GC Heterozygotes Research Articles

The association of E2F1 and E2F2 single nucleotide polymorphisms with laryngeal squamous cell carcinoma pathomorphological features

BackgroundLaryngeal squamous cell carcinoma (LSCC) is one of the most common types of cancer in the upper respiratory tract. It is well-known that it has a high mortality rate and poor prognosis in advanced stages. There are well-known risk factors for LSCC, though new specific and prognostic blood-based markers for LSCC development and prognosis are essential. The current study aimed to evaluate the impact of four different single nucleotide polymorphisms (SNPs), E2F1 (rs3213183 and rs3213180) and E2F2 (rs2075993 and rs3820028), on LSCC development, morphological features, and patient 5-year survival rate.MethodsA total of 200 LSCC patients and 200 controls were included in this study; both groups were matched by age and sex. In the present study, we analyzed four single nucleotide polymorphisms (SNPs) in the genes E2F1 (rs3213183 and rs3213180) and E2F2 (rs2075993 and rs3820028) and evaluated their associations with the risk of LSCC development, its clinical and morphological manifestation, and patients 5-year survival rate. Genotyping was carried out using RT-PCR.ResultsNone of the analyzed SNPs showed a direct association with LSCC development. E2F2 rs2075993 G allele carriers (OR = 4.589, 95% CI 1.050-20.051, p = 0.043) and rs3820028 A allele carriers (OR = 4.750, 95% CI 1.088–20.736, p = 0.038) had a statistically significantly higher risk for poor differentiated or undifferentiated LSCC than non-carriers. E2F1 rs3213180 GC heterozygotes were found to have a 3.7-fold increased risk for lymph node involvement (OR = 3.710, 95% CI 1.452–9.479, p = 0.006). There was no statistically significant association between investigated SNPs and patient 5-year survival rate.ConclusionsThe present study indicates that E2F2 rs2075993 and rs3820028 impact LSCC differentiation, whereas E2F1 rs3213180 - on lymph node involvement.

Association between interleukin 6 gene polymorphism and human papilloma virus infection in Oral Squamous Cell Carcinoma patients

Background: Both HPV and IL 6 gene polymorphism have independently proven their association with OSCC. And we assume that the positivity of both HPV and IL 6 in a patient with OSCC would raise the threshold of patient towards the aggressiveness of the disease.So the aim was to find an association between Human Papilloma Virus and IL 6 gene polymorphism in Oral Squamous Cell Carcinoma patients. Methods and materials: Methodology: This cross-sectional study was conducted at Ziauddin Hospital, Karachi, between Jan 2014 to May 2015. And of consisted a total of 140 oral squamous cell carcinoma patients of 18 y and above (104 males and 36 females). Detailed questionnaire followed by sample collection from each patient was done. These samples were analyzed by polymerase chain reaction for human papilloma virus and IL 6 gene polymorphism was analyzed through restriction fragment length polymorphism. Results: Mean age of the patients was 43.5 ± 11.84 y (range 31–40 y). Most of the patients (45; 32.1%) belonged to the Urdu speaking ethnic group. Pan (87; 62.1%) and Gutka (82; 58.6%) were used by most of the patients. (17;12.1%) patients had history of systemic disease (e.g hypertension, diabetes). And (3021.4%) patients had a positive family history of OSCC. The most common site of OSCC was buccal mucosa (86; 61.4%) in these patients. Majority of the patients (77; 55%) had histologically moderately differentiated OSCC, and more than half of these patients (78; 55.7%) had Group B (stage III & IV) of OSCC. (12;8.6%) out of 140 samples tested positive for human papilloma virus gene and the following pattern was observed for IL 6 gene polymorphism, GG: (46.4%), GC (39.3%), CC (14.3%). A positive association was observed for Group B (stages III & IV) of oral squamous cell carcinoma with IL 6 genotypes: GC heterozygote (OR = 3.819, 95% CI = 1.782-8.183, p = 0.001) and CC homozygote (OR = 6.833, 95% CI = 2.046-22.822, p = 0.002), and also a strong positive association was found between human papilloma virus and CC homozygote genotype (OR = 21.333, 95% CI = 2.318-196.311, p = 0.007). Conclusion: Human papilloma virus association with IL 6 gene polymorphism in oral squamous cell carcinoma patients suggests rapid and aggressive progress of oral carcinogenesis.

