Blood-Based Epigenetic Age Acceleration and Incident Colorectal Cancer Risk: Findings from a Population-Based Case-Control Study.

This study investigates the association between epigenetic age acceleration (EAA) derived from DNA methylation and the risk of incident colorectal cancer (CRC). We utilized data from a random population sample of 9,360 individuals (men and women, aged 45-69) from the HAPIEE Study who had been followed up for 16 years. A nested case-control design yielded 35 incident CRC cases and 354 matched controls. Six baseline epigenetic age (EA) measures (Horvath, Hannum, PhenoAge, Skin and Blood (SB), BLUP, and Elastic Net (EN)) were calculated along with their respective EAAs. After adjustment, the odds ratios (ORs) for CRC risk per decile increase in EAA ranged from 1.20 (95% CI: 1.04-1.39) to 1.44 (95% CI: 1.21-1.76) for the Horvath, Hannum, PhenoAge, and BLUP measures. Conversely, the SB and EN EAA measures showed borderline inverse associations with ORs of 0.86-0.87 (95% CI: 0.76-0.99). Tertile analysis reinforced a positive association between CRC risk and four EAA measures (Horvath, Hannum, PhenoAge, and BLUP) and a modest inverse relationship with EN EAA. Our findings from a prospective population-based-case-control study indicate a direct association between incident CRC and four markers of accelerated baseline epigenetic age. In contrast, two markers showed a negative association or no association. These results warrant further exploration in larger cohorts and may have implications for CRC risk assessment and prevention.

The Relationship between All-Cause Natural Mortality and Copy Number of Mitochondrial DNA in a 15-Year Follow-Up Study.

We explored the relationship between the copy number of mitochondrial DNA (mtDNA-CN) and all-cause natural mortality. We examined a random population sample in 2003/2005 (n = 9360, men/women, 45-69, the HAPIEE project) and followed up for 15 years. Using a nested case-control design, we selected non-external deaths among those free from baseline cardiovascular diseases (CVD) and cancer (n = 371), and a sex- and age-stratified control (n = 785). The odds ratios (ORs) of death were 1.06 (95%CI 1.01-1.11) per one-decile decrease in mtDNA-CN independent of age, sex, metabolic factors, smoking, alcohol intake and education. The age-sex-adjusted ORs of death in the second and first tertiles of mtDNA-CN vs. the top tertile were 2.35 (95% CI 1.70-3.26) and 1.59 (1.16-2.17); an increased risk was confined to the second tertile after controlling for smoking and metabolic factors. The multivariable-adjusted OR of CVD death was 1.92 (95% CI 1.18-3.15) in tertile 2 vs. the top tertile of mtDNA-CN, and for cancer-related death the ORs were 3.66 (95% CI 2.21-6.05) and 2.29 (95% CI 1.43-3.68) in tertiles 2 and 1 vs. the top tertile. In the Siberian population cohort, the mtDNA-CN was an inverse predictor of the 15-year risk of natural mortality, due to the greatest impact of CVD and cancer-related death. The findings merit attention for exploring further the role of mtDNA in human ageing and the diversity of mortality.

Association of Common Variants of APOE, CETP, and the 9p21.3 Chromosomal Region with the Risk of Myocardial Infarction: A Prospective Study.

The individual risk of an unfavorable cardiovascular outcome is determined by genetic factors in addition to lifestyle factors. This study was aimed at analyzing possible associations of several genetic factors with the risk of myocardial infarction (MI). For our study, we selected genes that have been significantly associated with MI in meta-analyses: the chromosomal region 9p21.3, the CETP gene, and the APOE gene. In total, 2286 randomly selected patients were included. Rs708272 and rs429358 and rs7412 were analyzed using RT-PCR via the TaqMan principle, and rs1333049 vas analyzed via a commercial KASP assay. In our sample, the frequencies of alleles and genotypes were consistent with frequencies in comparable populations of Eastern and Western Europe. Allele C of rs1333049 was significantly associated with MI among males (p = 0.027) and in the whole study sample (p = 0.008). We also revealed a significant association of the ɛ2/ɛ4 genotype of APOE with MI among males (p < 0.0001) and in the whole study sample (p < 0.0001). Thus, among the tested polymorphisms, some genotypes of rs1333049 and rs429358 and rs7412 are the most strongly associated with MI and can be recommended for inclusion into a genetic risk score.

