TG Haplotype Research Articles

Genetic variation in the 3'-untranslated region of PAK1 influences schizophrenia susceptibility.

The present study aimed to investigate the association of two polymorphisms (rs2844337 and rs11237200) in the P21 protein (cell division control protein 42/Rac)-activated kinase 1 gene with susceptibility to schizophrenia (SCZ) in Chinese Zhuang and Chinese Han populations. A total of 700 patients with SCZ and 700 healthy controls were recruited. Rs2844337 and rs11237200 polymorphisms were genotyped using Sequenom technology. A total of 591 patients completed the Positive and Negative Syndrome Scale (PANSS) assessment. Data were statistically analyzed using PLINK version 1.07 and SPSS version 17.0. In the Chinese Han population, the genotypic (P=0.038) and allelic (P=0.033) frequencies of the 3'-untranslated region (UTR) genetic variation of rs2844337 in patients were significantly decreased compared to that in controls; these frequencies were significantly associated with SCZ susceptibility in the additive model (Padj=0.032) and in the recessive model (Padj=0.031). Moreover, the TG haplotype constructed by rs2844337 and rs11237200 polymorphisms remained significantly associated with SCZ risk following adjustment for gender and age and applying a Bonferroni correction in the Chinese Han population (Padj=0.003, PBC=0.009). The adjacent 5'-UTR genetic variation of rs11237200 was significantly associated with the total score (Padj=0.006), positive scale score (Padj=0.014) and general psychopathology scale scores (Padj=0.009) in the recessive model of the Chinese Han population. However, these polymorphisms were not significantly associated with SCZ susceptibility or the PANSS scores in the Chinese Zhuang population. In conclusion, variations in the PAK1 gene influenced the susceptibility and severity of the clinical symptoms of SCZ in the Chinese Han population investigated in the present study.

Genetic polymorphisms of CYP3A4 among Chinese patients with steroid-induced osteonecrosis of the femoral head.

Background:Steroid therapy has been an important reason of nontraumatic osteonecrosis of the femoral head (ONFH). Steroids are metabolized by hepatic cytochrome P4503A, a low endogenous activity of this enzyme can contribute to the pathogenesis of ONFH. The aim of this study was to investigate the associations of polymorphisms of cytochrome P4503A4 (CYP3A4) gene with steroid-induced ONFH in Chinese patients.Methods:A total of 150 steroid-induced ONFH patients and 250 healthy controls were enrolled. We evaluated 5 single-nucleotide polymorphisms of the CYP3A4 gene in this case–control study.Results:We identified rs2242480 in the CYP3A4 gene that was potentially associated with an increased risk of steroid-induced ONFH in the allele model (P = 0.023; odds ratio [OR]: 1.47; 95% confidence intervals [CI]: 1.05–2.04) and in the additive model (P = 0.028; OR: 1.44; 95% CI: 1.04–1.99) adjusted age + gender. Furthermore, we also observed a protective effect of haplotype “TG” (P = 0.025; OR: 0.69; 95% CI: 0.49–0.96) and a risk effect of haplotype “CG” (P = 0.006; OR: 1.81; 95% CI: 1.19–2.77) of the CYP3A4 gene adjusted age + gender.Conclusion:These findings suggested that polymorphisms of CYP3A4 gene may be associated with susceptibility to steroid-induced ONFH.

Combination effect of cytochrome P450 1A1 gene polymorphisms on uterine leiomyoma: A case-control study.

Uterine leiomyoma (UL) is an estrogen-dependent neoplasm of the uterus, and estrogen metabolizing enzymes affect its progression. This study aimed to evaluate the association between two single-nucleotide polymorphisms of cytochrome P450 1A1 (CYP1A1) gene and UL risk. The study consisted of 105 patients with UL and 112 healthy women as controls. Ile462Val (A/G) and Asp449Asp (T/C) polymorphisms of CYP1A1 gene were analyzed by DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism methods, respectively. The findings indicated no association between Ile462Val (A/G) and Asp449Asp (T/C) polymorphisms of CYP1A1 gene and UL (p < 0.05). However, the combination effect of TT/AG genotypes of the Asp449Asp (T/C) and Ile462Val (A/G) polymorphisms was associated with 4.3-fold higher risk of UL. In addition, haplotype analysis revealed that TG haplotype of the Asp449Asp (T/C) and Ile462Val (A/G) polymorphisms could increase the UL risk nearly 4.9-fold. Asp449Asp (T/C) and Ile462Val (A/G) polymorphisms of CYP1A1 gene were not associated with UL susceptibility; however, the combination of the TT/AG genotypes and TG haplotype could increase the UL risk.

