Genetic epistasis in female suicide attempters

Background

Complex behaviors such as suicidal behavior likely exhibit gene–gene interactions. The main aim of this study is to explore potential single nucleotide polymorphisms combinations with epistatic effect in suicidal behavior using a data mining tool (Multifactor Dimensionality Reduction).

Methods

Genomic DNA from peripheral blood samples was analyzed using SNPlex Technology. Multifactor Dimensionality Reduction was used to detect epistatic interactions between single nucleotide polymorphisms from the main central nervous system (CNS) neurotransmitters (dopamine: 9; noradrenaline: 19; serotonin: 23; inhibitory neurotransmitters: 60) in 889 individuals (417 men and 472 women) aged 18 years or older (585 psychiatric controls without a history of suicide attempts, and 304 patients with a history of suicide attempts). Individual analysis of association between single nucleotide polymorphisms and suicide attempts was estimated using logistic regression models.

Results

Multifactor Dimensionality Reduction showed significant epistatic interactions involving four single nucleotide polymorphisms in female suicide attempters with a classification test accuracy of 60.7% (59.1%–62.4%, 95% CI): rs1522296, phenylalanine hydroxylase gene (PAH); rs7655090, dopamine receptor D5 gene (DRD5); rs11888528, chromosome 2 open reading frame 76, close to diazepam binding inhibitor gene (DBI); and rs2376481, GABA-A receptor subunit γ3 gene (GABRG3). The multivariate logistic regression model confirmed the relevance of the epistatic interaction [OR(95% CI) = 7.74(4.60–13.37)] in females.

Conclusions

Our results suggest an epistatic interaction between genes of all monoamines and GABA in female suicide attempters.     

Microinflammation induces endothelial damage in hemodialysis patients: the role of convective transport

Cardiovascular complications are a major cause of mortality in hemodialysis patients. On-line hemofiltration combines convective clearance for removing large solutes with diffusion to remove small solutes and is associated with a significant reduction of inflammation and improved patient survival. We compared on-line hemofiltration to high-flux hemodialysis (HF-HD) in patients in a sequential manner. At baseline, 15 stable patients on HF-HD as compared with five control subjects showed significant increases in CD14+CD16+ cells, endothelial microparticles, and endothelial progenitor cells (EPCs). After 4 months of on-line hemofiltration, the number of CD14+CD16+ cells, microparticles, and EPCs decreased. After returning to HF-HD for 4 months, all measured parameters returned to their respective baseline values. The number of CD14+CD16+ cells correlated with both endothelial microparticles and EPCs. We conclude that on-line hemofiltration attenuates endothelial dysfunction possibly by decreasing microinflammation. This effect may be directly caused by a modulatory effect of on-line hemofiltration on proinflammatory cells or by a complex interaction that encompasses a wider removal of uremic toxins.     

Association of schizophrenia with DTNBP1 but not with DAO, DAOA, NRG1 and RGS4 nor their genetic interaction

Recent reports indicate that DAO, DAOA, DTNBP1, NRG1 and RGS4 are some of the most-replicated genes implicated in susceptibility to schizophrenia. Also, the functions of these genes could converge in a common pathway of glutamate metabolism. The aim of this study was to evaluate if each of these genes, or their interaction, was associated with schizophrenia. A case-control study was conducted in 589 Spanish patients having a diagnosis of schizophrenia, and compared with 617 equivalent control subjects. Several single nucleotide polymorphisms (SNPs) in each gene were determined in all individuals. SNP and haplotype frequencies were compared between cases and controls. The interaction between different SNPs at the same, or at different gene, loci was analyzed by the multifactor dimensionality reduction (MDR) method. We found a new schizophrenia risk and protective haplotypes in intron VII of DTNBP1; one of the most important candidate genes for this disorder, to-date. However, no association was found between DAO, DAOA, NRG1 and RGS4 and schizophrenia. The hypothesis that gene-gene interaction in these five genes could increase the risk for the disorder was not confirmed in the present study. In summary, these results may provide further support for an association between the dysbindin gene (DTNBP1) and schizophrenia, but not between the disease and DAO, DAOA, NRG1 and RGS4 or with the interaction of these genes. In the light of recent data, these results need to be interpreted with caution and future analyses with dense genetic maps are awaited.