A prospective randomized comparative placebo-controlled double-blind study in two groups to assess the effect of the use of biologically active additives with Siberian fir terpenes for the biological age of a person.

A prospective randomized comparative placebo-controlled double-blind study was carried out based on Arterial Indices model of biological age. The study involved 60 men and women aged 40-65 years that were randomly divided into two equal groups of 30 people: the main group and the control one. The study participants from the main group received a dietary supplement containing Siberian fir terpenes, limonene, alpha-linolenic acid, and vitamin E-1 capsule 3 times a day for 90 days. Patients in the comparison group received a placebo according to a similar scheme. Anthropometric and biochemical characteristics of patients from both groups have not undergone any significant changes. According to ultrasound examination of the carotid arteries, we observed a statistically significant decrease in the minimum thickness of the intima-media complex (by 45%). The maximum carotid artery stenosis on the right or left and the expansion index in patients of both groups did not change significantly during treatment. According to the results of applanation tonometry, it was revealed that when taking the studied dietary supplement, the pulse wave velocity significantly decreased compared to the initial one (by 10%). Accordingly, the Arterial Indices biological age decreased by 2.5 years compared to the baseline level in patients of the main group and did not change in patients from the comparison group. Supplementation of fir terpenes in middle-aged patients of both sexes reduces the biological age reflecting the condition of the arteries.

The Mutation Spectrum of Rare Variants in the Gene of Adenosine Triphosphate (ATP)-Binding Cassette Subfamily C Member 8 in Patients with a MODY Phenotype in Western Siberia.

During differential diagnosis of diabetes mellitus, the greatest difficulties are encountered with young patients because various types of diabetes can manifest themselves in this age group (type 1, type 2, and monogenic types of diabetes mellitus, including maturity-onset diabetes of the young (MODY)). The MODY phenotype is associated with gene mutations leading to pancreatic-ß-cell dysfunction. Using next-generation sequencing technology, targeted sequencing of coding regions and adjacent splicing sites of MODY-associated genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1) was carried out in 285 probands. Previously reported missense variants c.970G>A (p.Val324Met) and c.1562G>A (p.Arg521Gln) in the ABCC8 gene were found once each in different probands. Variant c.1562G>A (p.Arg521Gln) in ABCC8 was detected in a compound heterozygous state with a pathogenic variant of the HNF1A gene in a diabetes patient and his mother. Novel frameshift mutation c.4609_4610insC (p.His1537ProfsTer22) in this gene was found in one patient. All these variants were detected in available family members of the patients and cosegregated with diabetes mellitus. Thus, next-generation sequencing of MODY-associated genes is an important step in the diagnosis of rare MODY subtypes.

Associations of APOE Gene Variants rs429358 and rs7412 with Parameters of the Blood Lipid Profile and the Risk of Myocardial Infarction and Death in a White Population of Western Siberia.

The present study aimed to analyze possible associations of rs7412 and rs429358 of the APOE gene with lipid profile parameters, the risk of myocardial infarction, and death in the mostly white population of Western Siberia (Russia). The study population was selected from a sample surveyed within the framework of the Health, Alcohol and Psychosocial Factors In Eastern Europe (HAPIEE) study (9360 subjects, age 53.8 ± 7.0 years, males/females 50/50). PCR was conducted with fluorescence detection according to the TaqMan principle on a real-time PCR machine. The frequency of a minor allele (C) of rs429358 was 0.13, and the frequency of a minor allele (T) of rs7412 was 0.09. In our study, the woman with the rare ɛ1/ɛ4 genotype had substantial aberrations in blood lipid levels. In Kaplan-Meier curves, statistically significant differences were revealed in the prognosis of survival within the subgroup of females who had a myocardial infarction (p = 0.0006): the prognosis was worse for carriers of the ɛ2/ɛ2 genotype and for ɛ4/ɛ4 carriers. Survival analysis regarding deaths from all causes showed (p = 0.0238) that female carriers of the ɛ2/ɛ4 genotype had a worse prognosis than did carriers of other genotypes. Thus, in the population of Western Siberia (Russia), we confirmed statistically significant associations between rs7412 & rs429358 genotypes and lipid profile parameters.

