Dettling M, Schaub R T, Mueller-Oerlinghausen B, Roots I, Cascorbi I
Department of Psychiatry, University Hospital Benjamin Franklin, Free University of Berlin, Germany.
Pharmacogenetics. 2001 Mar;11(2):135-41. doi: 10.1097/00008571-200103000-00004.
To further examine the human leukocyte antigen (HLA)-encoded genetic susceptibility to clozapine-induced agranulocytosis (CA) we performed HLA-genotyping in a sample of German schizophrenic patients, who suffered from this haematotoxic side-effect. Thirty-one schizophrenic patients with CA (17 women and 14 men) and 77 schizophrenic comparison subjects (40 women and 37 men) were included in the study. HLA-genotyping included identification of major histocompatibility complex (MHC) class I (HLA-A, B, Cw) and class II (HLA-DR, DQ) antigens. CA was significantly associated with HLA-Cw7 (P<0.02), DQB0502 (P<0.04), DRB10101 (P<0.03) and DRB30202 (P<0.02). These HLA-haplotypes are also partly linked to other diseases with a strong genetic background. All other antigens revealed no association to this haematotoxic reaction. In addition, we did not find gender-related effects, whereas age seemed to be a further major risk factor of CA (P<0.0003). Thus, HLA loci may serve as genetic marker to identify subjects of different ethnic subgroups prone to this severe idiosyncratic drug reaction of clozapine. Further studies are needed to investigate whether these associations with CA are due to causal involvement or linkage disequilibrium.
为了进一步研究人类白细胞抗原（HLA）编码的对氯氮平诱导的粒细胞缺乏症（CA）的遗传易感性，我们对一组患有这种血液毒性副作用的德国精神分裂症患者进行了HLA基因分型。该研究纳入了31例患有CA的精神分裂症患者（17名女性和14名男性）以及77名作为对照的精神分裂症患者（40名女性和37名男性）。HLA基因分型包括对主要组织相容性复合体（MHC）I类（HLA - A、B、Cw）和II类（HLA - DR、DQ）抗原的鉴定。CA与HLA - Cw7（P<0.02）、DQB0502（P<0.04）、DRB10101（P<0.03）和DRB30202（P<0.02）显著相关。这些HLA单倍型也部分与其他具有强大遗传背景的疾病相关。所有其他抗原均未显示与这种血液毒性反应有关。此外，我们未发现性别相关影响，而年龄似乎是CA的另一个主要风险因素（P<0.0003）。因此，HLA基因座可作为遗传标记，用于识别不同种族亚组中易患这种氯氮平严重特异质药物反应的个体。需要进一步研究来调查这些与CA的关联是由于因果关系还是连锁不平衡。
