Search

GeneGeneInteR is an R package dedicated to the detection of an association between a case-control phenotype and the interaction between two sets of biallelic markers (single nucleotide polymorphisms or SNPs) in case-control genome-wide associations studies. The development of statistical procedures for searching gene-gene interaction at the SNP-set level has indeed recently grown in popularity as these methods confer advantage in both statistical power and biological interpretation. However, all these methods have been implemented in home made softwares that are for most of them available only on request to the authors and at best have a web interface. Since the implementation of these methods is not straightforward, there is a need for a user-friendly tool to perform gene-based genegene interaction. The purpose of GeneGeneInteR is to propose a collection of tools for all the steps involved in gene-based gene-gene interaction testing in case-control association studies. Illustrated by an example of a dataset related to rheumatoid arthritis, this paper details the implementation of the functions available in GeneGeneInteR to perform an analysis of a collection of SNP sets. Such an analysis aims at addressing the complete statistical pipeline going from data importation to the visualization of the results through data manipulation and statistical analysis.

Paracoccidioidomycosis (PCM) is an important endemic, systemic disease in Latin America caused by Paracoccidioides spp. This mycosis has been associated with high morbidity and sequels, and its clinical manifestations depend on the virulence of the infecting strain, the degree and type of immune response, infected tissues, and intrinsic characteristics of the host. The T helper(Th)1 and Th17/Th22 cells are related to resistance and control of infection, and a Th2/Th9 response is associated with disease susceptibility. In this study, we focused on interleukin(IL)-12p35 (IL12A), IL-18 (IL18), and IFN-γ receptor 1 (IFNGR1) genetic polymorphisms because their respective roles have been described in human PCM. Real-time PCR was employed to analyze IL12A-504 G/T (rs2243115), IL18-607 C/A (rs1946518), and IFNGR1-611 A/G (rs1327474) single nucleotide polymorphisms (SNP). One hundred forty-nine patients with the acute form (AF), multifocal chronic (MC), or unifocal chronic (UC) forms of PCM and 110 non-PCM individuals as a control group were included. In the unconditional logistic regression analysis adjusted by ethnicity and sex, we observed a high risk of the IL18-607 A-allele for both AF [p = 0.015; OR = 3.10 (95% CI: 1.24–7.77)] and MC groups [p = 0.023; OR = 2.61 (95% CI: 1.14–5.96)] when compared with UC. The IL18-607 A-allele associated risk for the AF and MC groups as well as the protective role of the C-allele in UC are possibly linked to higher levels of IL-18 at different periods of the course of the disease. Therefore, a novel role of IL18-607 C/A SNP is shown in the present study, highlighting its importance in the outcome of PCM.

Paracoccidioidomycosis (PCM) is an important endemic, systemic disease in Latin America caused by Paracoccidioides spp. This mycosis has been associated with high morbidity and sequels, and its clinical manifestations depend on the virulence of the infecting strain, the degree and type of immune response, infected tissues, and intrinsic characteristics of the host. The T helper(Th)1 and Th17/Th22 cells are related to resistance and control of infection, and a Th2/Th9 response is associated with disease susceptibility. In this study, we focused on interleukin(IL)-12p35 (IL12A), IL-18 (IL18), and IFN-γ receptor 1 (IFNGR1) genetic polymorphisms because their respective roles have been described in human PCM. Real-time PCR was employed to analyze IL12A -504 G/T (rs2243115), IL18 -607 C/A (rs1946518), and IFNGR1 -611 A/G (rs1327474) single nucleotide polymorphisms (SNP). One hundred forty-nine patients with the acute form (AF), multifocal chronic (MC), or unifocal chronic (UC) forms of PCM and 110 non-PCM individuals as a control group were included. In the unconditional logistic regression analysis adjusted by ethnicity and sex, we observed a high risk of the IL18 -607 A -allele for both AF [ p = 0.015; OR = 3.10 (95% CI: 1.24–7.77)] and MC groups [ p = 0.023; OR = 2.61 (95% CI: 1.14–5.96)] when compared with UC. The IL18 -607 A -allele associated risk for the AF and MC groups as well as the protective role of the C -allele in UC are possibly linked to higher levels of IL-18 at different periods of the course of the disease. Therefore, a novel role of IL18 -607 C/A SNP is shown in the present study, highlighting its importance in the outcome of PCM. [ABSTRACT FROM AUTHOR]

