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Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11 Page 153

In another study, a link between HLA-DQB1*0201 and CIA has been documented in both Jewish and non-
[43]
Jewish patient populations . Association between NQ02 372 T>C and CIA was also observed but only in
[45]
the Jewish population . A following study in the Finnish population also found a significant correlation
[46]
between HLA-A1, HLA-A28, and HLA-B16 and CIA . In another study, CIA in the non-Jewish German
population was associated with more MHC polymorphisms, including HLA-Cw*7, HLA-DPB*0401,
HLA_DQB*0502, HLA-DRB1*0101, and HLA-DRB3*0202 . A later study from the same research group
[47]
replicated findings with HLA-Cw*7 but no other findings from the earlier study . In a recent meta-
[48]
analysis, two haplotypes, HLA-DQB1*0502 and HLA_DQB1 6672 G>C, were associated with increased risk
for CIA in Europeans . The following study by Van der Weide et al. replicated the link between CIA and
[124]
NQ02 polymorphisms in an earlier study [45,49] . Two prospective clozapine studies reported an odds ratio
(OR) of 17 for CIA in patients with an HLA-DQB1 SNP (i.e., 2G>C) with high specificity and sensitivity
rates . Later studies have also reported a correlation between clozapine-induced neutropenia and two
[50]
independent polymorphisms in HLA-DQB1 (126Q), previously associated with autoimmune disease, and
HLA-B (158T) with severe drug reactions .
[52]
Other genes have also been implicated in CIA in the European population, such as SNP rs149104283 on
chromosome 12p12.2 , but not in the Japanese population . However, HLA-B*5901 was correlated with
[51]
[125]
[126]
CIA in the Chinese population . One study proposed that patients with clozapine-related neutropenia in
the absence of HLA-B*59:01 may be given a clozapine retrial . In addition, CIA was also associated with
[53]
the tumor necrosis factor but not with CYPD26 variants or cytochrome b-245 α polypeptide .
[127]
[42]
[101]
Although African subjects may have a better clozapine response than Europeans, a higher genetic risk for
benign ethnic neutropenia (BEN), often misdiagnosed as CIA or clozapine-induced neutropenia, has
[128]
resulted in frequent discontinuation of clozapine treatment . Single studies have also reported ethnic
differences in genes associated with CIA, such as a large British study reporting more than a two-fold higher
risk of CIA in Asians than Caucasians . Another study showed a protective effect with TNFb5 and an
[104]
increased susceptibility with TNFd3 to CIA in schizophrenia patients with Jewish and non-Jewish
[42]
backgrounds . These findings suggest significant ethnic differences in genetic predictors for CIA [124,129] . In
addition, some studies investigating other polymorphisms have not produced promising results, such as a
weak correlation between an oxidative gene NADPH quinone 2 (NQO2) polymorphism and bone marrow
toxicity and negative findings with another oxidative gene for myeloperoxidase [101,127] .
[45]
Although it took some time to initiate genome-wide research in this area, a growing number of genome-
wide association studies (GWAS) have explored the genetic basis of CIA. The first GWAS supported a
significant association between CIA and HLA-DQB1-126Q and HLA-B-158T . Although not replicated,
[52]
HLA-DQB1 (126Q) has a strong linkage disequilibrium with HLA-DQB1*05:02, one of the most replicated
risk alleles for CIA [41,106] . Another study revealed a sensitivity of about 21% and specificity of about 98% for
[50]
the HLA-DQB1 6672G>C polymorphism for CIA [Table 1]. The second GWAS in the Japanese
population reported a significant association between HLA-B*59:01 and CIA , with a sensitivity of about
[53]
32% and a specificity of about 95% . The third GWAS in non-Jewish Europeans found SNP rs149104283 at
[53]
chromosome 12p12.2 associated with CIA . However, this finding was not replicated in a Japanese
[51]
sample . The latest GWAS conducted in the Chinese population identified a weak correlation between
[125]
[126]
clozapine-related leukopenia and SNP rs11753309 near HLA-B . These ethnic differences in risk alleles for
CIA across GWAS further support the need for studies with multi-ethnic representation. Some of the
findings from the candidate gene studies have also been endorsed by GWAS studies, such as the correlation
between CIA and HLA-DBQ1 and HLA-B*5901 polymorphisms. However, most results from reviewed
studies are based on small sample studies in various ethnic groups and should be interpreted cautiously