Methylenetetrahydrofolate reductase genotypes and haplotypes associated with susceptibility to colorectal cancer in an eastern Chinese Han population

Methylenetetrahydrofolate reductase (MTHFR) plays an important role in folate metabolism and is involved in DNA synthesis, DNA repair and DNA methylation. The two common functional polymorphisms of MTHFR, C677T and A1298C have been associated with several diseases, including cancer. We made a case-control study to analyze a possible association of MTHFR gene polymorphisms C677T and A1298C with risk for colorectal cancer in an eastern Chinese Han population of 137 patients with a confirmed histopathological diagnosis of CRC and 145 age- and gender-matched controls with no history of cancer. DNA was isolated from peripheral blood samples and the genotypes were determined by PCR-RFLP. The concentrations of folate in plasma were measured by chemiluminescence immunoassay. The MTHFR 677TT genotype had a protective effect against colorectal cancer, with an odds ratio (OR) = 0.467 (95% confidence interval (CI) = 0.225-0.966). The 1298CC genotype was significantly correlated with a reduced risk of colorectal cancer (OR = 0.192; 95%CI = 0.040-0.916). Compared with the MTHFR 677CC and MTHFR 1298 AA genotypes, for individuals who carried both MTHFR 677CC and 1298CC genotypes, the OR of colorectal cancer was 0.103 (95%CI = 0.012-0.900); among individuals who carried both MTHFR 677TT and 1298AC genotypes, the OR for risk of colorectal cancer was 0.169 (95%CI = 0.044-0.654). MTHFR 677TT+CT genotypes had a significantly lower plasma folate concentration than those with the MTHFR 677CC genotype. MTHFR 1298AC+CC genotypes had a lower plasma folate concentration than those with the MTHFR 1298AA genotype (P < 0.05). In conclusion, subjects with the MTHFR 677TT and MTHFR 1298CC genotypes appeared to have a significantly lower risk for colorectal cancer. MTHFR haplotypes 677CC/1298CC and 677TT/1298AC were less common in cases than in controls. These haplotypes, when compared to the most common haplotype 677CC/1298AA, were associated with a decreased risk for colorectal cancer. We conclude that plasma folate level is influenced by MTHFR genotypes.     

SLC2A9rs1014290位点基因多态性与北方汉族地区男性痛风发病的相关性研究

目的:探讨可溶性载体2家族成员9基因(SLC2A9)rs1014290位点的单核苷酸多态性与北方汉族地区男性原发性痛风的发病的相关性。方法:选取404例原发性痛风男性患者和412名健康体检者,分别检测其血清尿酸、血脂、肾功等生化指标,同时提取外周血DNA,应用连接酶检测反应(LDR)法分析其SLC2A9基因rs1014290位点基因型和等位基因频率。结果:痛风组空腹血糖、尿酸(UA)、甘油三酯(TG)、胆固醇(TC)、收缩压、BMI、肌酐(Cr)水平均显著高于对照组,差异有统计学意义(P0.05)。痛风组SLC2A9基因rs1014290位点各基因型频率(CC:12.8%;CT:53.5%;TT:38.7%)与对照组(CC:16.2%;CT:50.9%;TT:32.9%)相比差异有统计学意义(X2=3.978,P=0.041);两组的等位基因频率相比差异无统计学意义(X2=0.314,P=0.496)。结论:SLC2A9基因rs1014290位点多态性可能与我国北方汉族男性原发性痛风的易感性相关,携带TT基因型的个体更易患痛风。     

Single nucleotide polymorphism rs11614913 associated with CC genotype in miR-196a2 is overrepresented in laryngeal squamous cell carcinoma,but not salivary gland tumors in Polish population

The miRNA-196a2 has shown significance in the development of various neoplasms, including head and neck squamous cell carcinoma (HNSCC). The oncogenic functionality of this miRNA is mediated via its potential to target annexin A1 mRNA, a tumor suppressor gene involved in inhibition of the NF-κB pathway. Interestingly, recent data indicate a susceptibility for aforementioned neoplasms in patients with the CC genotype vs the CT and TT genotypes of the rs11614913 SNP located within the DNA sequence of the miR-196a2 that results in elevated expression of the gene. To further investigate this phenomenon, we genotyped this SNP in 40 patients with laryngeal squamous cell carcinoma (LSCC), the most common tumor of the head and neck region and 60 patients with salivary gland tumors (SGT) that show a yet unexplained incidence increase in the last two decades. In agreement with previous reports, we have identified a statistically significant (p?<?0.05) overrepresentation of the CC genotype in LSCC patients and demonstrated in LSCC cell lines that it results in elevated expression of miR-196a2 as compared to cell lines with the TT genotype of the respective SNP. Importantly, none of these correlations was found in patients with SGT. These findings underline the importance of the SNP rs11614913 for LSCC development in the Polish population and moreover highlight the different genetic background of the two studied neoplasms of the head and neck region.     