This study was conducted to test the association between promoter DNA methylation of α-Adducin (ADD1) gene and the risk of essential hypertension (EH). A total of 150 EH patients and 100 aged- and gender-matched controls were investigated. DNA methylation levels of five cytosine-phosphate-guanine (CpG) dinucleotides on ADD1 promoter were measured employing bisulfite pyrosequencing technology. Our results showed that females have a higher ADD1 DNA methylation than males and a significantly lower CpG1 methylation level is associated with increased risk of EH among them. As for males, a significant association between lower CpG2-5 methylation levels and increased risk of EH was shown. In addition, CpG2-5 methylation was found to be a highly significant predictor for EH among males. In females, CpG1 methylation was considered a predictor of hypertension. No significant correlations were found with biochemical measures, apart from the concentration of aspartate aminotransferase which was inversely correlated with ADD1 CpG2-5 methylation levels among female controls (r = −0.703). These findings highlight that ADD1 methylation may have a contributing role in the pathogenesis of EH with varying implications for both genders.

This study was conducted to test the association between promoter DNA methylation ofα-Adducin(ADD1) gene and the risk of essential hypertension (EH). A total of 150 EH patients and 100 aged- and gender-matched controls were investigated. DNA methylation levels of five cytosine-phosphate-guanine (CpG) dinucleotides on ADD1 promoter were measured employing bisulfite pyrosequencing technology. Our results showed that females have a higher ADD1 DNA methylation than males and a significantly lower CpG1 methylation level is associated with increased risk of EH among them. As for males, a significant association between lower CpG2-5 methylation levels and increased risk of EH was shown. In addition, CpG2-5 methylation was found to be a highly significant predictor for EH among males. In females, CpG1 methylation was considered a predictor of hypertension. No significant correlations were found with biochemical measures, apart from the concentration of aspartate aminotransferase which was inversely correlated with ADD1 CpG2-5 methylation levels among female controls (r = −0.703). These findings highlight that ADD1 methylation may have a contributing role in the pathogenesis of EH with varying implications for both genders. [ABSTRACT FROM PUBLISHER]

ATP-binding cassette transporter (ABC) protein group is one of the most abundant protein family exhibiting diverse functions. Proteins of this group are present and expressed in virtually every tissue, with ABCC subfamily functional spectrum of ion transport, cell-surface signaling and toxin secretion. ABCC proteins are adenosine triphosphate (ATP) dependent with hydrolysis-derived energy used for the transport of substrates through the cellular membranes. Research data also confirm their role in the regulation of cellular homeostasis, including metabolism of xenobiotics or the intracellular signal transmission. ABCC protein also play regulatory role in the aging processes of the thymus and bone marrow cells and transport of antiretroviral drugs. Association of the ABCC single nucleotide polymorphisms with levels of drugs and treatment efficacy, including antiretroviral agents was found to be in a significant relationship with pharmacodynamics of antiretroviral agents. ABCC proteins and its genetic variation may be associated with the transport of antiretroviral drugs, differences in the ARV concentrations and development of drug toxicity, especially in the context of the tenofovir-based treatment and renal tubulopathy. Associations of gene variants with efficacy and adverse effects of the antiretroviral therapy may provide the tools for the better selection of the therapies in the future and are important step toward personalized medicine. [ABSTRACT FROM AUTHOR]

Schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches—the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia. [ABSTRACT FROM AUTHOR]