Effects of EPHX1 rs2260863 polymorphisms on warfarin maintenance dose in very elderly, frail Han-Chinese population.

Aim: This study was conducted to investigate the effects of VKORC1, CYP2C9, CYP4F2 andEPHX1 and nongenetic factors on warfarin maintenance dose in a very elderly, frail Han-Chinese population. Materials & methods:16variants of VKORC1, CYP2C9, CYP4F2 and EPHX1 were genotyped. Univariate analysis and multivariable regression model were performed for the associations of gene variants and warfarin maintenance dose. Results & conclusion:EPHX1 rs2260863 nonvariant CC homozygotes required significantly lower daily warfarin dose than GC heterozygotes. In the multivariable model, VKORC1 rs9923231, CYP2C9 rs1057910, EPHX1 rs2260863, CYP4F2 rs2189784 and body surface area altogether explained 26.9% of dosing variability. This study revealed the main impact of genetic factors on warfarin response in this special population.

Association of the CHGA gene polymorphism in patients with hemorrhagic stroke and/or aneurysm

ABSTRACT Introduction: Cerebrovascular diseases have been associated with several genes. Chromogranin A (CHGA) has been used as maker in cardiovascular disease. Therefore, evaluating the polymorphism and verifying its association with this pathology is very important to better understand this disease. Objective: The aim of this study was to identify the association between coding region polymorphism in -264 position of the CHGA gene (Glu264Asp) and hemorrhagic stroke (HS)/aneurysm in the Federal District, Brazil. Methods: This is a population-based case-control, involving 45 cases with HS and/or aneurysm. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method is used for genotyping these samples. A significance level of 5% was adopted. Results: The absence of the CC genotype the Glu264Asp CHGA polymorphism in the study participants and the significant presence of the GC heterozygote genotype were observed in this study. However, the distribution of genotypes did not differ statistically in the groups. Conclusion: The Glu264Asp CHGA polymorphism does not seem to contribute to the genesis of the CHGA protein expression in this patients group, but to understand whether or not there is a possible association of the pathology in question and whether the mutation will contribute in the gene therapy and thus to improve patients’ quality of life.

Abstract WMP60: Adiponutrin Gene Polymorphism is Associated With Unexplained Embolic Covert Brain Infarction in the Northern Manhattan Study

Introduction: Adiponutrin, encoded by the patatin-like phospholipase domain-containing 3 gene ( PNPLA3 ), is involved in lipid metabolism. The PNPLA3 gene rs738409 C>G single nucleotide polymorphism (SNP), particularly when homozygous, is strongly associated with non-alcoholic fatty liver disease, which has been associated with vascular disease. We hypothesized that this PNPLA3 SNP is associated with covert brain infarction (CBI). Methods: We performed a cross-sectional analysis of individuals with rs738409 genotype data in the Northern Manhattan Study MRI sub-study. The exposure was rs738409 allele frequency; noncarriers (CC genotype) served as the reference. The primary outcome was the presence of any CBI. Secondary outcomes were independently adjudicated CBI mechanism categories based on available baseline and follow-up history and imaging data: large artery atherosclerosis, cardioembolism, small vessel disease, and embolism of unknown source (EUS). Multivariable logistic regression was used to assess the relationship between SNP frequency and CBI. Principle component analysis was used to account for population-specific variations in SNP distributions. Models were adjusted for principal components, demographics, vascular risk factors, and alcohol, statin, and antiplatelet use. Results: The sample included 1,063 Northern Manhattan Study participants (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%, with 381 GC heterozygotes and 67 GG homozygotes. The prevalence of CBI was 18% (N=185): 10% (N=19) large artery atherosclerosis, 12% (N=22) cardioembolism, 16% (N=30) small vessel disease, and 62% (N=114) EUS. Individuals heterozygous for the G allele were not at greater odds of any CBI (OR 0.8; 95% CI 0.6-1.2) or any individual type of CBI, compared to CC homozygotes. The odds of any CBI were also not increased among GG homozygotes (OR 1.6; 95% CI 0.8-3.2). However, GG homozygotes were at higher odds of EUS (OR 2.3; 95% CI 1.1-4.8), but not CBI due to other mechanisms. Conclusion: Homozygosity for the PNPLA3 rs738409[G] SNP was associated with greater odds of EUS and may account for some unexplained strokes. Further study is warranted to understand the contribution of PNPLA3 variants to cerebrovascular disease.

