Matrix metalloproteinases as target genes for gene regulatory networks driving molecular and cellular pathways related to a multistep pathogenesis of cerebrovascular disease

The present study investigated a joint contribution of matrix metalloproteinases (MMPs) genes to ischemic stroke (IS) development and analyzed interactions between MMP genes and genome-wide associated loci for IS. A total of 1288 unrelated Russians (600 IS patients and 688 healthy individuals) from Central Russia were recruited for the study. Genotyping of seven single nucleotide polymorphisms (SNPs) of MMP genes (rs1799750, rs243865, rs3025058, rs11225395, rs17576, rs486055, and rs2276109) and eight genome-wide associated loci for IS were done using Taq-Man–based assays and MALDI-TOF mass spectrometry iPLEX platform, respectively. Allele − 799T at rs11225395 of the MMP8 gene was significantly associated with a decreased risk of IS after adjustment for sex and age (OR = 0.82; 95%CI, 0.70-0.96; P = 0.016). The model-based multifactor dimensionality reduction method has revealed 21 two-order, 124 three-order, and 474 four-order gene-gene (G×G) interactions models meaningfully (P_perm < 0.05) associated with the IS risk. The bioinformatic analysis enabled establishing the studied MMP gene polymorphisms possess a clear regulatory potential and may be targeted by gene regulatory networks driving molecular and cellular pathways related to the pathogenesis of IS. In conclusion, the present study was the first to identify an association between polymorphism rs11225395 of the MMP8 gene and IS risk. The study findings also indicate that MMPs deserve special attention as a potential class of genes influencing the multistep mechanisms of cerebrovascular disease including atherosclerosis in cerebral arteries, acute cerebral artery occlusion as well as the ischemic injury of the brain and its recovery.     

Molecular diagnosis and frequencies of primary hypolactasia in populations of Russia and neighboring countries

Normally, the ability to digest milk sugar (lactose) is present in every child, but not in every adult. The decrease in lactase synthesis (hypolactasia) results in the inability to digest whole milk. Recent studies of the Finnish population have associated lactase persistence in adults with allele T of the C/T_?13910 polymorphism located upstream of the lactase gene; a 100% correlation of primary hypolactasia with genotype C/C has been proved. In this study, the allele and genotype frequencies of C/T_?13910 were determined in populations of Russia. The frequencies of genotype C/C, varying from 36.6% in Russians to 88.2% in Chukchi, were close to the published medical and epidemiological data on the hypolactasia frequencies in these populations. Genotyping was carried out by three different methods to determine the optimal one. Genotype C/C proved to be the key determinant of primary hypolactasia. It was assumed that DNA diagnosis of genotype C/C provides a predictive test to detect primary hypolactasia long before its clinical manifestation.     

Genetic variants in glutamate cysteine ligase confer protection against type 2 diabetes

Molecular Biology Reports - Oxidative stress contributes to the pathogenesis of type 2 diabetes (T2D). This study investigated whether single nucleotide polymorphisms (SNPs) at genes encoding...     

Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis

Chronic glomerulonephritis (CGN) is one of the most severe kidney diseases. Genes of vascular reactivity are thought to play an important role in development and progression of CGN. In this study, we analyzed association of genes of vascular homeostasis with hypertension and renal survival of CGN patients. The study sample included 238 patients with CGN and 304 healthy subjects of population control. Ten polymorphisms of ten genes of vascular homeostasis were genotyped through polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) analysis and TaqMan assays. Association of the genotypes with renal survival was analyzed by the Kaplan–Meier estimator. Genotypes 311SC and 311SS of the PON2 gene, (− 1166)AC and (− 1166)CC of the AGTR1 gene, (+ 46)AA of the ADRB2 gene, and 198KK and 198KN of the EDN1 gene were associated with decreased rate of renal survival of the patients. Polymorphisms S311C PON2, (− 1166)A/C AGTR1, (+ 46)G/A ADRB2, and K198N EDN1 were associated with the accelerated decline in kidney function in the CGN patients.     

Genetic Aspects of Chronic Rhinosinusitis

Chronic rhinosinusitis (CRS) is a syndrome associated with persistent inflammation of the mucous membranes of the nose and paranasal sinuses. There are two forms of CRS: chronic rhinosinusitis with nasal polyposis (CRSwNP) and chronic rhinosinusitis without nasal polyposis (NP) (CRSsNP). Available data indicate that innate immunity, adaptive immunity, tissue remodeling, and influence of microorganisms can play a modified role in the development of CRSwNP. The genetic predisposition to the development of CRS is also possible. Today there are several groups of genes which influence the development of chronic rhinosinusitis. They include the genes associated with CFTR locus, HLA genes, genes of innate immunity, genes involved in the development of TH2-inflammatory reactions, genes responsible for tissue remodeling of paranasal sinuses, genes involved in the metabolism of arachidonic acid, genes of xenobiotic transformation, and other pro-inflammatory genes. Identification of genetic susceptibility to CRS would make it possible to develop personalized approaches for prevention, tactics, and effective treatment of chronic rhinosinusitis.     

Polymorphisms of Intracellular Cholesterol Transporters Genes: Relationship to Blood Lipid Levels,Carotid Intima-Media Thickness,and the Development of Coronary Heart Disease

Russian Journal of Genetics - The influence of single nucleotide polymorphism (SNP) of genes encoding intracellular cholesterol transporters, such as rs1883025 of ABCA1, rs217406 of NPC1L1, and...     

