Genetic Polymorphisms In Susceptibility Research Articles

Replication of association at the LPP and UBASH3A loci in a UK autoimmune Addison's disease cohort.

Autoimmune Addison's disease (AAD) arises from a complex interplay between multiple genetic susceptibility polymorphisms and environmental factors. The first genome wide association study (GWAS) with patients from Scandinavian Addison's registries has identified association signals at four novel loci in the genes LPP, SH2B3, SIGLEC5, and UBASH3A. To verify these novel risk loci, we performed a case-control association study in our independent cohort of 420 patients with AAD from the across the UK. We report significant association of alleles of the LPP and UBASH3A genes [odds ratio (95% confidence intervals), 1.46 (1.21-1.75)and 1.40 (1.16-1.68), respectively] with AAD in our UK cohort. In addition, we report nominal association of AAD with SH2B3 [OR 1.18 (1.02-1.35)]. We confirm that variants at the LPP and UBASH3A loci confer susceptibility to AAD in a UK population. Further studies with larger patient cohorts are required to robustly confirm the association of SH2B3 and SIGLEC5/SPACA6 alleles.

Association of NOD1 and NOD2 Polymorphisms With Susceptibility to Subacute Sclerosing Panencephalitis.

Background: Subacute sclerosing panencephalitis is a progressive neurodegenerative disease that is a late complication of measles infection. However, to date, the pathogenesis of subacute sclerosing panencephalitis is still not explained; both viral and host factors seem to be associated. The present study aimed to investigate the relationship between NOD1 and NOD2 gene variants and subacute sclerosing panencephalitis. Methods: The gene variants of NOD1 (rs2075820 and rs2075818) and NOD2 (R334Q and R334W) were explored in 64 subacute sclerosing panencephalitis patients and 70 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: The frequencies of the AA genotype and A allele of rs2075820 (NOD1; c.796G>A) polymorphism were lower in patients compared with controls (P = .022 and .014, respectively). The presence of the A allele of rs2075820 may be considered as a protective factor for subacute sclerosing panencephalitis. There was a significant difference between the groups in rs2075818 (NOD1 G/C) polymorphism, and the CC genotype increased the risk of subacute sclerosing panencephalitis by 3.471-fold. The carriers of the C allele of rs2075818 (G/C) had a 1.855-fold susceptibility to subacute sclerosing panencephalitis (P = .018). The GC genotype might be associated with subacute sclerosing panencephalitis susceptibility in the patients compared with patients without having that haplotype (P = .03). Conclusions: Thus, we identified an association between subacute sclerosing panencephalitis and the rs2075820 (NOD1 G/A) and rs2075818 (NOD1 G/C) polymorphisms. These findings implicate a possible effect of this genetic polymorphism in susceptibility to subacute sclerosing panencephalitis, which needs to be confirmed in bigger populations.

The Implication of X-Linked Genetic Polymorphisms in Susceptibility and Sexual Dimorphism of Cancer.

The X-chromosome is implicated in cancer development through various mechanisms, including X-inactivation defects, loss of heterozygosity, and germline and somatic alterations of X-linked genes. Sex is a key factor which influences cancer susceptibility as many cancer types show sexual dimorphism in their incidence. The aim of this review was to summarize the germline genetic polymorphisms lying on the X-chromosome that have been associated with cancer susceptibility and to evaluate their possible implication in cancer-related sexual dimorphism. PubMed and Web of Science were searched using the terms "X-chromosome", "polymorphism" and "cancer". The literature review revealed 39 articles reporting 33 genetic variants in 22 X-linked genes as being associated with cancer risk. Most of these genes interact with each other in a direct or indirect way, as GeneMANIA software revealed, demonstrating the complication of the mechanisms through which they are involved in tumorigenesis. Polymorphisms in eight genes [androgen receptor (AR), fibroblast growth factor 13 (FGF13), forkhead box P3 (FOXP3), L1 cell adhesion molecule (L1CAM), nudix hydrolase 11 (NUDT11), Shroom family member 2 (SHROOM2), transcription elongation factor A-like 7 (TCEAL7) and TIMP metallopeptidase inhibitor 1 (TIMP1)] are reported to have a sex-specific association with cancer susceptibility, which might explain the sexual dimorphism of certain cancer types. All of the above eight mentioned genes, with the exception of L1CAM, exhibit differences in their expression pattern between breast tumor (sex-specific)/thyroid tumor (sex-influenced) vs. normal tissues according to our analysis using GENT2 software. Additionally, differences in breast or thyroid tumor compared with normal tissues were also observed in five genes analyzed with GENT2 software that were previously related to sex-influenced cancer according to literature. Finally, the present review points out the need for the development of appropriate free and user-friendly statistical software in order to reduce bias/errors in statistical analyses and overcome researchers' reluctance to include X-chromosome variants in their genetic-association studies.

