Mendelian Randomization Analysis Identifies Inverse Causal Relationship between External Eating and Metabolic Phenotypes.

Disordered eating contributes to weight gain, obesity, and type 2 diabetes (T2D), but the precise mechanisms underlying the development of different eating patterns and connecting them to specific metabolic phenotypes remain unclear. We aimed to identify genetic variants linked to eating behaviour and investigate its causal relationships with metabolic traits using Mendelian randomization (MR). We tested associations between 30 genetic variants and eating patterns in individuals with T2D from the Volga-Ural region and investigated causal relationships between variants associated with eating patterns and various metabolic and anthropometric traits using data from the Volga-Ural population and large international consortia. We detected associations between HTR1D and CDKAL1 and external eating; between HTR2A and emotional eating; between HTR2A, NPY2R, HTR1F, HTR3A, HTR2C, CXCR2, and T2D. Further analyses in a separate group revealed significant associations between metabolic syndrome (MetS) and the loci in CRP, ADCY3, GHRL, CDKAL1, BDNF, CHRM4, CHRM1, HTR3A, and AKT1 genes. MR results demonstrated an inverse causal relationship between external eating and glycated haemoglobin levels in the Volga-Ural sample. External eating influenced anthropometric traits such as body mass index, height, hip circumference, waist circumference, and weight in GWAS cohorts. Our findings suggest that eating patterns impact both anthropometric and metabolic traits.

Integrating Common Risk Factors with Polygenic Scores Improves the Prediction of Type 2 Diabetes.

We tested associations between 13 established genetic variants and type 2 diabetes (T2D) in 1371 study participants from the Volga-Ural region of the Eurasian continent, and evaluated the predictive ability of the model containing polygenic scores for the variants associated with T2D in our dataset, alone and in combination with other risk factors such as age and sex. Using logistic regression analysis, we found associations with T2D for the CCL20 rs6749704 (OR = 1.68, PFDR = 3.40 × 10-5), CCR5 rs333 (OR = 1.99, PFDR = 0.033), ADIPOQ rs17366743 (OR = 3.17, PFDR = 2.64 × 10-4), TCF7L2 rs114758349 (OR = 1.77, PFDR = 9.37 × 10-5), and CCL2 rs1024611 (OR = 1.38, PFDR = 0.033) polymorphisms. We showed that the most informative prognostic model included weighted polygenic scores for these five loci, and non-genetic factors such as age and sex (AUC 85.8%, 95%CI 83.7-87.8%). Compared to the model containing only non-genetic parameters, adding the polygenic score for the five T2D-associated loci showed improved net reclassification (NRI = 37.62%, 1.39 × 10-6). Inclusion of all 13 tested SNPs to the model with age and sex did not improve the predictive ability compared to the model containing five T2D-associated variants (NRI = -17.86, p = 0.093). The five variants associated with T2D in people from the Volga-Ural region are linked to inflammation (CCR5, CCL2, CCL20) and glucose metabolism regulation (TCF7L, ADIPOQ2). Further studies in independent groups of T2D patients should validate the prognostic value of the model and elucidate the molecular mechanisms of the disease development.

The Relationship Between Chemokine and Chemokine Receptor Genes Polymorphisms and Chronic Obstructive Pulmonary Disease Susceptibility in Tatar Population from Russia: A Case Control Study.

