neutropenia Across Ethnicities: Results From a New Cohort of Turkish and Other Caucasian Participants, and Meta-Analysis

Abstract

Clozapine (CLZ) is considered the most effective antipsychotic, but its use is associated with neutropenia (CIN) and agranulocytosis (CIA). Although the exact etiology of these hazardous side effects is unknown, 4 genetic polymorphisms have been implicated by genomewide association studies (GWAS), mostly performed in North-Western Europeans. These polymorphisms are rs113332494 (HLA-DQB1), rs41549217 (HLA-B), and rs1546308/rs149104283 (SLCO1B3/7), several of which were not directly genotyped but imputed. To test whether these 4 single-nucleotide polymorphisms (SNPs) are associated with CIN/CIA in a Turkish population and in a more extensive group of Caucasians, we directly genotyped these polymorphisms using Taqman and Sanger sequencing and performed logistic regression. We divided our participants (234 CLZ-using participants of whom 31 CIN/CIA cases) into (1) North-Western European, (2) Turkish, (3) Caucasian (=1 + 2); and (4) a total group (Caucasian + other ethnicities). Rs113332494 (HLA-DQB1) was significantly associated with CIN/CIA in the total group (P = 3.5 10-8), in the Caucasian group (P = 9.3 10-6) and in the Turkish group (P = 2.8 10-5). Rs41549217 (HLA-B) was nominally significant in the Caucasian group (P = .018). In meta-analysis of our results and the previously reported genome-wide results, 3 SNPs were significantly associated with CIN/CIA in participants with Caucasian ancestry: rs113332494 (P = 2.05 10-8), rs41549217 (P = 7.19 10-9), and rs149104283 (P = 5.54 10-9), with the result for rs1546308 (SCLO1B3/SCLO1B7) being significantly heterogeneous across studies. Our results hint at ethnicity-dependent and clinically relevant effects of genetic polymorphisms on the risk to develop CIN/CIA. Pharmacogenetic testing can complement clinical decision making and thus empower appropriate CLZ prescribing, but ancestry should be taken into account when performing such testing for CLZ. The Author(s) 2020.