TY - JOUR
T1 - Genetic Susceptibility to Clozapine-Induced Agranulocytosis/Neutropenia Across Ethnicities
T2 - Results From a New Cohort of Turkish and Other Caucasian Participants, and Meta-Analysis
AU - Okhuijsen-Pfeifer, Cynthia
AU - Ayhan, Yavuz
AU - Lin, Bochao D.
AU - Van Eijk, Kristel R.
AU - Bekema, Erwin
AU - Kool, Lindy J.G.B.
AU - Bogers, Jan P.A.M.
AU - Muderrisoglu, Ahmet
AU - Babaoglu, Melih O.
AU - Van Assche, Evelien
AU - Medic, Jelena
AU - Veerman, Selene
AU - Cohen, Dan
AU - Van Beek, Hanneke
AU - De Jonge, Annemieke A.M.
AU - Beld, Edwin
AU - Yoca, Gökhan
AU - Altlnyazar, Vesile
AU - Aydln, Memduha
AU - Görgülü, Yasemin
AU - Klvlrclk Akdede, Berna B.
AU - Alptekin, Köksal
AU - Üçok, Alp
AU - Danacl, Ayşen Esen
AU - Ilhan, Bilge Cetin
AU - Ulusoy, Semra
AU - Soygür, Haldun
AU - Özdemir, Hatice
AU - Çelik, Mustafa
AU - Orhan, Fatma Özlem
AU - Ozan, Hasret
AU - Kaygisiz, Ismet
AU - Yaǧcloǧlu, A. Elif Anll
AU - Luykx, Jurjen J.
N1 - Publisher Copyright:
© 2020 Oxford University Press. All rights reserved.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - adverse events
KW - pharmacogenetics
KW - precision medicine
KW - psychiatric
UR - http://www.scopus.com/inward/record.url?scp=85109353497&partnerID=8YFLogxK
U2 - 10.1093/schizbullopen/sgaa024
DO - 10.1093/schizbullopen/sgaa024
M3 - Article
AN - SCOPUS:85109353497
VL - 1
JO - Schizophrenia Bulletin Open
JF - Schizophrenia Bulletin Open
IS - 1
M1 - sgaa024
ER -