Association between Polymorphisms in Bitter Taste Receptor Genes and Clinical Features in Korean Asthmatics

Background: Bitter taste receptors (TAS2R) in human airway smooth muscle have recently been shown to have an important role in bronchodilation, together with β₂-adrenergic receptors. Object: To evaluate the association between genetic variations in TAS2R and clinical features, including bronchodilator response and asthma control. Method: We analyzed the association between single nucleotide polymorphisms (SNPs) of TAS2R10 and TAS2R14 and variables such as demographic data, atopy, duration of disease, and asthma control status, including variables such as asthma control test (ACT) score, percent predicted value of forced expiratory volume in 1 s (FEV₁), forced vital capacity (FVC), and FEV₁/FVC ratio, as well as bronchodilator response (BDR), in 721 asthma patients in Korea. Result: Three novel SNPs of 633G>A, 645C>A, and -79G>A in TAS2R10 and 3 known SNPs of -815T>C, -1267G>A, and -1897T>C in TAS2R14 were analyzed. Increased BDR was significantly associated with SNPs of -815T>C [OR (95% CI) = 1.88 (1.01-3.49), p = 0.04 ] [J Gen Physiol 2005;125:535-553; Am J Respir Cell Mol Biol 2010;42:373-3812], -1267A>G [OR (95% CI) = 2.07 (1.03-4.15), p = 0.04] and -1897T>C [OR (95% CI) = 3.05 (1.01-9.23), p = 0.04, in a dominant model, and OR = 1.91 (1.08−3.36), p = 0.02, in a codominant model] of the TAS2R14 gene. There was a significant association between -815T>C and a low mean ACT score [OR (95% CI) = 5.84 (1.94-17.61), p = 0.001]. In haplotype analysis, TAC, CAT, and TGT, or TG and CA haplotypes on TAS2R14 were significantly associated with increased BDR; CAT and CA haplotypes were significantly associated with a low ACT score. Conclusion: Genetic variations in TAS2Rs may be valuable genetic markers to predict therapeutic response and outcomes in asthma. Further research in an independent cohort is needed.

Amyotrophic Lateral Sclerosis (ALS): a study on cytokine polymorphisms

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder where neuroinflammation plays an important role; previous data suggest that cytokines are strongly involved. A group of ALS patients were studied for immune protein polymorphisms: a case-control study to determine statistically significant differences in allelic, genotypic and haplotypic frequencies of 22 genetic polymorphisms of 13 cytokines was performed. The aim was the detection of a risk profile for the potential identification of individuals prone to disease and the discovery of possible targets for medication or lifestyle modification. From statistical analysis a significant difference was observed in polymorphisms of IL-1β +3962 (genotype: CC p = 0.0347; CT p = 0.0149), TGF-β codon 25 (genotype: CG p = 0.0126; GG p = 0.013) and TNF-α -238 (genotype: AA p = 0.019). We take into consideration all possible haplotypes, observing a significance of TG haplotype in two IL-2 gene polymorphisms (-330, + 166; p =0.0038), and CC haplotype of TGF-β (codon 10, codon 25; p = 0.022).Furthermore, significant differences in IL-β1 and TNF-α mRNA expression between patients and controls were demonstrated. This is a starting study to understand the multiple factors involved in the onset and in the progression of ALS, with particular attention given on inflammatory genes.

