High Frequency of Occurrence of CYP2D6 Gene Duplication/Multiduplication Indicating Ultrarapid Metabolism Among Suicide Cases

Abstract

In Sweden, about 550 individuals die every year of drug intoxication. Many of these drugs are metabolized by CYP enzymes such as CYP2D6 and CYP2C19. A lack of these enzymes, resulting in poor metabolism, can lead to adverse reactions and even to fatality. On the other hand, an ultrarapid metabolism can lead to insufficient drug plasma concentration, resulting in failure of treatment, or it can lead to high concentrations of active/toxic metabolites. The aim of this project was to study the genetic profile of individuals with regard to the presence of CYP2D6 and CYP2C19 genes, in cases of fatal intoxication (242), suicide (intoxications excluded) (262), and natural death (212). PCR, followed by pyrosequencing, was used for all the analyses. We found that, among those who died of suicide (suicide cases), there was a higher number carrying more than two active CYP2D6 genes (corresponding to the phenotype of ultrarapid metabolizer) as compared with those who died of natural causes (natural-death cases) (P = 0.007).

CYP2D6 polymorphism in patients with eating disorders

“…However, further research is needed to overcome the limitations inherent in the present design, including the control for potential biases derived from recruiting individuals who volunteer for this type of study. 12 Present findings seem to be in agreement with previous results showing that UMs are more frequent among suicide cases, 13 persistent mood-disordered patients 14 and among women with symptoms of depression, 15 which usually overlap with ED. [16][17][18] In addition, we have previously reported that PMs are less frequent among schizophrenic patients than among healthy subjects (2.3 vs 8.5%, respectively), 19 which would be in accordance with lower scores on a measure of risk to psychopathology or general distress also found among PM healthy volunteers.…”

“…11 Moreover, we have shown that PMs appear to present lower psychopathology compared with EMs. [11][12] Consistently, UMs appear more frequent among individuals who commit suicide, 13 or who present persistent mood disorder, 14 as well as among women with postpartum depression. 15 In addition, altered serotonin neurotransmission and associated comorbid affective disorders are frequently described in ED.…”

Influence of CYP2D6 genotype on the disposition of the enantiomers of venlafaxine and its major metabolites in postmortem femoral blood

“…In another Finnish study, 33 cases positive for tramadol were genotyped and 12% PMs and 12% UMs were found [58]. Zackrisson et al [38] have in an earlier Swedish study genotyped 239 intoxication suicide cases, 254 violent suicide cases and 205 natural death cases. The mean number of PMs found in these three materials was 6.8% and the corresponding figure for UMs was 2.6% [38].…”

“…Three single nucleotide polymorphisms (SNPs), *3, *4 and *6, were included in the genotyping of CYP2D6 (Table 1). These alleles were identified by PCR and pyrosequencing as earlier described [37] with some minor modifications [38].…”

“…For determination of the gene copy number, the pseudogene CYP2D8 was co-amplified with the CYP2D6 gene in the PCR as described previously [39] with some minor modifications [38]. Identification of the genes that was multiplied in samples with more than two gene copies was determined using peak pattern recognition of programs from the SNP analysis [38].…”