Ekaterina A. Sokolova

Association of SNPs of CD40 Gene with Multiple Sclerosis in Russians

Multiple sclerosis (MS) is a serious, incurable neurological disease. In 2009, the ANZgene studies detected the suggestive association of located upstream of CD40 gene in chromosome 20q13 (p = 1.3×10−7). Identification of the causal variant(s) in the CD40 locus leads to a better understanding of the mechanism underlying the development of autoimmune pathologies. We determined the genotypes of rs6074022, rs1883832, rs1535045, and rs11086996 in patients with MS (n = 1684) and in the control group (n = 879). Two SNPs were significantly associated with MS: rs6074022 (additive model C allele OR = 1.27, 95% CI = [1.12–1.45], p = 3×10−4) and rs1883832 (additive model T allele OR = 1.20, 95% CI = [1.05–1.38], p = 7×10−3). In the meta-analysis of our results and the results of four previous studies, we obtain the association p-value of 2.34×10−12, which confirmed the association between MS and rs6074022 at a genome-wide significant level. Next, we demonstrated that the model including rs6074022 only sufficiently described the association. From our analysis, we can speculate that the association between rs1883832 and MS was induced by LD, whereas rs6074022 was a marker in stronger LD with the functional variant or was the functional variant itself. Our results indicated that the functional variants were located in the upstream region of the gene CD40 and were in higher LD with rs6074022 than LD with rs1883832.

New maastrichtian oxygen and carbon isotope record: Additional evidence for warm low latitudes

The Cretaceous period was generally characterized by greenhouse conditions. Nevertheless, our data on isotopic composition of biogenic carbonates from the Koryak Upland and Sakhalin (Russian Far East) show that during the Maastrichtian, temperatures dropped sharply at high and middle latitudes, with only a slight warming in the early Late Maastrichtian. At the same time, there is contradictory evidence on climatic conditions for low latitude areas during Maastrichtian time. The new and previously published isotopic data on Maastrichtian mollusks in the Western Interior Seaway (North America) (WIS) and some other areas suggest that tropical deep-sea surface temperatures calculated from the oxygen isotopic composition of the majority of investigated Maastrichtian planktic foraminifera are, obviously, underestimated. Unusually low isotopic temperatues were obtained for tropical planktic foraminifera. This probably reflects both local conditions provoked, first of all, by the influence of tropical upwelling zones, and the ability of Maastrichtian planktic foraminifera to migrate within a large vertical interval in the tropical zone in conditions of weakly stratified (well-mixed) ocean. The average tropical deep-sea surface paleotemperature estimates for the Maastrichtian could have been about 26.6–30.2°C, but, apparently, did not reach the level denoted for the Late Albian and Turonian (32±3°C). Negative carbon-isotopic shifts at the end of the early Maastrichtian and the Cretaceous-Tertiary boundary time seem to be connected with the fall of temperature and eventual reduction of oxygen content in the atmosphere and hydrosphere.

Genome-wide significant association with seven novel multiple sclerosis risk loci

Objective A recent large-scale study in multiple sclerosis (MS) using the ImmunoChip platform reported on 11 loci that showed suggestive genetic association with MS. Additional data in sufficiently sized and independent data sets are needed to assess whether these loci represent genuine MS risk factors. Methods The lead SNPs of all 11 loci were genotyped in 10 796 MS cases and 10 793 controls from Germany, Spain, France, the Netherlands, Austria and Russia, that were independent from the previously reported cohorts. Association analyses were performed using logistic regression based on an additive model. Summary effect size estimates were calculated using fixed-effect meta-analysis. Results Seven of the 11 tested SNPs showed significant association with MS susceptibility in the 21 589 individuals analysed here. Meta-analysis across our and previously published MS case-control data (total sample size n=101 683) revealed novel genome-wide significant association with MS susceptibility (p<5×10−8) for all seven variants. This included SNPs in or near LOC100506457 (rs1534422, p=4.03×10−12), CD28 (rs6435203, p=1.35×10−9), LPP (rs4686953, p=3.35×10−8), ETS1 (rs3809006, p=7.74×10−9), DLEU1 (rs806349, p=8.14×10−12), LPIN3 (rs6072343, p=7.16×10−12) and IFNGR2 (rs9808753, p=4.40×10−10). Cis expression quantitative locus effects were observed in silico for rs6435203 on CD28 and for rs9808753 on several immunologically relevant genes in the IFNGR2 locus. Conclusions This study adds seven loci to the list of genuine MS genetic risk factors and further extends the list of established loci shared across autoimmune diseases.

Swelling of Polyheteroarylenes in Supercritical Carbon Dioxide

Two series of polyheteroarylenes have been investigated with regard to their physical properties before and after swelling with supercritical carbon dioxide. The study of the dependence of glass transition temperature and free volume of polymers on their conformational rigidity showed that the process of swelling in supercritical carbon dioxide is influenced by the voluminous side groups and by the high boiling solvent N-methylpyrolidinone used for the preparation of the polymers which facilitates the formation of crosslinks or complexes with the macromolecular chains.