Functional haplotypes of INCENP affect promoter activity and bovine semen quality

To explore the association between single nucleotide polymorphisms (SNPs) in the promoter region of the inner centromere protein (INCENP) gene and bovine semen quality, the haplotypes in 250 Chinese Holstein bulls were detected using PCR-RFLP method in this study. Two SNPs (g.-556 G>T, rs 136823901 and g.-692 C>T, rs 211010999) and three haplotypes (CG, TT, TG) were identified in the promoter region of INCENP. The genotype frequency and allele frequency of these two SNPs as well as the correlation between different SNP haplotype combinations and bovine semen quality were then analyzed. Our results showed that fresh sperm motility of the GT genotype was significantly higher than that of the GG genotype (P<0.05) at the SNP site g.-556 G>T, while fresh and frozen-thawed sperm motilities of the haplotype combinations H1H1(CCGG), H1H3(CTGT), H2H3(TTGT) and H3H3(TTTT) were significantly higher than that of H1H2 (P<0.05). To further study the possible mechanisms by which g.-556 G>T and g.-692 C>T affect semen quality, three haplotype plasmids were respectively transfected into MLTC-1 cells. The TG haplotype demonstrated the highest luciferase activity, suggesting that g.-556 G>T and g.-692 C>T are functional mutations which could regulate INCENP gene expression by affecting promoter activity and thus affect semen quality.

Genetic variants in IL12 influence both hepatitis B virus clearance and HBV-related hepatocellular carcinoma development in a Chinese male population.

IL12 plays a major role not only in inducing appropriate immune responses against viral infections (including HBV) but also in the antitumor immune response. This study was conducted to investigate the relationships of genetic variants in IL12 with hepatitis B virus (HBV) clearance and development of HBV-related hepatocellular carcinoma (HCC). We genotyped three single nucleotide polymorphisms (SNPs) of the IL12A (rs568406 and rs2243115) and IL12B (rs3212227) in 395 HBV-positive HCC patients, 293 persistent HBV carriers and 686 subjects with HBV natural clearance from southern China, using the improved multiplex ligase detection reaction (iMLDR) method. Logistic regression analysis adjusted for age, smoking, and alcohol consumption status showed that rs568408 variant genotypes were significantly associated with host HBV-related HCC risk when compared with persistent HBV carriers, and carriers of the GA + AA genotype decreased the HCC risk in comparison with GG carriers (adjusted OR = 0.53, 95% CI 0.35-0.80, P = 0.002). No relationships between the rs2243115 and rs3212227 SNPs and HCC risk were observed (all P > 0.05). Besides, rs568408 showed an approaching significant effect on susceptibility to HBV persistent infection (adjusted OR = 1.34, 95% CI 0.99-1.81, P = 0.057 in dominant genetic models). Furthermore, the TG haplotype was observed to be associated with a significantly increased risk of HBV-related HCC (OR = 1.42, 95% CI 1.10-1.83, P = 0.006), while TA haplotype was associated with a decreased risk of HBV-related HCC (OR = 0.61, 95% CI 0.45-0.83, P = 0.002). Our results reveal that the IL12A rs568408 variant may be a marker SNP for risk of both HBV clearance and HBV-related HCC development.

HIGH EXPRESSION OF HMOX1 IN BLUE-SHELLED CHICKENS IS ASSOCIATED WITH A TG HAPLOTYPE

HMOX1 is an important gene in biosynthesis of the eggshell pigment of blue eggs. Previous studies found that HMOX1 is highly expressed in the shell gland of hens laying blue eggs (BlueH) compared with hens laying brown eggs (BrownH); however, the reasons for the differential expression are unclear. In this study five single nucleotide polymorphism (SNP) in HMOX1 were genotyped in 111 BlueH and 115 BrownH. The association of haplotypes of these SNP with the blue egg phenotype was tested. Haplotype-specific expression of HMOX1 was detected in the shell gland. The interaction of sequence variants and transcription factors was analyzed using electrophoretic mobility shift assay (EMSA). A TG haplotype covering upstream 1.4 kb region of HMOX1 was significantly associated with blue eggs (p<0.05). Furthermore, the birds (n=12) with the haplotype expressed 3.8 fold more transcripts than those (n=12) without the haplotype (p<0.05). After re-sequencing a 2.2 kb region harboring the TG haplotype, a total of 26 SNP were found, of which a SNP was predicted to create a binding site of Nrf2, a transcription factor initiating HMOX1 expression. However, subsequent EMSA failed to confirm the Nrf2-DNA interaction. Taken together, the data suggested that the TG haplotype is not directly involved in regulation of HMOX1 expression; a regulatory mutation located near the haplotype and linked with the haplotype may exist and be responsible for the differential expression ofHMOX1.