A polymorphism in the promoter region of PD-L1 serves as a binding-site for SP1 and is associated with PD-L1 overexpression and increased occurrence of gastric cancer.

PD-L1 is a member of the B7 family co-inhibitory molecules and plays a critical role in tumor immune escape. In this study, we found a polymorphism rs10815225 in the PD-L1 promoter region was significantly associated with the occurrence of gastric cancer. The GG homozygous frequency was higher in the cancer patients than that in the precancerous lesions, which was higher than that in the health controls. This polymorphism locates in the binding-site of Sp1 transcription factor (SP1). The expression level of PD-L1 mRNA in the GG homozygous cancer patients was apparently higher than that in the GC heterozygotes. Luciferase reporter results showed that SP1 bonded to rs10815225 G-allelic PD-L1 promoter instead of C-allelic. Upregulation and knockdown of SP1 resulted in elevation and attenuation of PD-L1 in SGC-7901 cells, respectively. The chromatin immunoprecipitation results further confirmed the binding of SP1 to the promoter of PD-L1. Additionally, rs10815225 was found to be in disequilibrium with a functional polymorphism rs4143815 in the PD-L1 3'-UTR, and the haplotypes of these two polymorphisms were also markedly related to gastric cancer risk. These results revealed a novel mechanism underlying genetic polymorphisms influencing PD-L1 expression modify gastric cancer susceptibility.

Association of Macrophage Migration Inhibitory Factor Polymorphisms with Total Plasma IgE Levels in Patients with Atopic Dermatitis in Korea.

The macrophage migration inhibitory factor (MIF) gene is located on human chromosome 22q11.2 and is linked to atopic phenotypes. Plasma MIF and log [total IgE] levels are significantly elevated in atopic dermatitis (AD) patients. The aim of this study was to evaluate the relationship between two MIF polymorphisms, −173 G to C and −794 CATT5–8, and total plasma IgE levels in AD patients in Korea. We performed PCR-RFLP analysis in 178 AD patients and 80 control subjects to determine whether MIF SNPs are associated with susceptibility to AD. Plasma total IgE and MIF levels were determined, and then logistic regression analyses were performed to determine the associations between a SNP or haplotype and plasma total IgE or MIF levels. The −173 G/C polymorphism, located in the MIF promoter, was significantly associated with AD; the odds ratios (ORs) for the CC homozygotes and GC heterozygotes were 9.3 and 2.5, respectively. The MIF C/5-CATT and the MIF C/7-CATT haplotypes were significantly associated with AD; the ORs for the MIF C/5-CATT and MIF C/7-CATT haplotypes were 9.7 and 4.5, respectively. Log [total IgE] levels were highly associated with the MIF −794 7-CATT polymorphism. Notably, the MIF C/7-CATT haplotype was associated with a decrease in plasma log [total IgE] levels in a gene dose-dependent manner. Although log [MIF] levels were not associated with the MIF polymorphisms, the frequencies of the MIF C/5-CATT haplotype-containing genotypes decreased in order of MIF levels. Our results demonstrate that MIF promoter polymorphisms in the −173 C allele and the MIF C/5-CATT and C/7-CATT haplotypes were significantly associated with an increased risk for AD. In particular, the −794 7-CATT locus and the MIF C/7-CATT haplotype were significantly associated with decreased total IgE levels in the plasma, suggesting that these polymorphisms might be a marker for intrinsic AD rather than extrinsic AD that shows high total IgE levels and presence of allergen-specific IgE.

Effect of interleukin 6 -174G>C gene polymorphism on opioid requirements after total hip replacement.

