119carbon dioxide, muscle rigidity, acidosis, tachycardia, tachypnea, hyperthermia,
and evidence of rhabdomyolysis. This process is a result of an abnormally increased
release of calcium from the sarcoplasmic reticulum, which is often caused by an
inherited mutation in the gene for the ryanodine receptor (RYR1) that resides in the
membrane of the sarcoplasmic reticulum. The gold standard for determination of
MH susceptibility is the caffeine-halothane contracture test. However, it is invasive,
requiring skeletal muscle biopsy and is not widely available. Researchers have
begun to map mutations within the ryanodine receptor gene (chromosome 19q13.1)
responsible for conferring MH susceptibility. Ryanodine receptor mutations are
found in at least 25 % of known MH susceptible individuals in North America.
Mutation analysis is now available commercially and is expected to play an integral
role in the diagnosis of MH susceptibility in the future.
Pharmacogenetics of Clozapine-Induced Agranulocytosis
Clozapine has long been accepted as one of the most effective medications for treat-
ing schizophrenia but has had limited utilization due to the risk of inducing agranu-
locytosis, a life-threatening decrease of white blood cells that requires frequent
blood testing of patients. In 2004, CARING (Clozapine and Agranulocytosis
Relationships Investigated by Genetics) study, reported the discovery of genetic
biomarkers that predict who is at risk of developing clozapine-induced agranulocy-
tosis. This raised the hope for a one-time genetic test may obviate the need for
continuous blood monitoring for the majority of clozapine- treated patients. These
fi ndings have uncovered new clues to the underlying biological and physiologic
mechanisms of drug-induced agranulocytosis and provide a starting point for eluci-
dating a common mechanism across drugs from different classes that carry this rare
but devastating side effect. The sensitivity and selectivity of these biomarkers could
support further development of a diagnostic test. One of the associations identifi ed
in the HLA (Human Leukocyte Antigen) complex has been previously reported to
be associated with clozapine-induced agranulocytosis.
However, no genetic test is currently available for clozapine-induced agranulo-
cytosis. The proposed test of HLA-DQB1 6672G > C has high specifi city but low
sensitivity, and fails to reduce the agranulocytosis risk in the LR group to a point
that monitoring could be reduced or ceased (Verbelen et al. 2014 ). Candidate gene
studies have failed to identify a strong, replicated genetic variant that substan-
tially increases risk of clozapine-induced agranulocytosis. The fi rst genome-wide
association study of clozapine-induced agranulocytosis detected signifi cant asso-
ciations at two HLA amino acids (Goldstein et al. 2014 ). At least one further
study of development of pharmacogenomic biomarkers for schizophrenia,
CRESTAR, is in progress ( http://www.crestar-project.eu/ ). Combined analysis of
such studies may identify associated genetic variants that can be rapidly translated
to clinical practice.
Role of Pharmacogenetics in Pharmaceutical Industry