Analysis of Association between Interleukin-6 (<i>IL</i>6), Interleukin-13 (<i>IL</i>13) and Tumor Necrosis Factor-Alpha (<i>TNF-alpha</i>) Gene Polymorphisms and Genetic Susceptibility of Rheumatoid Arthritis in Kuwaiti Arab

Background: Rheumatoid arthritis (RA) is a common autoimmune disease in which a combination of risk alleles from different susceptibility genes predisposes the patients to develop clinical symptoms following exposure to environmental factors. RA is a chronic and progressive disease characterized by synovial inflammation that results in destruction in the affected joints and severe problems in individual’s mobility. Several immune-related risk factors have been associated with RA, these include single nucleotide polymorphisms (SNPs) in cytokine genes. The impact of these cytokine gene polymorphisms is due to their association either with elevated serum levels and/or variations in their serum levels are associated with disease-onset and progression. The objective of this study was to investigate the role of Interleukin-6 (IL6), Interleukin-13 (IL13) and Tumor necrosis factor-alpha (TNF-alpha) gene polymorphisms in genetic susceptibility of RA in Kuwaiti patients. Methods: We have determined the genotypes of IL6 gene (-174G/C; rs1800795), IL13 gene (R130Q; rs20541) and TNF-alpha gene (-308A/G' rs1800629) polymorphisms in 192 Kuwaiti patients with RA and compared it to that in 104 healthy controls. The diagnosis of RA was based on the American College of Rheumatology (ACR) classification criteria. The genotypes for IL6, IL13 and TNF-alpha gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods and confirmed by DNA sequencing. Results: The frequency of IL6 gene (-174G/C; rs1800795) and TNF-alpha gene (-308A/G' rs1800629) polymorphisms manifested a statistically significant difference between Kuwaiti RA patients and controls (P = 0.02 and 0.002 respectively). In contrast, the frequency of IL13 gene (R130Q; rs20541) polymorphism did not show a significant difference between Kuwaiti RA patients and controls. Conclusions: Our data showed an association of two cytokine gene polymorphisms (i.e. IL6 gene -174G/C; rs1800795 polymorphism, and TNF-alpha gene -308A/G, rs1800629 polymorphism) with RA in Kuwaiti patients highlighting their significant contribution in genetic susceptibility of this chronic disease possibly along with other factors.

The predictive role of toll-like receptor-4 genetic polymorphisms in susceptibility to and prognosis of prostatic hyperplasia.

Objective(s):This study was aimed to evaluate whether single nucleotide polymorphisms (SNPs) of TLR4 and common living habits of prostate hyperplasia (BPH) patients would affect the subjects’ risk and prognosis.Materials and Methods:We totally recruited 501 BPH patients and 964 healthy controls. The patients’ international prostate symptom score (IPSS) and quality of life assessment (QoL) were designated as the prognostic indexes for BPH patients. Altogether 7 SNPs within TLR4 were selected, and the interactions among SNPs and living habits were explained with multi-factor dimensionality reduction (MDR) modeling. Results:The mutant alleles of rs10983755 (G>A) and rs1927907 (G>A) tended to put on risk of BPH, yet the wide alleles of rs4986791 (C>T) and rs115336889 (G>C) were associated with incremental susceptibility to BPH (P<0.05). The rs10983755 (GA) and rs1927907 (GA) were suggested as the marker of non-aggressive BPH, whereas rs4986791 (TT) could symbolize aggressive BPH (P<0.05). The homozygotes of rs4986791 (TT) and rs115336889 (CC) could improve the IPSS change, and rs115336889 (CC) was also correlated with more obviously ameliorated Qol change (P<0.05). Finally, MDR modeling suggested that rs4986791 (TT) and rs115336889 (GG) shaped the genotyping combination featured by the lowest risk of BPH when smoking or drinking history was also evaluated.Conclusion:The SNPs situated within TLR4 were potent candidates for predicting risk and prognosis of BPH patients, and their interactions within environmental parameters also helped to develop effective strategies for preventing and treating BPH.