ObjectiveIn recent years, increasing attention has been paid to the contribution of genetic factors to variability in patient pain threshold and the efficacy of pain management. One of the genes implicated in pain pathology and treatment response is interleukin 6 (IL6). The aim of the present study was to evaluate the association between IL6 (rs1800795: –174G>C) and opioid requirements in patients after total hip replacement (THR).MethodsA total of 196 patients eligible for the study (126 women, 70 men) were subjected to THR. The THR procedure was performed using spinal anaesthesia after implementing routine peri-operative monitoring. After the procedure each patient was individually observed, and the patient-specific chart of dynamic changes in pain perception was recorded, using the five-level Verbal Rating Scale (VRS). The multimodal analgesic treatment after THR was defined by the operating surgeons after considering indications and contraindications to the use of different groups of drugs (opioid and non-opioid analgesics). Postoperative pain was controlled by the patient-controlled analgesia method and VRS during the day-time, as well as night-time nurse-controlled analgesia. All medication adjustments were recorded in the individual patient files. In the case of moderate pain intensity (VRS-assessed), a patient was administered the non-opioid analgesic drug, and for high intensity pain the opioid. The analysis of pain relief therapy included information on the drugs applied, mode of dosing (single or multiple), daily dose, route of administration, and drug refusal due to the absence of pain recorded each study day, i.e. on the day of surgery and recovery in the postoperative room (day 0), and then daily from day 1 to day 6. Polymorphism rs1800795:G>C in the promoter region of the IL6 gene (–174G>C) was determined using the PCR–RFLP method.ResultsThe patients carrying at least one IL6 –174G allele (GG homozygote and GC heterozygote) were administered opioids significantly more often on days 0 (p = 0.0029), 3 (p = 0.019) and 4 (p = 0.031) after surgery compared with CC homozygous patients. Those patients also required a significantly higher opioid dose on days 3 (p = 0.029) and 4 (p = 0.030). Multivariate analysis demonstrated that the presence of the –174G allele was an independent factor predisposing patients to the administration of opioids during the first 24 h [p = 0.001, odds ratio (OR) 7.1, 95 % confidence interval (CI) 2.17–22.7], on day 3 (p = 0.01, OR 2.79, 95 % CI 1.25–6.26) and day 4 (p = 0.01, OR = 2.61, 95 % CI 1.17–5.79).ConclusionThe presence of the G allele IL6 gene (–174G>C) polymorphism was found to be an independent factor predisposing to a higher dose and more frequent administration of opioids in the first days after total hip replacement.

Molecular Identification of Intron 2 Splice Mutation and 8bp Deletion in CYP21 Gene for Congenital Adrenal Hyperplasia (CAH) Patients in Kashmir (North India)

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder caused by alteration in CYP21 gene which ultimately leads to 21-hydroxylase deficiency. The present study aimed at evaluation of 2 common mutations viz, Intron 2 Splice (INT2S) mutation and 8 bp deletions in exon 3 of CYP21 gene and to establish their frequencies in Kashmir population (North India). The mutations were tested by Amplification Refractory Mutation System-PCR (ARMS-PCR) in 50 cases of CAH, proven by clinical features and raised 17-hydroxy progesterone (17OHP) levels. The results revealed that 15(30%) cases had INT2S mutation while as 8 bp deletion was not detected in any patient. In INT2S mutation, 7 cases were homozygous with I2-G genotype and 8 cases were heterozygous. The frequency of AG heterozygotes was found in 5 cases and CG heterozygote genotype was found in 3 cases. CAH patients with ambiguous genitalia were seen to harbor most of the INT2S mutations with I2-G in 3 cases and CG heterozygotes in 2 cases. In non-consanguineous group of patients, 4 homozygous I2-G mutations and 4 were I2- GC heterozygotes were detected in comparison to 3 and 1 in consanguineous patients respectively. Our study confirms that INT2S mutations but not 8 bp deletions exist in CYP21 gene in CAH patients in Kashmir population.

Contribution of IL6 -174 G>C and IL1B +3954 C>T polymorphisms to congenital infection with Toxoplasma gondii.