Analysis of Rare Variants in Genes Related to Lipid Metabolism in Patients with Familial Hypercholesterolemia in Western Siberia (Russia).

The aim of this work was to identify genetic variants potentially involved in familial hypercholesterolemia in 43 genes associated with lipid metabolism disorders. Targeted high-throughput sequencing of lipid metabolism genes was performed (80 subjects with a familial-hypercholesterolemia phenotype). For patients without functionally significant substitutions in the above genes, multiplex ligation-dependent probe amplification was conducted to determine bigger mutations (deletions and/or duplications) in the LDLR promoter and exons. A clinically significant variant in some gene associated with familial hypercholesterolemia was identified in 47.5% of the subjects. Clinically significant variants in the LDLR gene were identified in 19 probands (73.1% of all variants identified in probands); in three probands (11.5%), pathogenic variants were found in the APOB gene; and in four probands (15.4%), rare, clinically significant variants were identified in genes LPL, SREBF1, APOC3, and ABCG5. In 12 (85.7%) of 14 children of the probands, clinically significant variants were detectable in genes associated with familial hypercholesterolemia. The use of clinical criteria, targeted sequencing, and multiplex ligation-dependent probe amplification makes it possible to identify carriers of rare clinically significant variants in a wide range of lipid metabolism genes and to investigate their influence on phenotypic manifestations of familial hypercholesterolemia.

Basic Research in Endocrinology: A Modern Strategy for the Development and Technologies of Personalized Medicine.

The first all-Russia conference with international participation, "Basic Research in Endocrinology: A Modern Strategy for the Development and Technologies of Personalized Medicine", was held in Novosibirsk on 26-27 November 2020. [...].

The Risk of Type 2 Diabetes Mellitus in a Russian Population Cohort According to Data from the HAPIEE Project.

The aim of this study is to investigate the 14-year risk of type 2 diabetes mellitus (T2DM) and develop a risk score for T2DM in the Siberian cohort. A random population sample (males/females, 45-69 years old) was examined at baseline in 2003-2005 (Health, Alcohol, and Psychosocial Factors in Eastern Europe (HAPIEE) project, n = 9360, Novosibirsk) and re-examined in 2006-2008 and 2015-2017. After excluding those with baseline T2DM, the final analysis included 7739 participants. The risk of incident T2DM during a 14-year follow-up was analysed using Cox regression. In age-adjusted models, male and female hazard ratios (HR) of incident T2DM were 5.02 (95% CI 3.62; 6.96) and 5.13 (95% CI 3.56; 7.37) for BMI ≥ 25 kg/m2; 4.38 (3.37; 5.69) and 4.70 (0.27; 6.75) for abdominal obesity (AO); 3.31 (2.65; 4.14) and 3.61 (3.06; 4.27) for fasting hyperglycaemia (FHG); 2.34 (1.58; 3.49) and 3.27 (2.50; 4.26) for high triglyceride (TG); 2.25 (1.74; 2.91) and 2.82 (2.27; 3.49) for hypertension (HT); and 1.57 (1.14; 2.16) and 1.69 (1.38; 2.07) for family history of diabetes mellitus (DM). In addition, secondary education, low physical activity (PA), and history of cardiovascular disease (CVD) were also significantly associated with T2DM in females. A simple T2DM risk calculator was generated based on non-laboratory parameters. A scale with the best quality included waist circumference >95 cm, HT history, and family history of T2DM (area under the curve (AUC) = 0.71). The proposed 10-year risk score of T2DM represents a simple, non-invasive, and reliable tool for identifying individuals at a high risk of future T2DM.

The Mutation Spectrum of Maturity Onset Diabetes of the Young (MODY)-Associated Genes among Western Siberia Patients.