Case-control association study of ABCB1 gene and major depressive disorder in a local Chinese Han population.

BackgroundHuman P-glycoprotein encoded by the ATP-binding cassette sub-family B member 1 (ABCB1) gene is expressed in the blood–brain barrier. ABCB1 protects the brain from many drugs and toxins such as glucocorticoids through the efflux pump. Recent evidence suggests that a specific allele of the ABCB1 gene confers susceptibility to major depressive disorder (MDD) in the Japanese population. The aim of this study was to explore the association of ABCB1 gene polymorphisms with MDD in a local Chinese Han population.MethodsTwo hundred and ninety-two MDD patients and 208 unrelated individuals were matched by age and sex and examined using a case-control design. Six single nucleotide polymorphisms (SNPs) of the ABCB1 gene, including rs1045642, rs2032583, rs2032582, rs2235040, rs1128503, and rs2235015, were genotyped by ligase detection reaction and multiplex polymerase chain reaction. Linkage disequilibrium and haplotype analysis were investigated in the two study groups.ResultsSignificant protection for MDD individuals carrying the TG haplotype of rs1045642–rs2032582 was observed (odds ratio 0.470, 95% confidence interval 0.251–0.897, P=0.01). The rs2032582 (G2677T) and rs1128503 (C1236T) SNPs of ABCB1 showed nominal associations with MDD; the other four SNPs of the ABCB1 gene were not associated with MDD.ConclusionChinese individuals carrying the TG haplotype of rs1045642–rs2032582 had a nearly 53% lower risk of developing MDD. To the best of our knowledge, this is the first report to analyze the effect of ABCB1 polymorphism on the risk of MDD in a Chinese population.

Association of adiponectin gene polymorphisms with an elevated risk of diabetic peripheral neuropathy in type 2 diabetes patients

ObjectiveIn this study, we examined the association between two adiponectin (ADPN) gene polymorphisms, +45T/G and +276G/T, and susceptibility to diabetic peripheral neuropathy (DPN) in type 2 diabetes mellitus (T2DM) patients. MethodsA total of 180 T2DM patients were enrolled in this study and assigned to two groups: DPN group (n=90) and non-DPN (NDPN) group (n=90). In addition, 90 healthy subjects were chosen as healthy normal control (NC). The plasma level of ADPN was quantified by ELISA method and polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) was used for genotype analysis of the two ADPN polymorphisms, +45T/G (rs2241766) and +276G/T (rs1501299), in all the study subjects. Statistical analysis of data was performed with SPSS version 20.0 software. ResultsSerum levels of ADPN were markedly reduced in the DPN group compared to NDPN and NC groups (all P<0.05). The frequencies of TT, TG and GG genotypes and the T and G alleles of T45G and G276T polymorphisms in DPN group were significantly different than the NDPN group (all P<0.05). Notably, T45G and G276T polymorphisms were associated with significantly reduced plasma levels of ADPN in DPN and NDPN groups, compared to the NC group (P<0.001). Significant difference in ADPN plasma levels were also observed between TT, TG and GG genotypes of T45G and G276T polymorphisms. Our results indicate that the T allele in +45T/G and +276G/T polymorphisms is correlated with an elevated risk of DPN in T2DM patients. Haplotype analysis showed that GG and GT haplotypes showed a negative relationship with DPN, while TG haplotype positively correlated with risk of DPN in T2DM patients (all P<0.05). ConclusionOur results show that T45G and G276T polymorphisms of ADPN are associated with a significantly elevated risk of DPN in T2DM patients, likely by down-regulating ADPN serum level.

Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms With Acute Rejection in Liver Transplant Recipients.