The purpose of this investigation was the determination of the distribution of genotypes and alleles, residing within interleukin 6 (IL6) and interleukin 1 (IL1) polymorphisms, among fetuses and neonates, congenitally infected with Toxoplasma gondii, and among uninfected control cases. The study included 22 fetuses and newborns infected with T. gondii and 49 control cases. Screening for IgG and IgM antibodies against the parasite and IgG avidity was performed by enzyme-linked fluorescent assay (ELFA) tests. Quantitation of T. gondii DNA in amniotic fluids was assayed by the real-time Q PCR technique for the parasitic B1 gene. Genotypes at IL6 and IL1 single nucleotide polymorphisms (SNPs) were determined by a self-designed, nested polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Representative genotypes at the studied loci were confirmed by sequencing. All the genotypes were estimated for Hardy–Weinberg equilibrium and IL1 genotypes were tested for linkage disequilibrium. Genotypes and haplotypes at the studied SNPs were investigated for their possible association with the occurrence of congenital T. gondii infection, using a logistic regression model. GC heterozygotes at the IL6 −174 G>C SNP were significantly associated with toxoplasmosis and increased the risk of T. gondii infection [odds ratio (OR) 4.24, 95 % confidence interval (CI) 1.24–14.50 in the codominant model, p ≤ 0.050]. In case of IL1 SNPs, similar prevalence rates were observed between T. gondii-infected and -uninfected offspring. Regarding allelic variability, the C alleles at both IL6 and IL1B SNPs were significantly more frequent in the infected than in the uninfected cases (p ≤ 0.050). It is concluded that IL6 −174 G>C and IL1B +3954 C>T SNPs might be involved in the development of congenital T. gondii infection.

Transient receptor potential melastatin 8 gene polymorphism is associated with cold-induced airway hyperresponsiveness in bronchial asthma.

Cold-induced airway hyperresponsiveness (CAH) is common in bronchial asthma (BA) patients and represents a problem for those living in cold climate. Transient receptor potential melastatin 8 (TRPM8) channel is the main cold temperature sensor in humans that could mediate cold response in asthmatics with CAH. No associations between TRPM8 gene polymorphisms and CAH have been reported. The present study involved 123 BA patients. CAH was assessed by 3-min isocapnic (5% CO2 ) cold air (-20°C) hyperventilation challenge. The c.750G > C (rs11562975), c.1256G > A (rs7593557), c.3048C > T (rs11563208) and c.3174C > G (rs11563071) polymorphisms of TRPM8 gene were genotyped by allele-specific polymerase chain reaction (PCR) and PCR with subsequent restriction fragment length polymorphism analysis. GC genotype and C allele carriers of the c.750G > C (rs11562975) polymorphism were more frequently observed to exhibit CAH. The estimated odds ratio for the GC genotype was 3.73 95%CI (1.48; 9.37), P = 0.005. Furthermore, GC heterozygotes had a prominent decrease in forced expiratory volume in 1 s after the challenge as compared to GG homozygotes (-12% (-16; -8.1) vs -6.45% (-11; -2.1), P < 0.001). GC carriers also had a marked reduction in other spirometric parameters. The GC variant of the TRPM8:c.750G > C (rs11562975) polymorphism is associated with CAH in patients with BA, which suggests a potential role of TRPM8 in CAH development.

The -137G/C Polymorphism in Interleukin-18 Gene Promoter Contributes to Chronic Myeloid Leukemia Risk in Turkish Patients

Interleukin-18 (IL-18) is a cytokine which belongs to the interleukin-1 superfamily and secreted by various immune and non-immune cells. Evidence has shown that IL-18 has both anticancer and procancer effects. The aim of this study was to evaluate the relationship between -137G/C (rs187238) IL-18 gene polymorphism and susceptibility to chronic myelogenous leukemia(CML) in Turkish patients. The frequencies of polymorphism -137G/C were studied in thirty chronic myelogenous and thirty healthy individuals. The genotyping was performed by polymerase chain reaction and DNA sequencing analysis. Significant associations were detected between the IL-18 rs187238 (G/C) polymorphism and CML patients. A higher prevalence of the C allele was found in CML cases with respect to controls (p<0.05). The GC heterozygote and CC homozygote genotypes are associated with the risk of CML when compared with controls (OR, 1.9023; 95% CI, 0.6171-5.8636 for GC genotype and OR, 10.3585; 95% CI, 0.5326-201.4622 for CC genotype). These results indicate that individuals that are either heterozygote (GC) or homozygote for CC genotype are associated with the development of chronic myelogenous leukemia in Turkish population. Further large-scale studies combined with haplotype and expression analysis are required to validate the current findings. DisclosuresNo relevant conflicts of interest to declare.