Maturity onset diabetes of the young (MODY) is a congenital form of diabetes characterized by onset at a young age and a primary defect in pancreatic-ß-cell function. Currently, 14 subtypes of MODY are known, and each is associated with mutations in a specific gene: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1. The most common subtypes of MODY are associated with mutations in the genes GCK, HNF1A, HNF4A, and HNF1B. Among them, up to 70% of cases are caused by mutations in GCK and HNF1A. Here, an analysis of 14 MODY genes was performed in 178 patients with a MODY phenotype in Western Siberia. Multiplex ligation-dependent probe amplification analysis of DNA samples from 50 randomly selected patients without detectable mutations did not reveal large rearrangements in the MODY genes. In 38 patients (37% males) among the 178 subjects, mutations were identified in HNF4A, GCK, HNF1A, and ABCC8. We identified novel potentially causative mutations p.Lys142*, Leu146Val, Ala173Glnfs*30, Val181Asp, Gly261Ala, IVS7 c.864 -1G>T, Cys371*, and Glu443Lys in GCK and Ser6Arg, IVS 2 c.526 +1 G>T, IVS3 c.713 +2 T>A, and Arg238Lys in HNF1A.

The rs78378222 prevalence and the copy loss of the protective allele A in the tumor tissue of diffuse large B-cell lymphoma.

BACKGROUND: Rare single nucleotide polymorphisms (SNPs) are likely to be a crucial genetic factor for human diseases, including cancer. rs78378222 is rare SNP in 3'-untranslated region (UTR) of TP53 gene leading to disturbance of 3'-end mRNA processing. The frequency of rs78378222 varies in several studied populations. The meta-analysis of 34 genome-wide association studies indicated that rs78378222 was significantly associated with an increased risk of cancer overall. Bioinformatic analysis indicates that somatic loss of the protective A allele of rs78378222 occurs in the tumor tissue of some malignant. The goal of the current study is to document the rs78378222 prevalence and evaluate the copy loss status of the protective allele A in the tumor tissue of patients with diffuse large B-cell lymphoma (DLBCL). METHODS: Total DNA was isolated from FFPE-samples and peripheral blood of patients with DLBCL and comparable in age and sex controls. rs78378222 genotyping was performed by the PCR-RFLP method using restriction endonuclease HindIII. Direct Sanger's sequencing was used to confirm the presence of C allele of the rs78378222. The search for TP53 gene mutations was carried out by Sanger's direct sequencing method, according to the IARC protocol. RESULTS: The result of genotyping of 136 DNA samples from DLBCL tumor tissue suggested that frequency of the rs78378222 was 11/136 (8.1%). Rare allele C frequency was 11/272 (4.2%). A total of 5/11 DLBCL rs78378222 heterozygous samples had the heterozygosity loss in the TP53 gene. Only one of these cases was combined with TP53 gene mutations which have proven oncogenic potential-p.Arg196Gln, other four cases have not mutations in the coding regions of gene. CONCLUSIONS: At the stages of DLBCL initiation or progression a loss of the protective allele A of rs78378222 occurs. Further efforts are needed to study possible molecular mechanisms underlying somatic alterations in DLBCL in this region of the TP53 3'-UTR as well as functional studies to illustrate how the presents of rs78378222 may affect tumor progression of lymphoma.

Impact of Mitochondrial DNA Mutations on Carotid Intima-Media Thickness in the Novosibirsk Region.

The search for markers of predisposition to atherosclerosis development is very important for early identification of individuals with a high risk of cardiovascular disease. The aim of the present study was to investigate the association of mitochondrial DNA mutations with carotid intima-media thickness and to determine the impact of mitochondrial heteroplasmy measurements in the prognosis of atherosclerosis development. This cross-sectional, population-based study was conducted in 468 subjects from the Novosibirsk region. It was shown that the mean (carotid intima-media thickness) cIMT correlated with the following mtDNA mutations: m.15059G>A (r = 0.159, p = 0.001), m.12315G>A (r = 0.119; p = 0.011), m.5178C>A (r = 0.114, p = 0.014), and m.3256C>T (r = 0.130, p = 0.011); a negative correlation with mtDNA mutations m.14846G>A (r = -0.111, p = 0.042) and m.13513G>A (r = -0.133, p = 0.004) was observed. In the linear regression analysis, the addition of the set of mtDNA mutations to the conventional cardiovascular risk factors increased the ability to predict the cIMT variability from 17 to 27%. Multi-step linear regression analysis revealed the most important predictors of mean cIMT variability: age, systolic blood pressure, blood levels of total cholesterol, LDL and triglycerides, as well as the mtDNA mutations m.13513G>A, m.15059G>A, m.12315G>A, and m.3256C>T. Thus, a high predictive value of mtDNA mutations for cIMT variability was demonstrated. The association of mutation m.13513G>A and m.14846G>A with a low value of cIMT, demonstrated in several studies, represents a potential for the development of anti-atherosclerotic gene therapy.