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease affecting primarily distal respiratory pathways and lung parenchyma. This study aimed to determine possible genetic association of chemokine and chemokine receptor genes polymorphisms with COPD in a Tatar population from Russia. SNPs of CCL20, CCR6, CXCL8, CXCR1, CXCR2, CCL8, CCL23, CCR2, and CX3CL1 genes and their gene-gene interactions were analyzed for association with COPD in cohort of 601 patients and 617 controls. As a result statistically significant associations with COPD in the study group under the biologically plausible assumption of additive genetic model were identified in CCL20 (rs6749704) (P = 0.00001, OR 1.55), CCR6 (rs3093024) (P = 0.0003, OR 0.74), CCL8 (rs3138035) (P = 0.0001, OR 0.67), CX3CL1 (rs170364) (P = 0.023, OR 1.21), CXCL8 (rs4073) (P = 0.007, OR 1.23), CXCR2 (rs2230054) (P = 0.0002, OR 1.32). Following SNPs CCL20 (rs6749704), CX3CL1 (rs170364), CCL8 (rs3138035), CXCL8 (rs4073), CXCR2 (rs2230054) showed statistically significant association with COPD only in smokers. The association of CCR6 (rs3093024) with COPD was confirmed both in smokers and in non-smokers. A relationship between smoking index and CCL20 (rs6749704) (P = 0.04), CCR6 (rs3093024) (P = 0.007), CCL8 (rs3138035) (P = 0.0043), and CX3CL1 (rs170364) (P = 0.04) was revealed. A significant genotype-dependent variation of Forced Vital Capacity was observed for CCL23 (rs854655) (P = 0.04). Forced Expiratory Volume in 1 s / Forced Vital Capacity ratio was affected by CCL23 (rs854655) (P = 0.05) and CXCR2 (rs1126579) (P = 0.02). Using the APSampler algorithm, we obtained nine gene-gene combinations that remained significantly associated with COPD; loci CCR2 (rs1799864) and CCL8 (rs3138035) were involved in the largest number of the combinations. Our results indicate that CCL20 (rs6749704), CCR6 (rs3093024), CCR2 (rs1799864), CCL8 (rs3138035), CXCL8 (rs4073), CXCR1 (rs2234671), CXCR2 (rs2230054), and CX3CL1 (rs170364) polymorphisms are strongly associated with COPD in Tatar population from Russia, alone and in combinations. For the first time combination of the corresponding SNPs were considered and as a result 8 SNP patterns were associated with increased risk of COPD.

The association between eating behavior and polymorphisms in GRIN2B, GRIK3, GRIA1 and GRIN1 genes in people with type 2 diabetes mellitus.

Excess body weight is the main risk factor of type 2 diabetes. Recent studies have shown that psychological and behavioral factors affect weight. Additionally, emerging evidence indicates that polymorphisms of neurotransmitter genes can impact eating behavior. The aim of this study was to detect the associations between SNPs in glutamatergic system genes and type 2 diabetes in the ethnic group of Tatars origin living in the Republic of Bashkortostan (Russian Federation). In our case-control cross-sectional study, 501 patients with type 2 diabetes (170 men and 331 women, 60.9 ± 9.2 years old (mean ± SD), BMI 30.9 ± 3.9 kg/m2 (mean ± SD) of Tatar ethnicity, and a control group of 420 Tatars (170 men and 250 women, 56.3 ± 11.6 years old (mean ± SD), BMI 24.4 ± 4.3 kg/m2 (mean ± SD), were genotyped for five SNPs in four glutamatergic genes (GRIN2B, GRIK3, GRIA1, GRIN1). Three SNPs were associated with type 2 diabetes: rs7301328 in GRIN2B [odds ratio adjusted for age, sex and BMI (ORadj) = 0.77 (95% CI 0.63-0.93), padj = 0.0077], rs1805476 in GRIN2B [ORadj = 1.25 (95% CI 1.03-1.51), padj = 0.0240], and rs2195450 in GRIA1 [ORadj = 1.35 (95% CI 1.02-1.79), padj = 0.0340]. Regression analysis revealed that rs1805476 in GRIN2B was associated with LDL level, glomerular filtration rate, BMI (p = 0.020, p = 0.012 and p = 0.018, respectively). The SNP rs7301328 in GRIN2B was associated with triglyceride levels and HbA1c (p = 0.040, p = 0.023, respectively). These associations were not significant after Bonferroni correction. We found the association between rs534131 in GRIK3, rs2195450 in GRIA1, rs1805476 in GRIN2B and diabetic retinopathy (p = 0.005, p = 0.007, p = 0.040, respectively); rs7301328 in GRIN2B was associated with hypertension (p = 0.025) and cerebrovascular disease (p = 0.013). The association between rs534131 of GRIK3, rs2195450 of GRIA1 genes and diabetic retinopathy remained significant after Bonferroni correction. The SNPs rs6293 in GRIN1 was significantly associated with eating behavior in patients with type 2 diabetes (p = 0.01). Our results demonstrate that polymorphic variants of glutamatergic genes are associated with eating behavior and diabetic complications in Tatar ethnic group residing in the Republic of Bashkortostan. We detected novel associations of the polymorphic loci in GRIN1 (rs6293) gene with external eating behavior in type 2 diabetes patients, GRIK3 (rs534131) and GRIA1 (rs2195450) genes with diabetic retinopathy.