Polymorphisms of genes involved in inflammation and blood vessel development influence the risk of varicose veins

Heredity plays an important role in the etiology of varicose veins (VVs). However, the genetic basis underlying this condition remains poorly understood. Our aim was to replicate top association signals from genome-wide association studies (GWASs) for VVs of lower extremities using 2 independent datasets-our sample of ethnic Russian individuals (709 cases and 278 controls) and a large cohort of British residents from UK Biobank (10 861 cases and 397 594 controls). Associations of polymorphisms rs11121615, rs6712038, rs507666, rs966562, rs7111987, rs6062618, and rs6905288 were validated in the UK Biobank individuals at a Bonferroni-corrected significance level. In Russian cohort, only rs11121615 reached a nominal significance level of P < .05. Results of original GWAS and replication studies were combined by a meta-analysis, and polymorphisms listed above as well as rs111434909 and rs4463578 passed a genome-wide significant threshold. Notably, the majority of these polymorphisms were located within or near genes involved in vascular development and remodeling, and regulation of inflammatory response. Our results confirm the role of these polymorphisms in genetic susceptibility to VVs and indicate the revealed genomic regions as good candidates for further fine-mapping studies and functional analysis. Moreover, our findings implicate inflammation and abnormal vascular architecture in VVs pathogenesis.

The Role of Caspase Genes Polymorphisms in Genetic Susceptibility to Philadelphia-Negative Myeloproliferative Neoplasms in a Portuguese Population.

Our main aim was to evaluate the role of caspases' genes SNPs in Philadelphia-chromosome negative chronic myeloproliferative neoplasms (PN-MPNs) susceptibility. A case-control study in 133 Caucasian Portuguese PN-MPNs patients and 281 matched controls was carried out, studying SNPs in apoptosis related caspases: rs1045485 and rs1035142 (CASP8), rs1052576, rs2308950, rs1132312 and rs1052571 (CASP9), rs2227309 and rs2227310 (CASP7) and rs13006529 (CASP10). After stratification by pathology diagnosis for essential thrombocythemia (ET), female gender or JAK2 positive, there is a significant increased risk for those carrying at least one variant allele for CASP9 (C653T) polymorphism (OR 2.300 CI 95% [1.180-4.484], P = 0.014). However, when considered individually, none of the studied caspases polymorphisms was associated with PN-MPNs risk. Our results do not reveal a significant involvement of caspase genes polymorphisms on the individual susceptibility towards PN-MPNs as a whole. However, for essential thrombocythemia (ET), female gender or JAK2 positive, there is a significant increased risk to those carrying at least one variant allele for CASP9. Although larger studies are required to confirm these results and to provide conclusive evidence of association between these and other caspases variants and PN-MPNs susceptibility, these new data may contribute to a best knowledge of the pathophysiology of these disorders and, in the future, to a more rational and efficient choice of therapeutic strategies to be adopted in PN-MPNs treatment.

Occupational Exposure to Pesticides in Tobacco Fields: The Integrated Evaluation of Nutritional Intake and Susceptibility on Genomic and Epigenetic Instability.