Analysis of APPL1 Gene Polymorphisms in Patients with a Phenotype of Maturity Onset Diabetes of the Young.

The APPL1 gene encodes a protein mediating the cross-talk between adiponectin and insulin signaling. Recently, it was found that APPL1 mutations can cause maturity onset diabetes of the young, type 14. Here, an analysis of APPL1 was performed in patients with a maturity-onset diabetes of the young (MODY) phenotype, and prevalence of these mutations was estimated in a Russian population, among type 2 diabetes mellitus (T2DM) and MODY patients. Whole-exome sequencing or targeted sequencing was performed on 151 probands with a MODY phenotype, with subsequent association analysis of one of identified variants, rs11544593, in a white population of Western Siberia (276 control subjects and 169 T2DM patients). Thirteen variants were found in APPL1, three of which (rs79282761, rs138485817, and rs11544593) are located in exons. There were no statistically significant differences in the frequencies of rs11544593 alleles and genotypes between T2DM patients and the general population. In the MODY group, AG rs11544593 genotype carriers were significantly more frequent (AG vs. AA + GG: odds ratio 1.83, confidence interval 1.15-2.90, p = 0.011) compared with the control group. An association of rs11544593 with blood glucose concentration was revealed in the MODY group. The genotyping data suggest that rs11544593 may contribute to carbohydrate metabolism disturbances.

Data on association of mitochondrial heteroplasmy with carotid intima-media thickness in subjects from Russian and Kazakh populations.

The search for variants of mitochondrial genome associated with atherosclerosis, in particular, with carotid intima-media thickness (cIMT), is necessary to understand the role of the damage of mitochondrial genome in the development of atherosclerosis. Such data can be useful to provide novel genetic markers of predisposition to atherosclerosis and molecular targets for further development of technologies aimed to prevent age-related degenerative pathologies. Data presented in this article demonstrate the association of several heteroplasmic variants of mitochondrial DNA (mtDNA) previously described as proatherogenic ones with cIMT in 251 participants (190 participants from Novosibirsk, Russia, and 61 participant from Almaty, Kazakhstan). It was shown that the occurrence of some variants of mitochondrial genome is different in samples derived from Russian and Kazakh populations; the level of mitochondrial heteroplasmy m.13513G > A correlates negatively with mean cIMT in both Russian and Kazakh participants.

Potential regulatory SNPs in the ATXN7L3B and KRT15 genes are associated with gender-specific colorectal cancer risk.

Aim: According to the current data, a major factor for phenotypic variation of complex traits and disease susceptibility is the cis-acting effects of noncoding variants on gene expression. Our purpose was to evaluate the association between colorectal cancer (CRC) and six single nucleotide polymorphisms identified using our original bioinformatics approach as regulatory and putatively related to CRC. Materials: One hundred and sixty CRC patients and 185 healthy controls have been genotyped for rs590352, rs2072580, rs78317230, rs3829202, rs11542583 and rs4796672. Results: Genotypes and alleles distributions of rs590352 of ATXN7L3B gene were significantly different between the male CRC subjects and controls. Significant correlation of genotype with CRC is observable for women only for the rs4796672 of KRT15 gene. Analysis of haplotypes reveals that rs2072580 of the ISCU and SART3 genes can be also associated with CRC. Conclusion: We have identified three SNPs associated with CRC risk and demonstrated a gender specificity of rs590352 and rs4796672.

Association of RS708272 (CETP Gene Variant) with Lipid Profile Parameters and the Risk of Myocardial Infarction in the White Population of Western Siberia.