Association between single nucleotide polymorphisms of DOT1L gene and risk of knee osteoarthritis in a Chinese Han population.

To investigate associations between single nucleotide polymorphisms rs12982744 and rs12459350 in the DOT1L gene and knee osteoarthritis (OA) susceptibility in a Chinese Han population. DOT1L rs12982744 and rs12459350 polymorphisms were genotyped in patients with knee OA and age- and sex-matched OA-free controls from a Chinese Han population. A total of 605 patients with knee OA and 615 controls were enrolled in the study. GC and CC genotypes of rs12982744, and variant C, were associated with a significantly increased risk of knee OA. On stratification analysis, the association between the risk of OA and rs12982744 GC heterozygotes compared with GG homozygotes was stronger in females and those aged >65 years. In contrast, the GA and AA genotypes of rs12459350 were not significantly associated with the risk of knee OA, even after further stratification analysis according to age or sex. Our results showed that DOT1L rs12982744 G to C change and variant C genotype may contribute to knee OA risk in a Chinese Han population.

Association between single nucleotide polymorphisms of sterol regulatory element binding protein-2 gene and risk of knee osteoarthritis in a Chinese Han population

To investigate associations between single nucleotide polymorphisms (SNPs) rs2228314 and rs2267443 in the sterol regulatory element binding protein-2 gene (SREBP-2) and knee osteoarthritis (OA) susceptibility in a Chinese Han population. SREBP-2 rs2228314 and rs2267443 polymorphisms were genotyped in patients with knee OA and age- and sex-matched OA-free controls from a Chinese Han population. A total of 402 patients with knee OA and 410 controls were enrolled in the study. GC and CC genotypes of rs2228314, and variant C, were associated with a significantly increased risk of knee OA. On stratification analysis, the association between the risk of OA and rs2228314 GC heterozygotes compared with GG homozygotes was stronger in females and those aged >65 years. In contrast, the GA and AA genotypes of rs2267443 were not significantly associated with the risk of knee OA, even after further stratification analysis according to age or sex. SREBP-2 rs2228314 G to C change and variant C genotype may contribute to knee OA risk in a Chinese Han population.

A common variant in pre-miR-146 is associated with coronary artery disease risk and its mature miRNA expression

miRNAs are small non-coding RNAs that play an important role in numerous physiological processes. Common single nucleotide polymorphisms (SNPs) in pre-miRNAs may change their property through altering miRNAs expression and/or maturation, resulting in diverse functional consequences. To date, the role of genetic variants in pre-miRNAs on coronary artery disease (CAD) risk remains poorly understood. Here we aimed to evaluate the influence of three common SNPs in pre-miRNAs (miR-146a rs2910164 G>C, miR-196a2 rs11614913 C>T, miR-499 rs3746444 T>C) on individual susceptibility to CAD in a Chinese population of 295 CAD patients and 283 controls. Genotyping was performed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) method. In a logistic regression analysis, we detected an association of rs2910164 in pre-miR-146a with the CAD risk; compared with the GG homozygotes, the GC heterozygotes [odds ratio (OR)=1.89, 95% confidence interval (CI)=1.06–3.36, P=0.029] and the CC homozygotes (OR=1.83, 95% CI=1.01–3.32, P=0.046) genotype were statistically significantly associated with the increased risk for CADs. As we used further genotype association models, we found a similar trend of the association in recessive model (OR=1.86, 95% CI=1.09–3.19, P=0.023). We also found that the genotypes of miR-146a rs2910164 were associated with its mature miRNA expression by analyzing 23 PBMC samples from CAD patients. Individuals carrying rs11614913 GC or CC genotypes showed 3.2-fold higher expression compared to GG genotype carriers (P<0.05). We observed no association of the other two SNPs in miR-196a2 (rs11614913) and miR-499 (rs3746444) with the CAD incidence. Our data provide the first evidence that the miR-146a rs2910164 polymorphism is associated with increased risk of CAD in Chinese Han population, which may be through influencing the expression levels of the miRNA.