Pesticides used at tobacco fields are associated with genomic instability, which is proposed to be sensitive to nutritional intake and may also induce epigenetic changes. We evaluated the effect of dietary intake and genetic susceptibility polymorphisms in MTHFR (rs1801133) and TERT (rs2736100) genes on genomic and epigenetic instability in tobacco farmers. Farmers, when compared to a nonexposed group, showed increased levels of different parameters of DNA damage (micronuclei, nucleoplasmic bridges, and nuclear buds), evaluated by cytokinesis-block micronucleus cytome assay. Telomere length (TL) measured by quantitative PCR was shorter in exposed individuals. Global DNA methylation was significantly decreased in tobacco farmers. The exposed group had lower dietary intake of fiber, but an increase in cholesterol; vitamins such as B6, B12, and C; β-carotene; and α-retinol. Several trace and ultratrace elements were found higher in farmers than in nonfarmers. The MTHFR CT/TT genotype influenced nucleoplasmic bridges, nuclear buds, and TL in the exposed group, whereas TERT GT/TT only affected micronucleus frequency. We observed a positive correlation of TL and lipids and an inverse correlation of TL and fibers. The present data suggest an important role of dietary intake and subjects' genetic susceptibility to xenobiotics-induced damages and epigenetic alterations in tobacco farmers occupationally exposed to mixtures of pesticides.

Role of common sarcomeric gene polymorphisms in genetic susceptibility to left ventricular dysfunction.

Mutations in sarcomeric genes are common genetic cause of cardiomyopathies. An intronic 25-bp deletion in cardiac myosin binding protein C (MYBPC3) at 3' region is associated with dilated and hypertrophic cardiomyopathies in Southeast Asia. However, the frequency of sarcomeric gene polymorphisms and associated clinical presentation have not been established with left ventricular dysfunction (LVD). Therefore, the aim of the present study was to explore the association of MYBPC3 25-bp deletion, titin (TTN) 18 bp I/D, troponin T type 2 (TNNT2) 5 bp I/D and myospryn K2906N polymorphisms with LVD. This study includes 988 consecutive patients with angiographically confirmed coronary artery disease (CAD) and 300 healthy controls. Among the 988 CAD patients, 253 with reduced left ventricle ejection fraction (LVEF≤45%) were categorized as LVD. MYBPC3 25-bp deletion, TTN 18 bp I/D and TNNT2 5 bp I/D polymorphisms were determined by direct polymerase chain reaction method, while myospryn K2906N polymorphism by TaqMan assay. Our results showed that MYBPC3 25-bp deletion polymorphism was significantly associated with elevated risk of LVD (LVEF <45) (healthy controls versus LVD: OR=3.85, P <0.001; and nonLVD versus LVD: OR=1.65, P = 0.035), while TTN 18 bp I/D, TNNT2 5 bp I/D and myospryn K2906N polymorphisms did not show any significant association with LVD. The results also showed that MYBPC3 25-bp deletion polymorphism was significantly associated with other parameters of LV remodelling, i.e. LV dimensions (LV end diastole dimension, LVEDD: P = 0.037 and LV end systolic dimension, LVESD: P = 0.032). Our data suggests that MYBPC3 25-bp deletion may play significant role in conferring LVD as well as CAD risk in north Indian population.

Ancestry informative markers and selected single nucleotide polymorphisms in immunoregulatory genes on preterm labor and preterm premature rupture of membranes: a case control study.