Polymorphisms of the endothelial nitric oxide synthase gene have been associated with altered endothelial nitric oxide synthase activity. The purpose of this study was to investigate the relation between endothelial nitric oxide synthase -786T/C and 894G/T polymorphism and their haplotypes on the occurrence of acute rejection episodes in liver transplant recipients. We conducted a case control study in which 100 liver transplant recipients and 100 healthy controls were recruited from Shiraz Transplant Center. The patients used triple therapy including tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression maintenance. DNA was extracted from peripheral blood and endothelial nitric oxide synthase polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism. Patients included 60 men and 40 women (mean age, 32.35 ± 10.2 y). There was a significant association of endothelial nitric oxide synthase 894G/T and acute rejection episode. The GT* gen-otype and acute rejection episodes had a significant association (odds ratio, 2.42; 95% confidence interval, 0.97-6.15; P = .03). The GG and GT* genotype and T* allele frequency were significantly different between patients and control subjects (P = .001). Haplotype TT* was higher in recipients than control subjects (odds ratio, 2.17; 95% confidence interval, 1.12-4.25; P = .01). Haplotype TG was higher in the control group (odds ratio, 0.62; 95% confidence interval, 0.40-0.96; P = .02). Our results suggest a relation between different endothelial nitric oxide synthase geno-types and risk of acute rejection episodes. However, further study is necessary to determine genetic susceptibility for transplant patients.

The Impact of IFN-γ Gene Polymorphisms on Spontaneous Clearance of HCV Infection in Fars Province, Southern of Iran.

Certain polymorphisms in cytokine genes such as IFN-γ may influence the outcome of hepatitis C virus (HCV) infection. Here the frequency of the genotype, allele, and haplotype of IFN-γ gene at some loci is investigated in HCV-infected patients. Totally 255 patients with chronic HCV infection and 44 spontaneously cleared individuals were included. The chronic or clearance states were confirmed using enzyme-linked immunosorbent assay (ELISA) and two different qualitative reverse transcriptase polymerase chain reaction (RT-PCR) techniques. IFN-γ gene polymorphisms were performed by PCR using sequence-specific primers and PCR-RLFP on extracted genomic DNA. The frequency of GG genotype (P = 0.0001, OR: 5.69 and CI: 2.21-14.62) and allele (P = 0.0003, OR: 2.73 and CI: 1.54-4.83) of IFN-γ gene at +2109 locus was significantly higher in cases that spontaneously cleared the infection. Haplotype analysis showed the association of AG haplotype (P = 0.0046, OR = 6.14 and CI = 1.56-25) with spontaneous clearance of the infection. Our finding indicated that individuals with GG genotype at +2109 loci of IFN-γ gene and also AG haplotype (A allele at +874 loci and G allele at +2109 loci) may clear HCV infection more frequently than those with AA and AG genotype at +2109 loci and AA, TA, and TG haplotype.

Evidence that MHC I-E dampens thyroid autoantibodies and prevents spreading to a second thyroid autoantigen in I-A(k) NOD mice.

NOD.H2k and NOD.H2h4 mice carry the MHC class II molecule I-Ak associated with susceptibility to experimentally-induced thyroiditis. Dietary iodine enhanced spontaneous thyroid autoimmunity, well known in NOD.H2h4 mice, has not been investigated in NOD.H2k mice. We compared NOD.H2h4 and NOD.H2k strains for thyroiditis and autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) without or with dietary sodium iodide (NaI) for up to 32 weeks. TgAb levels were significantly higher in NOD.H2h4 than NOD.H2k mice on NaI and TPOAb developed in NOD.H2h4 but not NOD.H2k mice. DNA exome analysis revealed, in addition to the differences in the chromosome (Chr) 17 MHC regions, that NOD.H2k and particularly NOD.H2h4 mice have substantial non-MHC parental DNA. KEGG pathway-analysis highlighted thyroid autoimmunity and immune-response genes on Chr 17 but not on Chr 7 and 15 parental B10.A4R DNA. Studies of parental strains provided no evidence for non-MHC gene contributions. The exon 10 thyroglobulin haplotype, associated with experimentally-induced thyroiditis, is absent in NOD.H2h4 and NOD.H2k mice and is not a marker for spontaneous murine thyroid autoimmunity. In conclusion, the absence of I-E is a likely explanation for the difference between NOD.H2h4 and NOD.H2k mice in TgAb levels and, as in humans, autoantibody spreading to TPO.