Associations of the NRF2/KEAP1 pathway and antioxidant defense gene polymorphisms with chronic obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system affecting primarily distal respiratory pathways and lung parenchyma. This work was designed as a case-control study aimed at investigating the association of the NRF2/KEAP1 signaling system, and antioxidant defense gene polymorphisms with COPD in population from Russia. METHODS: Ten SNPs: NFE2L2 (rs35652124), KEAP1 (rs1048290), MPO (rs2333227), PRNP (rs1799990), PTGR1 (rs2273788), HSPA1A (rs1008438), TXNRD2 (rs1139793), GSR (rs1002149), SIRT2 (rs10410544), and PTGS1 (rs1330344) were genotyped by the real-time polymerase chain reaction (TaqMan assays) in a case-control study (425 COPD patients and 457 controls, from the same region of Russia, representatives of Tatar population). Logistic regression was used to detect the association of SNPs in different models. Linear regression analyses were performed to estimate the relationship between SNPs and lung function parameters and smoking pack-years. THE RESULTS: In our population, a significant associations of KEAP1 (rs1048290) (P = 0.0015, OR = 0.72 in additive model), HSPA1A (rs1008438) (P = 0.006, OR = 2.26 in recessive model), GSR (rs1002149) (P = 0.037, OR = 1.31 in additive model) with COPD were revealed. NFE2L2 (rs35652124), PRNP (rs1799990), and HSPA1A (rs1008438) were significantly associated with COPD only in smokers. In nonsmokers, significant association was established for GSR (rs1002149). KEAP1 (rs1048290) was associated with COPD in both groups. The relationship between KEAP1 (rs1048290), NFE2L2 (rs35652124), and HSPA1A (rs1008438) and smoking pack-years was found (P = 0.005, P = 0.0028, P = 0.015). A significant genotype-dependent variation of forced vital capacity and forced expiratory volume in 1 s was observed for SIRT2 (rs10410544) (P = 0.04), NFE2L2 (rs35652124) (P = 0.028), and PRNP (rs1799990) (P = 0.044).

Chemokine gene polymorphisms association with increased risk of type 2 diabetes mellitus in Tatar ethnic group, Russia.

Recent studies have shown that chemokines play an important role in the development of chronic inflammation in adipose tissue, obesity pathogenesis, glucose intolerance and type 2 diabetes. It has also been revealed that some SNPs in chemokine genes are associated with obesity, insulin resistance, type 2 diabetes and diabetes complications in different ethnic groups. The aim of this study was to determine the associations between SNPs in chemokine genes and type 2 diabetes in participants of Tatar ethnic group, living in Bashkortostan. Case-control and cross-sectional study were included in our study design. Five SNPs were genotyped in 440 type 2 diabetes (160 men and 280 women), 58.8 ± 9.2 years old (mean ± SD), BMI 29.3 ± 3.9 kg/m2 (mean ± SD) patients of Tatar ethnicity, and a control group of 500 Tatars (180 men and 320 women), 55.2 ± 11.6 years old (mean ± SD), BMI 25.9 ± 4.3 kg/m2 (mean ± SD). The SNPs rs6749704 in CCL20 [odds ratio (OR) = 2.77 (95% CI 1.81-4.25), р = 0.0001], rs2107538 in CCL5 [odds ratio (OR) = 1.80 (95% CI 1.46-2.22), p = 0.0001] were significantly associated with type 2 diabetes. Regression analysis revealed that rs1696941 in CCL11 was associated with the onset age and duration of type 2 diabetes as well as with HbA1c level (p = 0.034, p = 0.036 and p = 0.0054, respectively). The SNPs rs223828 in CCL17 and rs6749704 in CCL20 were correlated with obesity as estimated by BMI (p = 0.0004, p = 0.029, respectively). Rs223828 in CCL17 revealed the association with postprandial glucose level (p = 0.024) and HbA1c (p = 0.008). These data demonstrate that variants of chemokine genes are associated with type 2 diabetes and obesity of Tatar ethnic group inhabiting Bashkortostan Republic. Novel associations of the polymorphic loci in CCL20 (rs6749704) and CCL5 (rs2107538) genes with type 2 diabetes had been identified as a result of the conducted research.