: The TaqI B (rs708272) single-nucleotide variant, i.e., the +279 G/A substitution in intron 1 of the CETP gene, is actively investigated as a risk factor of lipid metabolism disorders. The aim of this study was to analyze the association of rs708272 with lipid parameters and the risk of myocardial infarction in the population of Western Siberia (Russia). The study population was selected from a sample surveyed within the framework of the Health, Alcohol and Psychosocial Factors In Eastern Europe (HAPIEE) study (9360 participants, >90% white, aged 45-69 years, males: 50%). In total, 3132 randomly selected patients were included. Plasma lipid levels were determined by standard enzymatic assays. Rs708272 was analyzed by RT-PCR via TaqMan single-nucleotide polymorphism (SNP) Genotyping Assays (Thermo Fisher Scientific, USA). The frequencies of rs708272 genotypes AA (homozygote), AG (heterozygote), and GG were 0.21, 0.49, and 0.30, respectively, in this population. Allele A frequency was 0.46. We found an association of allele G with low levels of high-density lipoprotein cholesterol and a high index of atherogenicity in this population (p < 0.001 and p < 0.001, respectively). Allele G was significantly associated with the risk of myocardial infarction among the male participants (odds ratio 1.96, 95% confidence interval 1.208-3.178, p = 0.008) and in the study population (odds ratio 1.465, 95% confidence interval 1.028-2.087, p = 0.036). Thus, rs708272 is associated with myocardial infarction in the white population of Western Siberia (Russia).

Searching for Signatures of Cold Climate Adaptation in TRPM8 Gene in Populations of East Asian Ancestry.

Dispersal of Homo sapiens across the globe during the last 200,000 years was accompanied by adaptation to local climatic conditions, with severe winter temperatures being probably one of the most significant selective forces. The TRPM8 gene codes for a cold-sensing ion channel, and adaptation to low temperatures is the major determinant of its molecular evolution. Here, our aim was to search for signatures of cold climate adaptation in TRPM8 gene using a combined data set of 19 populations of East Asian ancestry from the 1000 Genomes Project and Human Genome Diversity Project. As a result, out of a total of 60 markers under study, none showed significant association with the average winter temperatures at the locations of the studied populations considering the multiple testing thresholds. This might suggest that the principal mode of TRPM8 evolution may be different from widespread models, where adaptive alleles are additive, dominant or recessive, at least in populations with the predominant East Asian component. For example, evolution by means of selectively preferable epistatic interactions among amino acids may have taken place. Despite the lack of strong signals of association, however, a very promising single nucleotide polymorphism (SNP) was found. The SNP rs7577262 is considered the best candidate based on its allelic correlations with winter temperatures, signatures of selective sweep and physiological evidences. The second top SNP, rs17862920, may participate in adaptation as well. Additionally, to assist in interpreting the nominal associations, the other markers reached, we performed SNP prioritization based on functional evidences found in literature and on evolutionary conservativeness.

Analysis of Polymorphism rs1333049 (Located at 9P21.3) in the White Population of Western Siberia and Associations with Clinical and Biochemical Markers.

The 9p21.3 chromosomal region is a marker of the risk of cardiovascular diseases. The aim of this study was to analyze single-nucleotide polymorphism rs1333049 (chr9:22125504) in the population of Western Siberia (Russia) and possible associations with clinical and biochemical parameters. The population included in the analyses was selected from a sample surveyed within the framework of the Health, Alcohol and Psychosocial Factors In Eastern Europe (HAPIEE) study (9360 participants, >90% white, aged 45-69, males: 50%). In total, 2729 randomly selected patients were included. Plasma lipid levels were determined by standard enzymatic assays. Rs1333049 was analyzed by RT-PCR (BioLabMix, Russia). Frequencies of rs1333049 genotypes C/C (homozygote), C/G (heterozygote), and G/G were 0.22, 0.51, and 0.27 in this population. The Allele G frequency was 0.53. We found an association of allele G with total cholesterol and low-density lipoprotein cholesterol levels among male participants (p = 0.004 and p = 0.002, respectively). Allele C was significantly associated with the risk of myocardial infarction among the male participants (odds ratio 1.96, 95% confidence interval 1.14-3.38, p = 0.017) and the study population (odds ratio 1.83, 95% confidence interval 1.23-2.72, p = 0.004). Thus, rs1333049 is associated with myocardial infarction in the white population of Western Siberia (Russia).