吉富罗非鱼IGF2基因分离及其单核苷酸多态性与体型、增重相关性

胰岛素样生长因子2(insulin-like growth factor2,IGF2)是控制动物生长和脂肪沉积的重要基因之一。本文采用PCR方法分离了吉富罗非鱼(GIFT strain Nile tilapia Oreochromis niloticus)IGF2基因5475bp,包含由4个外显子组成的整个阅读框669bp以及3个内含子。通过比对吉富罗非鱼10个个体IGF2序列,共发现11处单核苷酸多态性(single nucleotide polymorphism,SNP)位点,本文检测了内含子1的621nt(C/T)和外显子3的161nt(A/G)两位点在192尾吉富罗非鱼中的基因型分布,并分析不同基因型与体型、增重的相关性。使用四引物扩增受阻体系PCR检测内含子1的621nt基因型,结果显示,CC、CT、TT基因型频率在雄鱼中分别为0.32、0.32、0.36,在雌鱼中分别为0.38、0.38、0.24;与体型、增重的相关性分析表明,此位点不同基因型只与雄鱼体型(体高/体长)显著相关(P0.05),CC型个体显著高于CT和TT型个体。外显子3的A/G转换导致了MSPⅠ酶切位点改变,使用PCR-RFLP法检测该位点基因型,结果显示整个群体中不存在AA基因型,在雄鱼中,GG、AG基因型频率分别为0.71、0.29,而雌鱼中则为0.75和0.25;与体型、增重的相关性分析表明,此位点不同基因型只与雄鱼增重极显著相关(P0.01),GG型的雄鱼明显较AG型增重快。     

Association of a single-nucleotide polymorphism within the miR-146a gene with susceptibility for acute-on-chronic hepatitis B liver failure

Excessive activation of innate immune response contributes to the pathogenesis of acute-on-chronic hepatitis B liver failure (ACLF-HBV). miR-146a was recently found to be implicated in the regulation of innate immunity. In this study, we explored the biological significance of a single-nucleotide polymorphism (rs2910164) within the miR-146a gene in the risk of acquiring ACLF-HBV. We completed a hospital-based case–control study including 717 cases of HBV-infected patients—251 cases of ACLF-HBV and 466 cases of chronic hepatitis B. Whole blood samples were collected for isolation of DNA and peripheral blood mononuclear cells (PBMCs). The association between genotypes and risk of ACLF-HBV was analyzed by multivariate unconditional logistic regression, with adjustment for sex and age. Our results showed that the GG homozygote was a protective genotype in terms of susceptibility to ACLF-HBV, with odds ratio?=?0.496, 95 % confidence interval?=?0.309–0.797, P?=?0.004 compared with CC+GC genotypes. The amount of mature miR-146a in PBMCs was significantly higher in the GG homozygote group than those in the CC and CG genotype groups of ACLF-HBV patients. The GG genotype group also represented lower serum level of TNF-α and higher survival rate (follow-up period?=?4 months). In conclusion, The GG genotype within the pre-miR-146a is reversely associated with susceptibility of ACLF-HBV in the studied Chinese population. This may be partially explained by the relatively higher amount of mature miR-146a and the lower serum level of TNF-α in this genotype group.     

The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid‐regulated genes,dependent on trauma exposure

The FK506 binding protein 51 (FKBP5), an intrinsic regulator of the glucocorticoid receptor, has been associated with pathological behaviors particularly in the context of childhood trauma (CT), via a putatively regulatory polymorphism, rs1360780. However, trans‐ and cis‐acting effects of this locus and its interaction with CT are incompletely understood. To study its effects on the expression of glucocorticoid‐regulated genes including FKBP5, we used lymphoblastoid cell lines (LCLs) derived from 16 CT‐exposed patients with greater than two substance dependence/suicidal behavior diagnoses (casesCT+) and 13 non‐CT‐exposed controls (controlsCT?). This study in LCLs measures long‐term trait‐like differences attributable to genotype or lasting epigenetic modification. Through analysis of differential allelic expression (DAE) using an FKBP5 3′‐UTR reporter single nucleotide polymorphism (SNP), rs3800373, that is in strong linkage disequilibrium with rs1360780, we confirmed that the rs1360780 risk allele (A) (or conceivably that of a linked SNP) leads to higher FKBP5 expression in controlsCT?. Intriguingly, casesCT+ did not show DAE, perhaps because of a genotype‐predicted difference in FKBP5 DNA methylation restricted to casesCT+. Furthermore, through correlation analyses on FKBP5 expression at baseline and after induction by dexamethasone, we observed that casesCT+ had lower induction of FKBP5 expression, indicating that overall they may have strong ultra‐short negative‐feedback. Only casesCT+ showed an effect of rs1360780 genotype on expression of FKBP5 and other glucocorticoid‐regulated genes. Together, these results confirm that the rs1360780 locus alters FKBP5 expression and further that in trans‐fashion this locus affects the expression of other glucocorticoid‐regulated genes after a glucocorticoid challenge. The CT exposure appears to be essential for trans‐effects of rs1360780 on glucocorticoid‐regulated genes.     

