Genetic risk factors for restenosis after percutaneous coronary intervention in Kazakh population.

BACKGROUND: After coronary stenting, the risk of developing restenosis is from 20 to 35 %. The aim of the present study is to investigate the association of genetic variation in candidate genes in patients diagnosed with restenosis in the Kazakh population. METHODS: Four hundred fifty-nine patients were recruited to the study; 91 patients were also diagnosed with diabetes and were excluded from the sampling. DNA was extracted with the salting-out method. The patients were genotyped for 53 single-nucleotide polymorphisms. Genotyping was performed on the QuantStudio 12K Flex (Life Technologies). Differences in distribution of BMI score among different genotype groups were compared by analysis of variance (ANOVA). Also, statistical analysis was performed using R and PLINK v.1.07. Haplotype frequencies and LD measures were estimated by using the software Haploview 4.2. RESULTS: A logistic regression analysis found a significant difference in restenosis rates for different genotypes. FGB (rs1800790) is significantly associated with restenosis after stenting (OR = 2.924, P = 2.3E-06, additive model) in the Kazakh population. CD14 (rs2569190) showed a significant association in the additive (OR = 0.08033, P = 2.11E-09) and dominant models (OR = 0.05359, P = 4.15E-11). NOS3 (rs1799983) was also highly associated with development of restenosis after stenting in additive (OR = 20.05, P = 2.74 E-12) and recessive models (OR = 22.24, P = 6.811E-10). CONCLUSIONS: Our results indicate that FGB (rs1800790), CD14 (rs2569190), and NOS3 (rs1799983) SNPs could be genetic markers for development of restenosis in Kazakh population. Adjustment for potential confounder factor BMI gave almost the same results.

Type 2 diabetes mellitus: distribution of genetic markers in Kazakh population.

BACKGROUND: Ethnic differences exist in the frequencies of genetic variations that contribute to the risk of common disease. This study aimed to analyse the distribution of several genes, previously associated with susceptibility to type 2 diabetes and obesity-related phenotypes, in a Kazakh population. METHODS: A total of 966 individuals belonging to the Kazakh ethnicity were recruited from an outpatient clinic. We genotyped 41 common single nucleotide polymorphisms (SNPs) previously associated with type 2 diabetes in other ethnic groups and 31 of these were in Hardy-Weinberg equilibrium. The obtained allele frequencies were further compared to publicly available data from other ethnic populations. Allele frequencies for other (compared) populations were pooled from the haplotype map (HapMap) database. Principal component analysis (PCA), cluster analysis, and multidimensional scaling (MDS) were used for the analysis of genetic relationship between the populations. RESULTS: Comparative analysis of allele frequencies of the studied SNPs showed significant differentiation among the studied populations. The Kazakh population was grouped with Asian populations according to the cluster analysis and with the Caucasian populations according to PCA. According to MDS, results of the current study show that the Kazakh population holds an intermediate position between Caucasian and Asian populations. CONCLUSION: A high percentage of population differentiation was observed between Kazakh and world populations. The Kazakh population was clustered with Caucasian populations, and this result may indicate a significant Caucasian component in the Kazakh gene pool.

Genetic Risk Factors for Intracranial Aneurysm in the Kazakh Population.

An intracranial aneurysm (IA) is a weak or thin area on a blood vessel in the brain that balloons as it fills with blood. Genetic factors can influence the risk of developing an aneurism. The purpose of this study was to explore the relationship between single nucleotide polymorphisms (SNPs) and IA in Kazakh population. The patients were genotyped for 60 single nucleotide polymorphisms. Genotyping was performed on the QuantStudio 12K Flex (Life Technologies). A linear regression analysis found 13 SNPs' significant association with development and rupture of IA: the rs1800956 polymorphism of the ENG gene, rs1756 46 polymorphism of the JDP2 gene, variant rs1800255 of the COL3A1, rs4667622 of the UBR3, rs2374513 of the c12orf75, rs3742321 polymorphism of the StAR, the rs3782356 polymorphism of MLL2 gene, rs3932338 to 214 kilobases downstream of PRDM9, rs7550260 polymorphism of the ARHGEF, rs1504749 polymorphism of the SOX17, the rs173686 polymorphism of CSPG2 gene, rs6460071 located on LIMK1 gene, and the rs4934 polymorphism of SERPINA3. A total of 13 SNPs were identified as potential genetic markers for the development and risk of rupture of aneurysms in the Kazakh population. Similar results were obtained after adjusting for the confounding factors of arterial hypertension and age.

