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Page 152 Shad. J Transl Genet Genom 2023;7:141-65 https://dx.doi.org/10.20517/jtgg.2023.11

[105]
CIA than men due to an older age of onset of psychosis and clozapine initiation. Although few studies
have reported no gender differences in risk for CIA [20,106-108] , women may have a higher risk of clozapine-
[113]
induced leukopenia [109-111] than CIA . Women are also prescribed fewer clozapine treatments than men .
[112]
Taken together, these findings suggest a complex interaction between age and gender as summarized by an
earlier onset of psychosis and clozapine treatment in younger men contrasted with a later onset of psychosis
and clozapine treatment in older women with a higher age-related risk for CIA.

Genetic predictors for clozapine-induced agranulocytosis
The genetic predictors for CIA are pharmacodynamic (PD) in nature, and pharmacokinetic factors have
rarely been associated with CIA. The first evidence for PD genetic factors came from twin studies [114,115] ,
followed by several studies reporting a significant association between polymorphisms in the MHC and
CIA . One of these early studies in a small sample reported that 83% of the patients who developed CIA
[38]
carried the HLA-B38 marker . The predictability of CIA went up to 100% after 3 HLA alleles (i.e.,
[39]
HLA-B38, HLA-DR4, and HLA-DQw3) were combined compared to only 12% of controls . The finding
[39]
with HLA-B38 was replicated in other studies [41,44] . A couple of studies found a link between the MHC
complex of HSP-70 9.0A in both Jewish and non-Jewish populations [40,42] . Other genetic polymorphisms
[40]
that have been reported in the Ashkenazi Jewish population, in association with CIA, include HLA-
[41]
DQA1*0301, HLA-0302, HLA-0402, and HLA-DRB1*11 . The role of HLA-DRB1*04 in the CIA has been
replicated in a small number of non-Jewish German populations . However, it is worth mentioning that
[47]
the genetic patterns may vary between different Jewish people due to their migration from the Middle East
to many countries and intermarriages with local populations.

Although there is a relative lack of such studies in other ethnic groups, the ethnically diverse allele of HLA-
DRB1*04 is reported to be less frequent in Sub-Saharan, Native and North American, and Southeast Asian
subjects than the European population . More importantly, a recent review and meta-analysis found a
[116]
negative probability value of about 99% for CIA without the HLA-DRB1*0402 allele, which may allow
relaxed blood monitoring . Interestingly, the high negative predictability of the HLA-DRB1*0402 for
[38]
CIA is about the same as that of the HLA-B*58:01 with allopurinol and of HLA-B*1511 for
[117]
[38]
carbamazepine for skin reaction . However, the negative predictability of CIA for HLA-DRB1*0402 is
[118]
higher than that of HLA-B*5701 for abacavir reactions (i.e., 82%) . Although the positive predictability of
[119]
HLA-DRB1*04:02 for CIA is only about 4%, it is still higher than the positive predictability of HLA-B*15:11
[120]
for carbamazepine-induced Steven Johnson Syndrome (i.e., 1%) . These findings suggest that 99% of the
individuals without HLA-DRB1*0402 are unlikely to have CIA, while only about 4% of the individuals with
HLA-DRB1*0402 are predicted to develop CIA. However, the low positive predictability is counterbalanced
by the high negative predictability of HLA-DRB1*0402, making this allele a valuable predictive genetic test
for CIA . The high negative predictability of HLA-DRB1*0402 for a relatively rare occurrence of CIA
[38]
[121]
suggests its clinical utility in a much larger group of patients .
Like the positive predictability, the ability of HLA-DRB1*04:02 to detect true positive cases of CIA (i.e.,
sensitivity) is also relatively low but still higher than that of the HLA-A*31:01 (23%) , and HLA-B*15:11
[122]
(14%) for the carbamazepine-induced skin reactions. However, like the negative predictability, the ability
[118]
of HLA-DRB1*04:02 to detect true negative cases (i.e., specificity) is high (i.e., 94%) but slightly lower than
[118]
that of HLA-A*31:01 (i.e., 95%) and HLA-B*15:02 (i.e., 99%) for carbamazepine hypersensitivity. A
[122]
specificity of 94% with HLA-DRB1*04:02 is interpreted as six out of 100 individuals will be at high risk for
[123]
agranulocytosis, which is not that different from the actual population risk of 0.8% . Therefore, specificity
needs to exceed 99% to be clinically useful. Nevertheless, the predictive value and validity of an HLA-
DRB1*04:02 screening test for assessing the patient risk of CIA are comparable to the existing HLA
predictors currently used in clinical practice.