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.     

Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal)

Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population.     

DNA polymorphisms associated with lactase persistence,self-perceived symptoms of lactose intolerance,milk and dairy consumption,and ancestry,in the Uruguayan population

Uruguay has one of the highest per capita milk intakes worldwide, even with a limited supply of lactose-free products; furthermore, the admixed nature of its population is well known, and various frequencies of lactase persistence (LP) are observed in the source populations. We aimed to contribute to the understanding of the relation between allelic variants associated with LP, milk consumption, digestive symptoms, and genetic ancestry in the Uruguayan population. Samples of saliva or peripheral blood were collected from 190 unrelated individuals from two regions of Uruguay, genotypes for polymorphic sites in a fragment within the LCT enhancer were determined and allelic frequencies calculated in all of them. Data were collected on frequency of milk and dairy consumption and self-reported symptoms in a subsample of 153 individuals. Biparental and maternal ancestry was determined by analyzing individual ancestry markers and mitochondrial DNA. Twenty-nine percentage of individuals reported symptoms attributed to the ingestion of fresh milk, with abdominal pain, bloating and flatulence being the most frequent. European LP-associated allele T-13910 showed a frequency of 33%, while other LP-associated alleles like G-13915 and T-14011 were observed in very low frequencies. Associations between self-reported symptoms, fresh milk intake, and C/T-13910 genotype were statistically significant. No evidence of association between genetic ancestry and C/T-13910 was found, although individuals carrying one T-13910 allele appeared to have more European ancestry. In conclusion, the main polymorphism capable of predicting lactose intolerance in Uruguayans is C/T-13910, although more studies are required to unravel the relation between genotype and lactase activity, especially in heterozygotes.