BackgroundA genetic predisposition to Preterm Labor (PTL) and Preterm Premature Rupture of Membranes (PPROM) has been suggested; however the relevance of polymorphisms and ancestry to susceptibility to PTL and PPROM in different populations remains unclear. The aim of this study was to evaluate the contribution of maternal and fetal SNPs in the IL1B, IL6, IL6R, TNFA, TNFR, IL10, TLR2, TLR4, MMP9, TIMP1 and TIMP2 genes and the influence of ancestry background in the susceptibility to PTL or PPROM in Brazilian women.MethodsCase–control study conducted at a tertiary hospital in São Paulo State, Brazil. We included women with PTL or PPROM and their babies (PTL: 136 women and 88 babies; PPROM: 65 women and 44 babies). Control group included 402 mother-babies pairs of term deliveries. Oral swabs were collected for identification of AIMs by fragment analysis and SNPs by Taqman® SNP Genotyping Assays and PCR. Linkage Disequilibrium and Hardy-Weinberg proportions were evaluated using Genepop 3.4. Haplotypes were inferred using the PHASE algorithm. Allele, genotype and haplotype frequencies were compared by Fisher’s exact test or χ2 and Odds Ratio. Logistic regression was performed. Clinical and sociodemographic data were analyzed by Fisher’s exact test and Mann–Whitney.ResultsPTL was associated with European ancestry and smoking while African ancestry was protective. The fetal alleles IL10-592C (rs800872) and IL10-819C (rs1800871) were also associated with PTL and the maternal haplotype TNFA-308G-238A was protective. Maternal presence of IL10-1082G (rs1800896) and TLR2A (rs4696480) alleles increased the risk for PPROM while TNFA-238A (rs361525) was protective. Family history of PTL/PPROM was higher in cases, and time to delivery was influenced by IL1B-31T (rs1143627) and TLR4-299G (rs4986790).ConclusionThere is an association between European ancestry and smoking and PTL in our Brazilian population sample. The presence of maternal or fetal alleles that modify the inflammatory response increase the susceptibility to PTL and PPROM. The family history of PTL/PPROM reinforces a role for genetic polymorphisms in susceptibility to these outcomes.

Fruit and vegetable intake and vitamin C transporter gene (SLC23A2) polymorphisms in chronic lymphocytic leukaemia.

There is currently no convincing epidemiological evidence that fruit and vegetable consumption, the primary source of vitamin C, plays a role in chronic lymphocytic leukaemia (CLL) aetiology. We hypothesized that variations in vitamin C dietary intake as well as in genetic variability in vitamin C transporter gene SLC23A2 could explain some inconsistencies in the literature. Fruit/vegetable/vitamin C consumption from food frequency questionnaires and six low-penetrance genetic susceptibility polymorphisms in vitamin C transporter gene SLC23A2 (rs1715364, rs6133175, rs1776948, rs6139587, rs369270 and rs6052937) were examined in 434 CLL cases and 1257 randomly selected controls from primary care centres with genetic data of whom 275 cases and 1094 controls having both diet and genetic information. Logistic regression models were used to estimate odds ratio (OR) and 95% confidence intervals (CI). CLL patients were more likely to have a higher fruit consumption than controls (highest versus lowest quartile in g/day OR: 1.48; 95% CI: 1.00 to 2.18; P=0.03), whereas no associations were found with vegetable or total vitamin C intake. Based on log-additive models, rs6133175_A>G (OR: 1.19, 95% CI: 1.00 to 1.41; P=0.05) and rs1776948_T>A (OR: 1.20; 95%CI: 1.01 to 1.41; P=0.04) were associated with CLL. The haplogenotype analysis (rs1715364, rs6133175) supported the genotype results. No gene-diet interactions in CLL remained statistically significant after correction for multiple testing. These data suggest that both fruit intake and genetic marker in SLC23A2 may play an independent role in CLL biology.

Genotoxic Effects of GSTP1 Gene Polymorphisms with Respect to Respiratory Problems among Traffic Police

Genetic susceptibility is likely to play a role in response to vehicular pollution of GSTP1 and NAT2 (C481T). Genotoxic effects due to respiratory problems in traffic police occupationally exposed to vehicular exhaust have particular importance in the detoxification of inhaled toxicants since it is the most abundant in the lung function and the association.161 male traffic policemen and 170 control subjects were selected for this study. Gene polymorphism was studied using PCR and RFLP method. The results on gene polymorphism of GSTP1 and NAT2 (C481T) showed significant association of homozygous mutant genotype (GG) in GSTP1 gene and homozygous mutant genotype (CC) in NAT2 gene with traffic police having respiratory problems. However, no such association was observed in traffic police without respiratory problems and control group also. Our results suggest that long term exposure to urban air pollution (with traffic as the main contributor) polymorphisms in genetic susceptibility provides evidence to suggest a role in determining the respiratory problems in GSTP1 and NAT2 (C481T) variants associated with reduced detoxification ability, increase susceptibility to such damage and appears to be associated with occupationally exhaust vehicular exhaust in traffic policemen.