Replication of KCNJ11 (p.E23K) and ABCC8 (p.S1369A) Association in Russian Diabetes Mellitus 2 Type Cohort and Meta-Analysis

The genes ABCC8 and KCNJ11 have received intense focus in type 2 diabetes mellitus (T2DM) research over the past two decades. It has been hypothesized that the p.E23K (KCNJ11) mutation in the 11p15.1 region may play an important role in the development of T2DM. In 2009, Hamming et al. found that the p.1369A (ABCC8) variant may be a causal factor in the disease; therefore, in this study we performed a meta-analysis to evaluate the association between these single nucleotide polymorphisms (SNPs), including our original data on the Siberian population (1384 T2DM and 414 controls). We found rs5219 and rs757110 were not associated with T2DM in this population, and that there was linkage disequilibrium in Siberians (D’=0.766, r2= 0.5633). In addition, the haplotype rs757110[T]-rs5219[C] (p.23K/p.S1369) was associated with T2DM (OR = 1.52, 95% CI: 1.04-2.24). We included 44 original studies published by June 2014 in a meta-analysis of the p.E23K association with T2DM. The total OR was 1.14 (95% CI: 1.11-1.17) for p.E23K for a total sample size of 137,298. For p.S1369A, a meta-analysis was conducted on a total of 10 studies with a total sample size of 14,136 and pooled OR of 1.14 [95% CI (1.08-1.19); p = 2 x 10-6]. Our calculations identified causal genetic variation within the ABCC8/KCNJ11 region for T2DM with an OR of approximately 1.15 in Caucasians and Asians. Moreover, the OR value was not dependent on the frequency of p.E23K or p.S1369A in the populations.

Study of the Behavior of Some Polyheteroarylenes Treated with Supercritical Carbon Dioxide

Various polyheteroarylenes have been studied with regard to their physical properties before and after treatment with supercritical carbon dioxide (sc-CO 2). Thus, the study of dependence of glass transition temperature and free volume of polymer matrix on the conformational rigidity showed that the process of swelling in sc-CO2 is influenced by the residual solvent and by the formation of possible hydrogen bonds between CO2 and amide groups in the polymer chain.

Association GSTT1, GSTM1 and GSTP1 (Ile105Val) genetic polymorphisms in mothers with risk of congenital malformations in their children in Western Siberia: a case‐control study

Polymorphisms of glutathione S‐transferase (GST) genes in mothers may be involved in teratogenesis in their offspring. This study aims to investigate the association of GST genes (T1, M1 and P1) with the risk of having children with congenital malformations (CMs) in residents of the West Siberian region of Russia.

Polymorphic Variants rs13155212 (T/C) and rs7704267 (G/C) in the AGGF1 Gene and Risk of Varicose Veins of the Lower Extremities in the Population of Ethnic Russians

We analyzed associations between single nucleotide polymorphisms (SNP) rs13155212 and rs7704267 in the AGGF1 gene (angiogenic factor with G patch and FHA domains 1) and the risk of risk of varicose veins of the legs in ethnic Russians. Frequencies of alleles, genotypes, and haplotypes were estimated in the sample of patients with this disease (474 patients) and in the control group of participants (478 volunteers) without a history of chronic venous disease. None of the studied polymorphisms was associated with the risk of this pathology. The whole AGGF1 gene sequence lies in a single block of high linkage disequilibrium, and both studied polymorphic variants are representative of all other SNP within this region. From these results, a conclusion was made that AGGF1 gene polymorphism does not affect the risk of varicose veins of the legs in ethnic Russians, or its contribution is low and can be revealed only after analysis of larger cohorts.

Allele rs2010963 C of the VEGFA gene is associated with the decreased risk of primary varicose veins in ethnic Russians

Objective To study the association of polymorphisms rs699947, rs2010963, rs3025039 in the VEGFA gene region and rs1870377, rs2305949, rs2071559 in the VEGFR2 gene region with the risk of primary varicose veins in ethnic Russians. Methods Genotypes were determined by real-time PCR allelic discrimination. The case group consisted of 448 patients with primary varicose veins and the control group comprised 609 individuals without a history of chronic venous disease. Association was studied by logistic regression analysis. Results Allele rs2010963 C was associated with the decreased risk of varicose veins (additive model of inheritance: odds ratio = 0.73, 95% confidence interval = 0.59–0.91, P = 0.004). Conclusions Our results provide evidence that polymorphism rs2010963 located in the 5′ untranslated region of the VEGFA gene can influence genetic susceptibility to primary varicose veins in Russians. Otherwise, it can be in linkage disequilibrium with another functional single nucleotide polymorphism that can alter the level of vascular endothelial growth factor A protein.

Associations of a Polymorphism of the FAS/APO-1 Gene (rs2234767) with the Risk of Developing and Rapid Progression of Multiple Sclerosis

Objectives. To assess the association between a polymorphism of the FAS/APO-1 gene with the risk of developing and the dynamics of progression of multiple sclerosis (MS). Materials and methods. A total of 100 patients with remitting MS took part in a case-control study; patients were Russian and were born and living in the Altai Region, along with 100 volunteers without MS. The real-time polymerase chain reaction was used to genotype the single-nucleotide polymorphism 1377G>A in the promoter region of the FAS/APO-1 gene (rs2234767). The associations of this polymorphism with the risk of developing MS and the course of MS were studied. Results. Increased risk of MS was found to be associated with the G/A genotype and the A allele of the FAS/APO-1 gene (rs2234767). A high rate of disease progression was positively associated with the G/A genotype and the A allele and negatively with the G/G genotype and the G allele of the FAS/APO-1 gene. Conclusions. The predisposition to MS, like the rapid rate of disease progression, was associated with FAS/APO-1*G/A in Russians living in the Altai Region. Final conclusions require further studies.