Clustering suicidal phenotypes and genetic associations with brain-derived neurotrophic factor in patients with substance use disorders.

Suicide attempts (SA), especially recurrent SA or serious SA, are common in substance use disorders (SUD). However, the genetic component of SA in SUD samples remains unclear. Brain-derived neurotrophic factor (BDNF) alleles and levels have been repeatedly involved in stress-related psychopathology. This investigation uses a within-cases study of BDNF and associated factors in three suicidal phenotypes ('any', 'recurrent', and 'serious') of outpatients seeking treatment for opiate and/or cocaine use disorder. Phenotypic characterization was ascertained using a semi-structured interview. After thorough quality control, 98 SNPs of BDNF and associated factors (the BDNF pathway) were extracted from whole-genome data, leaving 411 patients of Caucasian ancestry, who had reliable data regarding their SA history. Binary and multinomial regression with the three suicidal phenotypes were further performed to adjust for possible confounders, along with hierarchical clustering and compared to controls (N = 2504). Bayesian analyses were conducted to detect pleiotropy across the suicidal phenotypes. Among 154 (37%) ever suicide attempters, 104 (68%) reported at least one serious SA and 96 (57%) two SA or more. The median number of non-tobacco SUDs was three. The BDNF gene remained associated with lifetime SA in SNP-based (rs7934165, rs10835210) and gene-based tests within the clinical sample. rs10835210 clustered with serious SA. Bayesian analysis identified genetic correlation between 'any' and 'serious' SA regarding rs7934165. Despite limitations, 'serious' SA was shown to share both clinical and genetic risk factors of SA-not otherwise specified, suggesting a shared BDNF-related pathophysiology of SA in this population with multiple SUDs.

QT length during methadone maintenance treatment: gene × dose interaction.

Methadone is known to be a risk factor for sudden death by enlarging ECG QT corrected (QTc) interval. For other medical conditions, QTc lengthening has been described as the result of interactions between pharmacological treatments and genetic factors. Former heroin-dependent subjects under methadone maintenance treatment in remission for at last 3 months were recruited. We studied the association between QTc length (Bazett formula) and 126 SNPs located on five genes (KCNE1, KCNQ1, KCNH2, NOS1AP and SCN5A) previously associated with drug-induced QT prolongation. Both SNP-based and gene-based approaches were used, and we tested also the interaction of the top SNP with methadone dosage to predict the QTc length. In our sample of 154 patients, current methadone daily dose was associated with QTc length (rPearson  = 0.26; P = 10-3 ). Only one SNP, rs11911509 on KCNE1, remained significantly associated with QT length after correction for multiple testing (P = 3.84 × 10-4 ; pcorrected  = 0.049). Using a gene-based approach, KCNE1 was also significantly associated with QTc length (pempirical  = 0.02). We found a significant interaction between methadone dosage and rs11911509 minor allele count (allele A vs. C; P = 0.01). Stratified analysis revealed that the correlation between QTc length and methadone dosage was restricted only to AA carriers of this top SNP. Patients' genetic background should be taken into account in the case of clinically relevant QT enlargement during methadone maintenance treatment.

KCNH2 polymorphism and methadone dosage interact to enhance QT duration.

BACKGROUND: Many drugs increase the duration of the QT interval of patients, potentially leading to harmful effects such as polymorphic ventricular arrhythmias. Most of these drugs do so by inhibiting the rapid component IKr of the delayed rectifier potassium current IK. Methadone is the most prescribed heroin maintenance treatment and is known to inhibit the cardiac potassium channel hERG, which recapitulates IKr. In order to evaluate if any polymorphism of potassium channels' genes could explain some of the "idiosyncratic" QT prolongations observed in patients treated with methadone, we tested the association between KCNE1, KCNE2, and KCNH2 polymorphism and the QT interval prolongation in those patients, controlling for other variables associated with a decrease of the repolarizing reserve. METHODS: A cohort of 82 patients treated with stable dosage of methadone (mean dosage 65 mg/d) for at least three months was genotyped for five polymorphisms in KCNE1, KCNE2 and KCNH2 genes and had their corrected QT (QTc) assessed. RESULTS: The mean QTc interval was 415±34ms. In a linear regression model, longer QTc interval was associated with methadone dosage and with one genetic factor. Each copy of a Lys allele at codon 897 of KCNH2, the gene that encodes the cardiac potassium voltage-gated channel hERG, was associated with a 15.4ms longer QTc (95% CI [4.6-26.2]; p=0.001). CONCLUSION: KCNH2 genotyping may be relevant in the analysis of cumulative risk factors for QT prolongation in patients on methadone maintenance treatment.

Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.

Familial hemophagocytic lymphohistiocytosis (FHL) is a genetically heterogeneous autosomal recessive immune disorder characterized by the occurrence of uncontrolled activation of lymphocytes and macrophages infiltrating multiple organs. Disease-causing mutations in the perforin (PRF1; also known as FHL2), Munc13-4 (UNC13D; also known as FHL3), and syntaxin-11 (STX11; also known as FHL4) genes have been identified in individuals with FHL. These genes all encode proteins involved in the cytotoxic activity of lymphocytes. Here, we show that the gene encoding syntaxin-binding protein 2 (Munc18-2; official gene symbol STXBP2) is mutated in another subset of patients with FHL (designated by us as "FHL5"). Lymphoblasts isolated from these patients had strongly decreased STXBP2 protein expression, and NK cells exhibited impaired cytotoxic granule exocytosis, a defect that could be overcome by ectopic expression of wild-type STXBP2. Furthermore, we provide evidence that syntaxin-11 is the main partner of STXBP2 in lymphocytes, as its expression required the presence of STXBP2. Our work shows that STXBP2 deficiency causes FHL5. These data indicate that STXBP2 is required at a late step of the secretory pathway for the release of cytotoxic granules by binding syntaxin 11, another component of the intracellular membrane fusion machinery.