Role of ADDUCIN Gly460Trp, ACE I/D and AGT M235T Gene Polymorphisms in Genetic Susceptibility to Diabetic Nephropathy

Diabetes mellitus is a metabolic disease with a high incidence of morbidity and mortality lowering the quality of life with acute and chronic complications and it needs to be followed up and treated throughout the lifespan. Concordant with the frequency of DM and the increase in the length of life frequency of DNP is also increased. The I allele of the ACE I/D polymorphism, AGT M235T’s T allele and ADD G460W’s W allele presence are purported to present a predisposition to DNP. In our study we aimed to investigate the effect of the AGT M235T, ACE I/D and ADD 460W polymorphisms in the development of DNP in patients with diabetes mellitus. The study group consisted of 194 patients with Diabetic nephropathy and the control group contained 100 DM patients. In the diabetic group the DD genotype of the ACE I/D polymorphism was 54 (54.0%) and the D allele was 69.0% and in the nephropathy group II genotype of the ID were 78 (40.2%) and 51 (26.3%) and the I allele was 46.4 respectively and the presence of the I allele was associated with the presence of nephropathy. There was no significance between the genotypes in the presence of a coexistence of AGT M235T and ACE I/D polymorphisms between the groups the MD alleles (42%) demonstrated significance in the diabetic and the T/I alleles (28.1) demonstrated significance in the nephropathy group. In the ADD G640W polymorphism on its own, subjects having GG (77.3%) and WW (7.7%) genotypes (p=0.025) might have been predisposed to nephropathy however when in combination with the ACE I/D, the presence of the DD/GG (45%) in the diabetic group and the presence of the ID/GG (29.9%) and II/GG (19.6%) combination in the DNP group were statistically significant. The D/G (64%) alleles were significant in the diabetic and the I/G (36.6) alleles were significant in the DNP groups respectively. As a conclusion we think that the II-ID/GG genotype and the I/G alleles in the presence of the ACE-ADD combination and TT/ID genotype and T/I alleles in the ACE-AGT combination may be effective in the predisposition of the diabetic patients to nephropathy.

Role of ACE and AGT gene polymorphisms in genetic susceptibility to diabetes mellitus type 2 in a Brazilian sample

The aim of the current study was to investigate the association between the InDel polymorphism in the angiotensin I-converting enzyme gene (ACE) and the rs699 polymorphism in the angiotensinogen gene (AGT) and diabetes mellitus type 2 (DM2) in a sample population from Southern Brazil. A case-control study was conducted with 228 patients with DM2 and 183 controls without DM2. The ACE InDel polymorphism was genotyped by polymerase chain reaction (PCR) with specific primers, followed by electrophoresis on 1.5% agarose gel. The AGT rs699 polymorphism was genotyped using a real-time PCR assay. No significant association between the ACE InDel polymorphism and DM2 was detected (P = 0.97). However, regarding the AGT rs699 polymorphism, DM2 patients had a significantly higher frequency of the AG genotype and lower frequency of the GG genotype when compared to the controls (P = 0.03). Our results suggest that there is an association between the AGT rs699 polymorphism and DM2 in a Brazilian sample.

Granzyme B gene polymorphism associated with subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a late complication of measles infection. Immune dysfunction related to genetic susceptibility has been considered in disease pathogenesis. A functional single nucleotide polymorphism (SNP) of granzyme B gene (GZMB) reported in several pathologies may also be involved in susceptibility to SSPE. An SNP (rs8192917, G → A, R→Q) was screened in 118 SSPE patients and 221 healthy controls (HC) by polymerase chain reaction-restriction fragment length polymorphism. Frequencies were compared between groups. In vitro production of GZMB was measured in controls with different genotypes. The SNP had a minor allele (G) frequency of 0.22 in patients and 0.31 in controls. GG genotype was significantly less frequent in patients (odds ratio, 0.23). G allele carriers produced relatively higher levels of GZMB, when stimulated in vitro. These findings implicate possible effect of this genetic polymorphism in susceptibility to SSPE which needs to be confirmed in bigger populations.