Analysis of the association of the G-7A polymorphism of the matrix Gla protein gene with ischemic atherothrombotic stroke in humans with its different risk factors

The G-7A polymorphism (rs1800801) of the matrix Gla protein (MGP) gene was determined in 170 patients with ischemic atherothrombotic stroke (IATS) and 124 control persons. It was found that the distribution of the major allele homozygotes, heterozygotes, and minor allele homozygotes was 35.9, 48.8, and 15.3% in patients with IATS (in the control, 43.5, 50.0, and 6.5%; P = 0.051 by the χ² test). Significant differences in the distribution of genotypes were revealed only in women (P = 0.022). The odds ratio (OR) for minor allele homozygotes (A/A) vs. major allele carriers (G/A + G/G) was 2.618 (P = 0.023), while in women it was equal to 6.645 (P = 0.015). In patients with the A/A genotype, the values of the blood coagulation parameters (prothrombin time) indicated increased their predisposition to hypercoagulability. The results obtained prove that the A/A variant of the MGP gene is associated with an increased risk of IATS in females of the Ukrainian population and may be related to blood hypercoagulability and formation of thrombi.     

Discovery of sexual dimorphisms in metabolic and genetic biomarkers

Metabolomic profiling and the integration of whole-genome genetic association data has proven to be a powerful tool to comprehensively explore gene regulatory networks and to investigate the effects of genetic variation at the molecular level. Serum metabolite concentrations allow a direct readout of biological processes, and association of specific metabolomic signatures with complex diseases such as Alzheimer's disease and cardiovascular and metabolic disorders has been shown. There are well-known correlations between sex and the incidence, prevalence, age of onset, symptoms, and severity of a disease, as well as the reaction to drugs. However, most of the studies published so far did not consider the role of sexual dimorphism and did not analyse their data stratified by gender. This study investigated sex-specific differences of serum metabolite concentrations and their underlying genetic determination. For discovery and replication we used more than 3,300 independent individuals from KORA F3 and F4 with metabolite measurements of 131 metabolites, including amino acids, phosphatidylcholines, sphingomyelins, acylcarnitines, and C6-sugars. A linear regression approach revealed significant concentration differences between males and females for 102 out of 131 metabolites (p-values<3.8×10(-4); Bonferroni-corrected threshold). Sex-specific genome-wide association studies (GWAS) showed genome-wide significant differences in beta-estimates for SNPs in the CPS1 locus (carbamoyl-phosphate synthase 1, significance level: p<3.8×10(-10); Bonferroni-corrected threshold) for glycine. We showed that the metabolite profiles of males and females are significantly different and, furthermore, that specific genetic variants in metabolism-related genes depict sexual dimorphism. Our study provides new important insights into sex-specific differences of cell regulatory processes and underscores that studies should consider sex-specific effects in design and interpretation.     

Differences between human plasma and serum metabolite profiles

Background

Human plasma and serum are widely used matrices in clinical and biological studies. However, different collecting procedures and the coagulation cascade influence concentrations of both proteins and metabolites in these matrices. The effects on metabolite concentration profiles have not been fully characterized.

Methodology/Principal Findings

We analyzed the concentrations of 163 metabolites in plasma and serum samples collected simultaneously from 377 fasting individuals. To ensure data quality, 41 metabolites with low measurement stability were excluded from further analysis. In addition, plasma and corresponding serum samples from 83 individuals were re-measured in the same plates and mean correlation coefficients (r) of all metabolites between the duplicates were 0.83 and 0.80 in plasma and serum, respectively, indicating significantly better stability of plasma compared to serum (p = 0.01). Metabolite profiles from plasma and serum were clearly distinct with 104 metabolites showing significantly higher concentrations in serum. In particular, 9 metabolites showed relative concentration differences larger than 20%. Despite differences in absolute concentration between the two matrices, for most metabolites the overall correlation was high (mean r = 0.81±0.10), which reflects a proportional change in concentration. Furthermore, when two groups of individuals with different phenotypes were compared with each other using both matrices, more metabolites with significantly different concentrations could be identified in serum than in plasma. For example, when 51 type 2 diabetes (T2D) patients were compared with 326 non-T2D individuals, 15 more significantly different metabolites were found in serum, in addition to the 25 common to both matrices.

Conclusions/Significance

Our study shows that reproducibility was good in both plasma and serum, and better in plasma. Furthermore, as long as the same blood preparation procedure is used, either matrix should generate similar results in clinical and biological studies. The higher metabolite concentrations in serum, however, make it possible to provide more sensitive results in biomarker detection.     

Molecular diagnosis and frequencies of primary hypolactasia in populations of RUSSIA and neighboring countries

The digestion of the milk sugar (lactose) is observed every normal child but not in every adult. The decreased lactase synthesis in some adults results in problems with digestion of the whole milk (primary hypolactasy). An association of lactase activity in adults with carrying of the allele T within the polymorphism C/T-13910 located upstream of the lactase gene and 100% association of hypolactasy with the genotype C/C has recently been shown for a Finnish sample. In the present work we determined the LCT* C/T_13910 genotypes and allele frequencies in populations from Russia. The genotype C/C frequencies varied from 36.6% for Russians to 88.2% for Chukchi and were close to the published medical and epidemiological data on hypolactasy frequencies in respective populations. Genotyping was performed by three different methods to identify the optimal one. Our results have shown that the studied locus is the key determinant for the primary hypolactasy development in various human populations. Consequently, the DNA diagnostics of the C/C genotype carrying is a promising predictive test to detect the primary hypolactasy long before its clinical development. Practical application of this type of diagnostics would be a step towards the individual-oriented medicine.