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.

Genetic predictors of sick sinus syndrome.

Sick sinus syndrome (SSS) encompasses a group of conduction disorders characterized by the inability of sinoatrial node to perform its pacemaker function. Our aim was to identify genetic predictors of SSS in a prospective cohort of patients admitted to the clinic for pacemaker implantation using single-locus and multilocus approaches. We performed genotyping for polymorphic markers of CLCNKA (rs10927887), SCN10A (rs6795970), FNDC3B (rs9647379), MIR146A (rs2910164), SYT10 (rs7980799), MYH6 (rs365990), and KCNE1 (rs1805127) genes in the group of 284 patients with SSS and 243 healthy individuals. Associations between the studied loci and SSS were tested using logistic regression under recessive genetic model using sex and age as covariates. Multilocus analysis was performed using Markov chain Monte Carlo method implemented in the APSampler program. Correction for multiple testing was performed using Benjamini-Hochberg procedure. We detected an individual association between KCNE1 rs1805127*A allele and SSS in the total study group (OR 0.43, PFDR = 0.028) and in the subgroup of patients with 2nd or 3rd degree sinoatrial block (OR 0.17, PFDR = 0.033), and identified seven allelic patterns associated with the disease. SCN10A rs6795970*T and MIR146A rs2910164*C alleles were present in all seven combinations associated with SSS. The highest risk of SSS was conferred by the combination SCN10A rs6795970*T+FNDC3B rs9647379*C+MIR146A rs2910164*C+SYT10 rs7980799*C+KCNE1 rs1805127*G (OR 2.98, CI 1.77-5.00, P = 1.27 × 10-5, PFDR = 0.022). Our findings suggest that KCNE1 rs1805127 polymorphism may play a role in susceptibility to sinoatrial node dysfunction, particularly presenting as 2nd or 3rd degree sinoatrial block, and the risk-modifying effect of other studied loci is better detected using multilocus approach.

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).

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.

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.