IREB2, CHRNA5, CHRNA3, FAM13A & hedgehog interacting protein genes polymorphisms & risk of chronic obstructive pulmonary disease in Tatar population from Russia.

BACKGROUND & OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a complex chronic inflammatory disease of the respiratory system affecting primarily distal respiratory pathways and lung parenchyma. This study was aimed at investigating the association of COPD with IREB2, CHRNA5, CHRNA3, FAM13A and hedgehog interacting protein (HHIP) genes in a Tatar population from Russia. METHODS: Six single nucleotide polymorphisms (SNPs) (rs13180, rs16969968, rs1051730, rs6495309, rs7671167, rs13118928) were genotyped by the real-time polymerase chain reaction in this study (511 COPD patients and 508 controls). Logistic regression was used to detect the association of SNPs and haplotypes of linked loci in different models. Linear regression analyses were performed to estimate the relationship between SNPs and lung function parameters and pack-years. RESULTS: The rs13180 (IREB2), rs16969968 (CHRNA5) and rs1051730 (CHRNA3) were significantly associated with COPD in additive model [Padj =0.00001, odds ratio (OR)=0.64; Padj =0.0001, OR=1.41 and Padj =0.0001, OR=1.47]. The C-G haplotype by rs13180 and rs1051730 was a protective factor for COPD in our population (Padj =0.0005, OR=0.61). These results were confirmed only in smokers. The rs16969968 and rs1051730 were associated with decrease of forced expiratory volume in 1 sec % predicted (Padj =0.005 and Padj =0.0019). INTERPRETATION & CONCLUSIONS: Our study showed the association of rs13180, rs16969968 and rs1051730 with COPD and lung function in Tatar population from Russia. Further studies need to be done in other ethnic populations.

Diagnostic and Prognostic Value of the Cerebrospinal Fluid Concentration of Immunoglobulin Free Light Chains in Clinically Isolated Syndrome with Conversion to Multiple Sclerosis.

BACKGROUND AND OBJECTIVE: In this study, we evaluated the diagnostic and prognostic significance of cerebrospinal fluid free light chains (CSF FLC) at the time of clinically isolated syndrome (CIS). METHODS: We compared FLC-parameters at the moment of CIS in patients with conversion to multiple sclerosis (MS) after 2 years (CIS-MS), patients who remained stable both clinically and radiologically after 2 years (CIS-nonMS), patients with non-inflammatory neurologic diseases (NIND) as a comparison group and patients with other inflammatory neurologic diseases (IND) with intrathecal oligoclonal bands (OCB) synthesis. ROC-analysis was conducted to define FLC-assay characteristics and cut-off values. We also compared FLC-concentrations in CIS patients to determine their OCB-status. A correlation analysis was performed between FLC-concentrations and the expanded disability scale score (EDSS), annualized relapse rate (ARR) and MRI-activity (i.e., number of new and gadolinium-enhancing (Gd+) lesions) in patients. RESULTS: The levels of kappa-FLC (k-FLCCSF) and lambda-FLC (λ-FLCCSF) as well as kappa- and lambda-quotients (Q-k and Q-λ) were elevated in CIS-MS compared to the CIS-nonMS and NIND groups. These levels did not differ significantly when compared with the IND group. We identified several patients with high k-FLCCSF and λ-FLCCSF in OCB-negative CIS and IND groups. The level of k-FLCCSF production was significantly higher in OCB-positive patients in the CIS-MS group compared to the CIS-nonMS group. The concentrations of k-FLCCSF and Q-k in the CIS-MS group showed significant correlation with the level of EDSS after 2 years (k-FLC: r = 0.4477,p = 0.0016; Q-k: r = 0.4621, p = 0.0016). λ-FLCCSF and Q-λ inversely correlated with the number of Gd+ lesions (CSF λ-FLC: r = -0.3698, p = 0.0223; Q-λ: r = -0.4527, p = 0.0056). CONCLUSION: The concentration of CSF FLC predicts conversion to MS within 2 years following CIS. OCB-positive patients with an early conversion have a higher concentration of CSF-FLC. We have also shown a prognostic significance of k-FLCCSF for future EDSS-progression.