Detection of CDH1 gene variants in early-onset diffuse gastric cancer in Chinese patients.

The type and frequency of E-cadherin (CDH1) germline variants in China for the early-onset diffuse gastric cancer (EODGC) has not been well established. Our study tend to screen and characterize germline variants for CDH1 gene in EODGC patients and in general population in China. Peripheral blood samples were collected from 57 EODGC patients (age ≤ 40 years) who underwent resection surgery for primary gastric cancer. DNA was extracted from peripheral blood leucocytes and polymerase chain reaction amplification (PCR) was performed to amplify and sequence the CDH1 gene. Statistical analysis was performed using the SPSS 19 software. CDH1 genetic screening results: 2 missense in exon 5 (c.778G > C, 26.3%) and 12 (c.2012C > G, 1.8%), and 1 synonymous (c.2200T > C, 72.8%) in exon 13. According to the c.2200T > C variant, the CDH1 C frequency was 62.3% and the T frequency 37.7%, while the CC homozygote frequency was 43.9%, the TT homozygote 19.3% and the CT heterozygote 36.8%. According to the c.778G > C variant, the CDH1 C frequency was 15.8% and the G frequency 84.2%, while the GG homozygote frequency was 68.4%, the GC heterozygote 31.6%. When comes to the c.2012C > G variant, the CDH1 C frequency was 98.2% and the G frequency 1.8%, while the CC homozygote frequency was 96.5%, the GC heterozygote 3.5%. Statistical association was analyzed among the EODGC patients and BDs group tested for the three variants. Lymph node metastasis rate was found to be significantly higher in patients with c.2200T > C (P = 0.04). The difference in OS with or without c.2200T > C variant was found to be sig- nificant (P < 0.05). No deletions or insertions were found in the CDH1 exon boundaries. All of the variants resulted com- mon polymorphisms. CDH1 germline variants are present in EODGC patients in Chinese population, but they are mainly missense variants with unknown function which are likely associated with lymph node metastasis and OS.

The association of the 174G > C polymorphism of interleukin 6 gene with diabetic nephropathy in patients with type 2 diabetes mellitus

AimsTo evaluate the association of 174G>C polymorphism on interleukin-6 (IL-6) gene with diabetic nephropathy in patients with type 2 diabetes. MethodsA total of 393 Greek subjects with type 2 diabetes (mean age 66.5±10.0years, men n=203, women n=190) were examined. Diabetic nephropathy was defined as presence of microalbuminuria and/or proteinuria. The IL-6 174G>C polymorphism was detected by polymerase chain reaction and appropriate restriction enzyme digestion. High sensitivity C-reactive protein was assayed by particle-enhanced immunonephelometry. ResultsThe genotype distribution (%) was GG: 49.1, GC: 26.8 and CC: 24.1, with no gender difference. The CC homozygotes had lower albumin excretion (mg/24h) in comparison with the GC genotype [CC: 8.9 (4.0–20.9) vs GC: 21.95 (9.1–53.35), P=0.004]. Participants with the GC genotype tended to have more frequently nephropathy than those with the GG or the CC genotype [GC: 44.55% vs GG: 35.1% and CC: 28.3%, P=0.07)]. The CC homozygotes in comparison with GC heterozygotes had lower odds to have nephropathy (odds ratio: 0.51, 95% confidence intervals=0.28–0.91, P=0.02), even after adjustment for sex, age, duration of diabetes, body mass index, smoking, hypertension, lipids and glycated hemoglobin, (P=0.01). ConclusionIn type 2 diabetes states, CC homozygotes have lower albumin excretion and are protected from nephropathy in comparison with GC genotypes.

