HLA-DQB1 6672G>C (rs113332494) is associated with clozapine-induced neutropenia and agranulocytosis in individuals of European ancestry

Abstract

The atypical antipsychotic clozapine is the only effective medication for treatment-resistant schizophrenia. However, it can also induce serious adverse drug reactions, including agranulocytosis and neutropenia. The mechanism by which it does so is largely unknown, but there is evidence for contributing genetic factors. Several studies identified HLA-DQB1 variants and especially a polymorphism located in HLA-DQB1 (6672G>C, rs113332494) as associated with clozapine-induced agranulocytosis and neutropenia. We analysed the risk allele distribution of SNP rs113332494 in a sample of 1396 controls and 178 neutropenia cases of which 60 developed agranulocytosis. Absolute neutrophil counts of 500/mm3 and 1500/mm3 were used for defining agranulocytosis and neutropenia cases, respectively. We also performed association analyses and analysed local ancestry patterns in individuals of European ancestry, seeking replication and extension of earlier findings. HLA-DQB1 (6672G>C, rs113332494) was associated with neutropenia (OR = 6.20, P = 2.20E−06) and agranulocytosis (OR = 10.49, P = 1.83E−06) in individuals of European ancestry. The association signal strengthened after including local ancestry estimates (neutropenia: OR = 10.38, P = 6.05E−08; agranulocytosis: OR = 16.31, P = 1.39E−06), with effect sizes being considerably larger for agranulocytosis. Using local ancestry estimates for prediction, the sensitivity of rs113332494 increased from 11.28 to 55.64% for neutropenia and from 16.67 to 53.70% for agranulocytosis. Our study further strengthens the evidence implicating HLA-DQB1 in agranulocytosis and neutropenia, suggesting components of the immune system as contributing to this serious adverse drug reaction. Using local ancestry estimates might help in identifying risk variants and improve prediction of haematological adverse effects.

Adverse Drug Reactions of Olanzapine, Clozapine and Loxapine in Children and Youth: A Systematic Pharmacogenetic Review

“…However, highlighting the possible association of DRD2 polymorphisms with increased weight gain, their findings supported Lencz et al's [64] conclusions. Otherwise, while our query yielded one study addressing the role of HLA gene variations in DILI (Ocete-Hita et al) [79], we did not retrieve similar approaches regarding clozapine-induced neutropenia and agranulocytosis that formerly have been investigated [83].…”

Distinctive pattern of neutrophil count change in clozapine-associated, life-threatening agranulocytosis

“…Second, genetic association studies are compromised by the inclusion of cases of neutropenia and agranulocytosis that are neither related to clozapine nor of clinical consequence. The highest sensitivity value ever obtained for a genetic test for clozapine-related agranulocytosis is 54% 14 . However, all studies so far conducted defined agranulocytosis as any measurement of ANC ≤ 0.5 × 10 9 /L and so inevitably included in their study samples a proportion of people with a nominal and inconsequential agranulocytosis.…”

“…The concept of clozapine-induced neutropenia might also be a blind-alley for research into genetic predisposition to clozapine-induced blood dyscrasia. Although the same genetic variants seem to be responsible for the increased risk of both neutropenia and agranulocytosis 13 , a recent study found a strong link between the human leucocyte antigen (HLA) polymorphism rs113332494 and agranulocytosis but not neutropenia 14 . Moreover, in studies where genetic associations with clozapine-associated neutropenia are suggested 15 , it is acknowledged that the majority of neutropenia cases do not develop into agranulocytosis.…”

Pharmacogenomics of Clozapine-induced agranulocytosis: a systematic review and meta-analysis

“…Results from our meta-analysis showed that HLA-DQB1 *05:02 (OR = 7.12, 95% CI 1.91–26.51) was significantly associated with CIA, before Bonferroni corrections were applied (Table 3 ). Furthermore, Legge et al (2017) [ 27 ] and Konte et al (2021) [ 54 ] provided independent replications for the association between HLA-DQB1 6672 G > C and CIA risk in individuals of European ancestry. These results implicate HLA-DQB1 in the pathophysiology of CIA and indicates that polymorphisms within this gene may be associated with risk of CIA in European populations.…”