Extracellular matrix remodeling genes polymorphisms and risk of chronic bronchitis and recurrent pneumonia in children.

We investigated the association of matrix metalloproteinases, the disintegrin and metalloprotease 33 and the tissue and serum inhibitors of proteinase gene polymorphisms with severe chronic respiratory diseases in Tatar children. We analyzed the case-control data sample from a total of 592 Tatar individuals, consisting of 119 children with chronic bronchitis, 138 with recurrent pneumonia and 335 control children residing in Ufa (Russia). The percentage of heterozygous genotype for the MMP9 (2660A>G) was higher among healthy children (52.54% vs 36.13% in chronic bronchitis patients, P(adj)=0.0033, P(cor)=0.033, odds ratio (OR)=0.51; and 36.96% in recurrent pneumonia group, P(adj)=0.0034, P(cor)=0.034, OR=0.53). The MMP12 (-82A>G) locus was associated with chronic bronchitis in the additive model (P(adj)=0.0091, P(cor)=0.09, OR=0.45, ß=-0.798). The relationship between the 6A6A genotype of MMP3 (-1171 5A>6A) (P(adj)=0.0013, P(cor)=0.013, OR=3.91) and the 6A-A haplotype of MMP3 (-1171 5A>6A) and MMP12 (-82A>G) and recurrent pneumonia were unraveled (Padj=0.001, P(cor)=0.01, OR=2.07). This haplotype was also associated with a higher risk of chronic bronchitis (P(adj)=0.0012, P(cor)=0.012, OR=2.15). The TIMP3 (-1296T>C) was associated with recurrent pneumonia in the dominant model (P(adj)=0.0031, P(cor)=0.031, OR=1.91). The MMP9, MMP3 and TIMP3 (tissue inhibitors of matrix metalloproteinases) polymorphisms and MMP3 and MMP12 haplotypes may play a substantial role in susceptibility to severe airway and lung injury in children with chronic bronchitis and recurrent pneumonia.

Polymorphisms of cytochrome p450 genes in three ethnic groups from Russia.

OBJECTIVE: To determine the prevalence of the most common allelic variants of CYP1A1, CYP1A2, CYP1B1, CYP2C9, CYP2E1, CYP2F1, CYP2J2 and CYP2S1 in a representative sample of the three ethnic groups (Russians, Tatars and Bashkirs) from Republic of Bashkortostan (Russia), and compare the results with existing data published for other populations. MATERIAL AND METHODS: CYPs genotypes were determined in 742 DNA samples of healthy unrelated individuals representative of three ethnic groups. The CYPs gene polymorphisms were examined using the PCR-RLFP method. RESULTS: Analysis of the CYP1A1 (rs1048943, rs4646903), CYP1A2 (rs762551), CYP2E1 (rs2031920) allele, genotype and haplotype frequencies revealed significant differences among healthy residents of the Republic of Bashkortostan of different ethnicities. Distribution of allele and genotype frequencies of CYP1A2 (rs35694136), CYP1B1 (rs1056836), CYP2C9 (rs1799853, rs1057910), CYP2F1 (rs11399890), CYP2J2 (rs890293), CYP2S1 (rs34971233, rs338583) genes were similar in Russians, Tatars, and Bashkirs. Analysis of the CYPs genes allele frequency distribution patterns among the ethnic groups from the Republic of Bashkortostan in comparison with the different populations worldwide was conducted. CONCLUSION: The peculiarities of the allele frequency distribution of CYPs genes in the ethnic groups of the Republic of Bashkortostan should be taken into consideration in association and pharmacogenetic studies. The results of the present investigation will be of great help in elucidating the genetic background of drug response, susceptibility to cancer and complex diseases, as well as in determining the toxic potentials of environmental pollutants in our region.