Survivin gene promoter polymorphism ‐31G/C as a risk factor for keratocystic odontogenic tumor development

Several single nucleotide polymorphisms in survivin gene promoters, notably -31G/C, have been shown to modulate the expression and activity of the survivin protein. Consequently, the -31G/C polymorphism has been identified as a risk factor for the development of several types of tumors. The aim of this study was to investigate a possible association between the -31G/C polymorphism and the risk for keratocystic odontogenic tumor (KCOT) development. DNA from 52 biopsy specimens of KCOTs and from 82 buccal swabs of healthy individuals was subjected to PCR restriction fragment length polymorphism analysis to identify individual genotypes. The distribution of genotypes in KCOT and control groups, respectively, was: GG: 30 (57.7%) vs. 26 (31.7%); CG: 17 (32.7%) vs. 45 (54.9%); and CC: 5 (9.6%) vs. 11 (13.4%), respectively. These differences were statistically significant. The G allele was more common in the KCOT group than in the control group: 76 (74%) vs. 96 (59%), respectively. Logistic regression analysis showed that GC heterozygotes had a considerably decreased susceptibility for KCOTs compared with GG homozygotes. The same was true for GC+CC vs. GG. The GG genotype of the -31G/C polymorphism might be a risk factor for KCOT development.

A Single Nucleotide Polymorphism in STK11 Influences Insulin Sensitivity and Metformin Efficacy in Hyperinsulinemic Girls With Androgen Excess

OBJECTIVESerine-threonine kinase STK11 catalyzes the AMP-activated protein kinase complex. We tested the hypothesis that a gene variant in STK11 contributes to variation in insulin sensitivity and metformin efficacy.RESEARCH DESIGN AND METHODSWe studied the effects of a single nucleotide polymorphism (SNP) (rs8111699) in STK11 on endocrine-metabolic and body composition indexes before and after 1 year of metformin in 85 hyperinsulinemic girls with androgen excess, representing a continuum from prepuberal girls with a combined history of low birth weight and precocious pubarche over to postmenarchial girls with hyperinsulinemic ovarian hyperandrogenism. Metformin was dosed at 425 mg/day in younger girls and 850 mg/day in older girls. STK11 rs8111699 was genotyped. Endocrine-metabolic features were assessed in the fasting state; body composition was estimated by absorptiometry.RESULTSGenotype effects were similar in younger and older girls. At baseline, the mutated G allele in STK11 rs8111699 was associated with higher insulin and IGF-I levels (both P < 0.005). The response to metformin differed by STK11 genotype: GG homozygotes (n = 24) had robust metabolic improvements, GC heterozygotes (n = 38) had intermediate responses, and CC homozygotes (n = 23) had almost no response. Such differences were found for 1-year changes in body composition, circulating insulin, IGF-I, free androgen index, and lipids (all P < 0.005).CONCLUSIONSIn hyperinsulinemic girls with androgen excess, the STK11 rs8111699 SNP influences insulin sensitivity and metformin efficacy, so that the girls with the least favorable endocrine-metabolic profile improve most with metformin therapy.

Association Between Two Functional Polymorphisms of Insulin-Like Growth Factor Binding Protein 3 and Colorectal Cancer Risk in a Chinese Population

Circulating levels of insulin-like growth factor binding protein 3 (IGFBP3) are modulated by functional variants of IGFBP3 and therefore may be associated with higher risk of colorectal cancer development. However, few studies have investigated the role of IGFBP3 polymorphisms in colorectal cancer in Chinese individuals. In this study, two common polymorphisms of IGFBP3 were determined by the Taqman genotyping platform in 202 Chinese colorectal cancer cases diagnosed between 2006 and 2008 and 212 cancer-free population controls. Data showed that the genotype distribution of G2133C (rs2864746), but not A-202C (rs2864744), was significantly different between cancer cases and controls. Unconditional logistic regression analyses revealed that participants carrying the G2133C GC heterozygote or CC homozygote had a significant 1.55-fold increased risk of colorectal cancer development in an allele dose-responsive manner. However, there was no evidence of a dose-effect relationship between number of variants and risk for CRC occurrence. Data suggest that the exon 1 G2133C missense variant of IGFBP3 may be a susceptibility factor for colorectal cancer in Chinese subjects. Larger studies are warranted to validate our findings in a Chinese population.