Associations of VEGF-C Genetic Polymorphisms with Urothelial Cell Carcinoma Susceptibility Differ between Smokers and Non-Smokers in Taiwan

BackgroundVascular endothelial growth factor (VEGF)-C is associated with lymphangiogenesis, pelvic regional lymph node metastasis, and an antiapoptotic phenotype in urothelial cell carcinoma (UCC). Knowledge of potential roles of VEGF-C genetic polymorphisms in susceptibility to UCC is lacking. This study was designed to examine associations between VEGF-C gene variants and UCC susceptibility and evaluate whether they are modified by smoking.Methodology/Principal FindingsFive single-nucleotide polymorphisms (SNPs) of VEGF-C were analyzed by a TaqMan-based real-time polymerase chain reaction (PCR) in 233 patients with UCC and 520 cancer-free controls. A multivariate logistic regression was applied to model associations between genetic polymorphisms and UCC susceptibility, and to determine if the effect was modified by smoking. We found that after adjusting for other covariates, individuals within the entire population and the 476 non-smokers carrying at least one A allele at VEGF-C rs1485766 respectively had 1.742- and 1.834-fold risks of developing UCC than did wild-type (CC) carriers. Among the 277 smokers, we found that VEGF-C rs7664413 T (CT+TT) and rs2046463 G (AG+GG) allelic carriers were more prevalent in UCC patients than in non-cancer participants. Moreover, UCC patients with the smoking habit who had at least one T allele of VEGF-C rs7664413 were at higher risk of developing larger tumor sizes (p = 0.021), compared to those patients with CC homozygotes.ConclusionsOur results suggest that the involvement of VEGF-C genotypes in UCC risk differs among smokers compared to non-smokers among Taiwanese. The genetic polymorphism of VEGF-C rs7664413 might be a predictive factor for the tumor size of UCC patients who have a smoking habit.

ASSOCIATION OF MYCOBACTERIUM TUBERCULOSIS LINEAGES WITH IFN-Γ AND TNF-Α GENE POLYMORPHISMS AMONG PULMONARY TUBERCULOSIS PATIENT

The six major lineages of Mycobacterium tuberculosis [MTB] are found to be strongly associated with specific geographical outbreaks. But whether these bacterial lineages influence the host genetic polymorphism is uncertain. The present study was designed to evaluate the relevance of strain diversity and host genetic polymorphisms in susceptibility to pulmonary tuberculosis [PTB]. For this reason, single –nucleotide polymorphisms [SNPs] in interferon- γ [IFN-γ] receptor-1[G-611A], IFNG [G+ 2109A] and tumor necrosis factors [TNF-α] genes [at −238, 308,−857position] in patients [n=151] were analyzed and compared with controls [n=83]. The genetic diversity of M. tuberculosis isolates was performed using spacer oligonucleotide typing. Thereafter, the profile of IFN-γ and TNF-α allele frequency were investigated in each subtype of M.tuberculosis. The results showed C allele of TNF 857 and A allele of TNF 238 were more frequent in PTB cases [[TNF 857 C allele OR [CI95%] 0.6[0.4–0.9], p= 0.02] for TNF 238 A allele OR [CI95%] 5.5[3.4–9.0], p= 0.00]]. Similarly, G allele in IFNG+ 2109 A/G polymorphism were significantly more in patients than control subject[OR[CI95%] 0.3; p< 0.05]. The major identified clinical isolates of M. tuberculosis were EAI[42; 27.8% ], Haarlem[ 31; 20.5% ], CAS [ 23;15.2% ], Beijing[14; 9.2%], and T [11; 7.2% ] lineages. No correction was observed between strains diversity and frequency of SNPs in studied PTB cases. In conclusions, we exclude the possibility of genetic mutation in IFN-γ and TNF-α gene by different subtypes of M. tuberculosis. Although, our results supports a positive correlation between host SNPs and susceptibility to PTB.