Exome-wide search and functional annotation of genes associated in patients with severe tick-borne encephalitis in a Russian population.

BACKGROUND: Tick-borne encephalitis (TBE) is a viral infectious disease caused by tick-borne encephalitis virus (TBEV). TBEV infection is responsible for a variety of clinical manifestations ranging from mild fever to severe neurological illness. Genetic factors involved in the host response to TBEV that may potentially play a role in the severity of the disease are still poorly understood. In this study, using whole-exome sequencing, we aimed to identify genetic variants and genes associated with severe forms of TBE as well as biological pathways through which the identified variants may influence the severity of the disease. RESULTS: Whole-exome sequencing data analysis was performed on 22 Russian patients with severe forms of TBE and 17 Russian individuals from the control group. We identified 2407 candidate genes harboring rare, potentially pathogenic variants in exomes of patients with TBE and not containing any rare, potentially pathogenic variants in exomes of individuals from the control group. According to DAVID tool, this set of 2407 genes was enriched with genes involved in extracellular matrix proteoglycans pathway and genes encoding proteins located at the cell periphery. A total of 154 genes/proteins from these functional groups have been shown to be involved in protein-protein interactions (PPIs) with the known candidate genes/proteins extracted from TBEVHostDB database. By ranking these genes according to the number of rare harmful minor alleles, we identified two genes (MSR1 and LMO7), harboring five minor alleles, and three genes (FLNA, PALLD, PKD1) harboring four minor alleles. When considering genes harboring genetic variants associated with severe forms of TBE at the suggestive P-value < 0.01, 46 genes containing harmful variants were identified. Out of these 46 genes, eight (MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) were additionally found among genes containing rare pathogenic variants identified in patients with TBE; and five genes (WDFY4, ALK, MAP4, BNIPL, EPPK1) were found to encode proteins that are involved in PPIs with proteins encoded by genes from TBEVHostDB. Three genes out of five (MAP4, EPPK1, ALK) were found to encode proteins located at cell periphery. CONCLUSIONS: Whole-exome sequencing followed by systems biology approach enabled to identify eight candidate genes (MAP4, WDFY4, ACTRT2, KLHL25, MAP2K3, MBD1, OR10J1, and OR2T34) that can potentially determine predisposition to severe forms of TBE. Analyses of the genetic risk factors for severe forms of TBE revealed a significant enrichment with genes controlling extracellular matrix proteoglycans pathway as well as genes encoding components of cell periphery.

The association between the FTO gene variant and alcohol consumption and binge and problem drinking in different gene-environment background: The HAPIEE study.

BACKGROUND: Alcohol intake and tobacco smoking have significant negative health consequences and both are influenced by genetic predispositions. Some studies suggest that the FTO gene is associated with alcohol consumption. We investigated whether a tagging variant (rs17817449) within the FTO gene is associated with alcohol intake, problem drinking and smoking behaviour. METHODS: We analysed data from 26,792 Caucasian adults (47.2% of males; mean age 58.9 (±7.3) years), examined through the prospective cohort HAPIEE study. The primary outcomes were daily alcohol consumption, binge drinking, problem drinking (CAGE score 2+) and smoking status in relation to tagging variants within the FTO and ADH1B genes. RESULTS: We found no significant association of the FTO polymorphism with smoking status in either sex. The associations of the FTO polymorphism with drinking pattern were inconsistent and differed by gender. In men, GG homozygote carriers had lower odds of problem drinking (OR 0.85, 95% CI 0.75-0.96, p = 0.03). In women, the combination of the FTO/ADH1B GG/+A genotypes doubled the risk of binge drinking (OR 2.10, 95% CI 1.19-3.71, p < 0.05), and the risk was further increased among smoking women (OR 4.10, 95% CI 1.64-10.24, p = 0.008). CONCLUSIONS: In this large population study, the FTO gene appeared associated with binge and problem drinking, and the associations were modified by sex, smoking status and the ADH1B polymorphism.