Association of MHC region SNPs with irritant susceptibility in healthcare workers.

Irritant contact dermatitis is the most common work-related skin disease, especially affecting workers in "wet-work" occupations. This study was conducted to investigate the association between single nucleotide polymorphisms (SNPs) within the major histocompatibility complex (MHC) and skin irritant response in a group of healthcare workers. 585 volunteer healthcare workers were genotyped for MHC SNPs and patch tested with three different irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH) and benzalkonium chloride (BKC). Genotyping was performed using Illumina Goldengate MHC panels. A number of SNPs within the MHC Class I (OR2B3, TRIM31, TRIM10, TRIM40 and IER3), Class II (HLA-DPA1, HLA-DPB1) and Class III (C2) genes were associated (p < 0.001) with skin response to tested irritants in different genetic models. Linkage disequilibrium patterns and functional annotations identified two SNPs in the TRIM40 (rs1573298) and HLA-DPB1 (rs9277554) genes, with a potential impact on gene regulation. In addition, SNPs in PSMB9 (rs10046277 and ITPR3 (rs499384) were associated with hand dermatitis. The results are of interest as they demonstrate that genetic variations in inflammation-related genes within the MHC can influence chemical-induced skin irritation and may explain the connection between inflamed skin and propensity to subsequent allergic contact sensitization.

Genetic Basis of Irritant Susceptibility in Health Care Workers.

OBJECTIVE: The aim of this study was to investigate the association of single nucleotide polymorphisms (SNPs) within genes involved in inflammation, skin barrier integrity, signaling/pattern recognition, and antioxidant defense with irritant susceptibility in a group of health care workers. METHODS: The 536 volunteer subjects were genotyped for selected SNPs and patch tested with three model irritants: sodium lauryl sulfate (SLS), sodium hydroxide (NaOH), and benzalkonium chloride (BKC). Genotyping was performed on genomic DNA using Illumina Goldengate custom panels. RESULTS: The ACACB (rs2268387, rs16934132, rs2284685), NTRK2 (rs10868231), NTRK3 (rs1347424), IL22 (rs1179251), PLAU (rs2227564), EGFR (rs6593202), and FGF2 (rs308439) SNPs showed an association with skin response to tested irritants in different genetic models (all at P < 0.001). Functional annotations identified two SNPs in PLAU (rs2227564) and ACACB (rs2284685) genes with a potential impact on gene regulation. In addition, EGF (rs10029654), EGFR (rs12718939), CXCL12 (rs197452), and VCAM1 (rs3917018) genes showed an association with hand dermatitis (P < 0.005). CONCLUSIONS: The results demonstrate that genetic variations in genes related to inflammation and skin homeostasis can influence responses to irritants and may explain inter-individual variation in the development of subsequent contact dermatitis.

Genetic variants within the MHC region are associated with immune responsiveness to childhood vaccinations.

The influence of genetic variability within the major histocompatibility complex (MHC) region on variations in immune responses to childhood vaccination was investigated. The study group consisted of 135 healthy infants who had been immunized with hepatitis B (HBV), 7-valent pneumococcal conjugate (PCV7), and diphtheria, tetanus, acellular pertussis (DTaP) vaccines according to standard childhood immunization schedules. Genotype analysis was performed on genomic DNA using Illumina Goldengate MHC panels (Mapping and Exon Centric). At the 1 year post vaccination check-up total, isotypic, and antigen-specific serum antibody levels were measured using multiplex immunoassays. A number of single nucleotide polymorphisms (SNPs) within MHC Class I and II genes were found to be associated with variations in the vaccine specific antibody responses and serum levels of immunoglobulins (IgG, IgM) and IgG isotypes (IgG1, IgG4) (all at p<0.001). Linkage disequilibrium patterns and functional annotations showed that significant SNPs were strongly correlated with other functional regulatory SNPs. These SNPs were found to regulate the expression of a group of genes involved in antigen processing and presentation including HLA-A, HLA-C, HLA-G, HLA-H, HLA-DRA, HLA-DRB1, HLA-DRB5, HLA-DQA1, HLA-DQB1, HLA-DOB, and TAP-2. The results suggest that genetic variations within particular MHC genes can influence immune response to common childhood vaccinations, which in turn may influence vaccine efficacy.