A haplotype of the norepinephrine transporter gene (SLC6A2) is associated with visual memory in attention-deficit/hyperactivity disorder

Attention-deficit/hyperactivity disorder (ADHD) is a common heritable childhood-onset psychiatric disorder with impaired visual memory. Based on the evidence from treatment effect of atomoxetine, which interacts directly with the norepinephrine transporter, on visual memory in children with ADHD, this study examined the linkage disequilibrium structure of the norepinephrine transporter gene (SLC6A2) and the association between SLC6A2 and ADHD and visual memory, a promising endophenotype for ADHD. This family-based association sample consisted of 382 probands with DSM-IV ADHD and their family members (n=1298 in total) of Han Chinese in Taiwan. Visual memory was assessed by the Pattern Recognition Memory (PRM) and Spatial Recognition Memory (SRM) tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB). We screened 21 polymorphisms across SLC6A2 and used the Family-Based Association Test (FBAT) to test the associations of SLC6A2 polymorphisms with ADHD and the PRM and SRM measures. In haplotype analyses, a haplotype rs36011 (T)/rs1566652 (G) was significantly associated with ADHD (minimal p=0.045) after adjustment for multiple testing. In quantitative analyses, this TG haplotype also demonstrated significant associations with visual memory measures, including mean latency of correct responses in PRM (minimal p=0.019), total correct responses in PRM (minimal p=0.018), and total correct responses in SRM (minimal p=0.015). Our novel finding of the haplotype rs36011 (T)/rs1566652 (G) as a novel genetic marker involved in both ADHD disease susceptibility and visual memory suggests that allelic variations in SLC6A2 could provide insight into the pathways leading from genotype to phenotype of ADHD.

Inherited variation at MC1R and ASIP and association with melanoma-specific survival.

Melanocortin-1 receptor (MC1R) is a marker of melanoma risk in populations of European ancestry. However, MC1R effects on survival are much less studied. We investigated associations between variation at MC1R and survival in an international, population-based series of single primary melanoma patients enrolled into the Genes, Environment, and Melanoma study. MC1R genotype data was available for 2,200 participants with a first incident primary melanoma diagnosis. We estimated the association of MC1R genotypes with melanoma-specific survival (i.e., death caused by melanoma) and overall survival using COX proportional hazards modeling, adjusting for established prognostic factors for melanoma. We also conducted stratified analyses by Breslow thickness, tumor site, phenotypic index, and age. In addition, we evaluated haplotypes involving polymorphisms near the Agouti signaling protein gene (ASIP) locus for their impacts on survival. Melanoma-specific survival was inversely associated with carriage of MC1R variants in the absence of consensus alleles compared to carriage of at least one consensus allele (hazard ratio (HR) = 0.60; 95% confidence interval (CI): 0.40, 0.90). MC1R results for overall survival were consistent with no association. We did not observe any statistical evidence of heterogeneity of effect estimates in stratified analyses. We observed increased hazard of melanoma-specific death among carriers of the risk haplotype TG near the ASIP locus (HR = 1.37; 95% CI: 0.91, 2.04) when compared to carriers of the most common GG haplotype. Similar results were noted for overall survival. Upon examining the ASIP TG/TG diplotype, we observed considerably increased hazard of melanoma-specific death (HR = 5.11; 95% CI: 1.88, 13.88) compared to carriers of the most common GG/GG diplotype. Our data suggest improved melanoma-specific survival among carriers of two inherited MC1R variants.

Genetic variation of TBX21 gene increases risk of asthma and its severity in Indian children.