LEUKOTRIENE C4 SYNTHASE AND LEUKOTRIENE RECEPTOR-1 GENES POLYMORPHISM AMONG ATOPIC ASTHMATIC PATIENTS

Asthma is a complex polygenic disease in which Cysteinyl Leukotrienes (Cys-LTs) are a potential risk factors causing airway inflammation and remodeling, which are characteristics of asthma. The polymorphisms in the leukotriene C4 synthase -444A/C and cysteinyl leukotriene receptor1 927 T/C genes has been implicated in susceptibility to asth ma. The objective of this study was to analyse two different polymorphisms, LTC4S-444 A/C and Cys-LTR1 927 T/C single nucleotide polymorphism and to determine whether there is an association betwee n these polymorphisms and asthma development. The study included two groups (30 asthmatics and 30 hea lthy controls). They were genotyped for the LTC4S444 A/C and CysLTR1 927 T/C polymorphisms by PCR-RFLP. Their total serum IgE levels and urinary LTE4 levels were measured by Enzyme Linked Immunosorbent Assay (ELISA). IgE levels and urinary leukotriene E4 levels were higher in patient group than control group. The genotype and allele frequencies of both LTC4S-444 A/C and CysLTR1 927 T/C polymorphism were not significantly different between asthmatic patients and control gr oup. While urinary leukotriene E4 levels were significantly higher in variant types of LTC4 synth ase (AC and CC) compared to wild type (AA). This study does not support the role of these polymorphi sms in genetic susceptibility to asthma but provide an evidence for a functional role of LTC4 synthase-444 A/C polymorphism on Cys-LT synthesis.

The ontology of genetic susceptibility factors (OGSF) and its application in modeling genetic susceptibility to vaccine adverse events.

BackgroundDue to human variations in genetic susceptibility, vaccination often triggers adverse events in a small population of vaccinees. Based on our previous work on ontological modeling of genetic susceptibility to disease, we developed an Ontology of Genetic Susceptibility Factors (OGSF), a biomedical ontology in the domain of genetic susceptibility and genetic susceptibility factors. The OGSF framework was then applied in the area of vaccine adverse events (VAEs).ResultsOGSF aligns with the Basic Formal Ontology (BFO). OGSF defines ‘genetic susceptibility’ as a subclass of BFO:disposition and has a material basis ‘genetic susceptibility factor’. The ‘genetic susceptibility to pathological bodily process’ is a subclasses of ‘genetic susceptibility’. A VAE is a type of pathological bodily process. OGSF represents different types of genetic susceptibility factors including various susceptibility alleles (e.g., SNP and gene). A general OGSF design pattern was developed to represent genetic susceptibility to VAE and associated genetic susceptibility factors using experimental results in genetic association studies. To test and validate the design pattern, two case studies were populated in OGSF. In the first case study, human gene allele DBR*15:01 is susceptible to influenza vaccine Pandemrix-induced Multiple Sclerosis. The second case study reports genetic susceptibility polymorphisms associated with systemic smallpox VAEs. After the data of the Case Study 2 were represented using OGSF-based axioms, SPARQL was successfully developed to retrieve the susceptibility factors stored in the populated OGSF. A network of data from the Case Study 2 was constructed by using ontology terms and individuals as nodes and ontology relations as edges. Different social network analys is (SNA) methods were then applied to verify core OGSF terms. Interestingly, a SNA hub analysis verified all susceptibility alleles of SNPs and a SNA closeness analysis verified the susceptibility genes in Case Study 2. These results validated the proper OGSF structure identified different ontology aspects with SNA methods.ConclusionsOGSF provides a verified and robust framework for representing various genetic susceptibility types and genetic susceptibility factors annotated from experimental VAE genetic association studies. The RDF/OWL formulated ontology data can be queried using SPARQL and analyzed using centrality-based network analysis methods.

Study about the Relationship between TNF-Α-308G/A and Essential Hypertension in Specific Population-Taking Chinese Minority Zhuang in Guangxi as an Example

objective: study the association between TNF gene and essential hypertension (EH) in Chinese minority Zhuang population. Method: select 170 normal as control group and 246 patients with EH as an object of study, use polymerase chain reaction - restriction fragment length polymorphism method to analyze polymorphic loci in the promoter region of TNF-α gene-308G / A allele, and genotype frequency distribution characteristics were analyzed, and the relationship between genetic susceptibility polymorphisms and EH was given.