T-box transcription factor protein (TBX21) is encoded by the TBX21 gene in human. It is crucial for naive T lymphocyte development, interferon-γ production, airway hyperresponsiveness and regulation of corticosteroid response in asthmatics. Polymorphisms rs4794067 and rs16947078 of TBX21 were found to be associated with acetylsalicylic acid-induced and allergic asthma, respectively. We examined whether sequence variants of TBX21 gene are associated with asthma and its severity in Indian population. In a hospital-based case-control study, 240 asthmatic children and 240 healthy controls were investigated for the association of TBX21 rs4794067 (C>T) and rs16947078 (G>A) polymorphisms with asthma and its severity using PCR-restriction fragment length polymorphism method. Heterozygous (CT) (odds ratio (OR)=2.33; P=0.001) and variant (TT) (OR=6.25; P=0.001) genotypes of rs4794067 were demonstrated significant risk of asthma. However, in asthma severity variant (TT) genotype revealed significant increase risk (intermittent: OR=5.9, P=0.001; mild: OR=8.0, P=0.001; moderate: OR=3.2, P=0.041; and severe: OR=43.6, P=0.001) in all subgroups. Furthermore, haplotypes TG (OR=2.83; P=0.001) and TA (OR=2.54; P=0.001) of TBX21 were associated with an increased risk of asthma. Conversely, rs16947078 G>A polymorphism was not associated with any asthma/asthma severity risk. These data suggest that TBX21 gene variation may modify individual's susceptibility to asthma and its severity in Indian population. However, further validation in large population-based studies is needed to confirm the finding.

Association between STAT4 gene polymorphisms and autoimmune thyroid diseases in a Chinese population.

The STAT4 gene encodes a transcriptional factor that transmits signals induced by several key cytokines which play important roles in the development of autoimmune diseases. The aim of this study was to explore the association of STAT4 polymorphism with Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). A total of 1048 autoimmune thyroid diseases (AITDs) patients (693 with GD and 355 with HT) and 909 age- and gender-matched controls were examined. STAT4 polymorphisms (rs7574865/rs10181656/rs7572482) were genotyped by multiplex polymerase chain reaction (PCR) and ligase detection reaction (LDR). The results indicated that the frequencies of rs7574865 genotypes in patients with GD differed significantly from the controls (p = 0.028), the T allele frequency of GD patients was also significantly higher than the controls (p = 0.020). The genotypes of rs10181656 differed significantly in GD patients from controls (p = 0.012); G allele frequencies were significantly higher in AITD patients than the controls (p = 0.014 and 0.031, respectively). The frequencies of haplotype GC with GD and HT patients were significantly lower than their controls (p = 0.015 and 0.030, respectively). In contrast, the frequencies of haplotype TG with GD and HT patients were significantly higher than their controls (p = 0.016 and 0.048, respectively). These findings strongly suggest that STAT4 rs7574865/rs10181656 polymorphisms increase the risk of AITD in a Chinese population.

A novel multiplex pyrosequencing assay for genotyping functionally relevant CTLA-4 polymorphisms: Potential applications in autoimmunity and cancer

CTLA-4 expression/function can be affected by single nucleotide polymorphisms (SNPs) of CTLA-4 gene, which have been widely associated with susceptibility or progression to autoimmune diseases and cancer development.In this study, we analyzed six CTLA-4 SNPs (−1661A>G, −1577G>A, −658C>T, −319C>T, +49A>G, CT60G>A) in 197 DNA samples from 43 B-lymphoblastoid cell lines (B-LCLs), 40 systemic sclerosis (SSc) patients, 14 pre-analyzed melanoma patients and 100 Italian healthy subjects.Genotyping of −1661A>G, −1577G>A, −658C>T and CT60G>A was performed by newly developed multiplex pyrosequencing (PSQ) assays, whereas −319C>T and +49A>G by T-ARMS PCR and direct sequencing. Genotype/allele frequency were analyzed using χ2 or Fisher exact test.Our study provides the first multiplex PSQ method that allows simultaneous genotyping of two CTLA-4 SNP pairs (i.e. −1661A>G/−658C>T and −1577G>A/CT60G>A) by two multiplex PSQ reactions. Herein, we show the CTLA-4 genotype distribution in the B-LCLs providing the first and best characterized cell line panel typed for functionally relevant CTLA-4 SNPs.We also report the significant association of the −1661A/G genotype, −1661 & −319 AC-GT diplotype and −319 & CT60 TG haplotype with susceptibility to SSc without Hashimoto’s thyroiditis occurrence. Furthermore, we confirmed previous genotyping data referred to melanoma patients and provided new genotyping data for Italian healthy subjects.

Tagging Snps in the Excision Repair Cross-Complementing Group 4 (ERCC4)Gene Increased Risk of Cervical Squamous Cell Carcinoma (CSCC) and Modulate the Disease Outcome

Background: Given the important role of ERCC4 gene in multiple DNA repair systems, we hypothesized that genetic variations within this gene may be a cervical squamous cell carcinoma (CSCC) risk and disease modulatory factor.Methods: In population-based, case-control association study including 143 CSCC patients and 207 healthy women, two ERCC4tagSNPs were studied.Results: A significant protective effect against CSCC was observed assuming a dominant model in case of ERCC4rs3136176 ([AA]+[AT]vs.[TT]: p=0.04,OR=0.43), and genotype [AA] strongly protects against poorly (G3) differentiated CSCC (pcorreced=0.008,OR=0.15) and significantly increased the disease remission rate (p=0.05,OR=0.48).A statistically significant increase frequency of ERCC4rs1799798 [A] allele was seen in patients with well differentiated (G1) CSCC (p=0.02, OR=2.40). Contrary, an opposite trend was observed when G1 was compared with G2 (moderately differentiated) CSCC (p=0.06). Furthermore, ERCC4rs1799798 [A] allele tended to be increased in patients with carcinoma planoepitheliale keratodes (Cpk) (p=0.07).Haplotype ERCC4rs3136176[A]/ERCC4rs1799798[G] significantly decreased risk of G1 as well as G3 CSCC (p=0.02,OR=0.50, and p=0.017,OR=0.42, respectively) and only tended to decrease risk of CSCC (p=0.07,OR=0.758) as well as carcinoma planoepitheliale akeratodes (Cpa) (p=0.059,OR=0.71).In contrast haplotype AA significantly increased risk of G1 CSCC and risk of Cpk (p=0.01, OR=2.51, and p=0.049, OR=1.96, respectively), whereas haplotype TG increased risk of G3 CSCC (p=0.037, OR=2.17).The overall survival rates showed similar mean survival rates according to patients' genotypes at both studied SNPs.Conclusion: The above findings consistently suggested that genetic variants in ERCC4 gene may play significant role in CSCC pathophysiology.

Polymorphisms in Base Excision Repair Genes Are Associated With Endometrial Cancer Risk Among Postmenopausal Japanese Women

Polymorphisms in base excision repair (BER) genes are associated with risk for several types of cancers but have not been studied with respect to endometrial cancer among Japanese women. Therefore, we conducted a case-control study to explore the association between polymorphisms in BER genes and the risk for endometrial cancer. This study included a total of 91 postmenopausal subjects with endometrial cancer and 261 controls without cancer who visited the Aichi Cancer Center between 2001 and 2005. We focused on single nucleotide polymorphisms within coding regions of 5 BER genes (OGG1, MUTYH, XRCC1, APEX1, and PARP1). To assess lifestyle in the etiology of endometrial cancer, we used a self-administered questionnaire. Associations were evaluated using multivariate unconditional logistic regression models. We also assessed whether there were intergenic associations or an interaction with obesity. We observed a significant association between endometrial cancer risk and XRCC1 rs1799782 (C > T, Arg194Trp) and XRCC1 rs25487 (G > A, Arg399Gln). We uncovered a significant association between obesity (body mass index, ≥ 25) and rs25487. The XRCC1 polymorphisms were in complete linkage disequilibrium, and the XRCC1 haplotype TG associated significantly with endometrial cancer risk. The interaction between the CA haplotype and body mass index was marginally significant, whereas interaction between haplotype in XRCC1 and rs1136410 (PARP1) was not significant. We found a significant association between endometrial cancer risk and XRCC1 polymorphisms and haplotype TG in postmenopausal Japanese women.