ABCG2基因rs2231142位点多态性与汉族女性痛风的相关性

目的：ABCG2基因第5外显子区单核苷酸多态性位点rs2231142与中国汉族男性痛风密切相关,基于痛风易感基因存在性别差异的考虑,本研究旨在探讨该单核苷酸多态性位点与中国汉族女性人群痛风易感性之间的相关性。方法：选取185例女性痛风患者和311例女性正常对照者,提取外周血基因组DNA,采用聚合酶链式反应（PCR技术）,特异性扩增ABCG2基因所需要的目的片段并测序,比较痛风组和正常对照组的基因型频率及等位基因频率分布情况。结果：rs2231142位点的CC、CA、AA基因型频率在两组间存在显著差异（x2=16.519,P〈0.001）,且痛风组中A等位基因频率显著高于正常对照组（分别为42.2%和29.3%,P〈0.001,OR 1.76[95%CI：1.35-2.31]）。结论：ABCG2基因第五外显子区rs2231142（C/A）位点的单核苷酸多态性与中国汉族女性人群痛风易感性密切相关,携带A等位基因的汉族女性人群有更高的痛风患病率。ABCG2基因首次被证实为中国汉族女性人群的痛风致病易感基因。     

Multi‐omics integrative analysis identified SNP‐methylation‐mRNA: Interaction in peripheral blood mononuclear cells

Genetic variants have potential influence on DNA methylation and thereby regulate mRNA expression. This study aimed to comprehensively reveal the relationships among SNP, methylation and mRNA, and identify methylation‐mediated regulation patterns in human peripheral blood mononuclear cells (PBMCs). Based on in‐house multi‐omics datasets from 43 Chinese Han female subjects, genome‐wide association trios were constructed by simultaneously testing the following three association pairs: SNP‐methylation, methylation‐mRNA and SNP‐mRNA. Causal inference test (CIT) was used to identify methylation‐mediated genetic effects on mRNA. A total of 64,184 significant cis‐methylation quantitative trait loci (meQTLs) were identified (FDR < 0.05). Among the 745 constructed trios, 464 trios formed SNP‐methylation‐mRNA regulation chains (CIT). Network analysis (Cytoscape 3.3.0) constructed multiple complex regulation networks among SNP, methylation and mRNA (eg a total of 43 SNPs simultaneously connected to cg22517527 and further to PRMT2, DIP2A and YBEY). The regulation chains were supported by the evidence from 4DGenome database, relevant to immune or inflammatory related diseases/traits, and overlapped with previous eQTLs from dbGaP and GTEx. The results provide new insights into the regulation patterns among SNP, DNA methylation and mRNA expression, especially for the methylation‐mediated effects, and also increase our understanding of functional mechanisms underlying the established associations.     

Association between polymorphisms in the promoter region of miR‐17‐92 cluster and systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association of genetic polymorphisms in the promoter region of miR‐17‐92 with systemic lupus erythematosus (SLE). The gene polymorphism was analysed using SNaPshot in 312 SLE patients and 396 controls. Relative expression of miR‐17‐92 was measured by quantitative real‐time PCR. Association was found between rs9515692 and a decreased risk of SLE (CT vs CC: OR = 0.65, 95%CI, 0.46‐0.92, P = .014; CT+TT vs CC: OR = 0.64, 95%CI, 0.46‐0.90, P = .009; T vs C: OR = 0.69, 95%CI, 0.52‐0.92, P = .010, respectively). Haplotype analysis showed that C‐G‐G, C‐A‐A haplotypes were associated with an increased SLE risk (OR=4.46, 95%CI, 2.17‐9.17, P < 0.001; OR=2.33, 95%CI, 1.44‐3.76, P < 0.001, respectively). T allele and CT+TT genotypes in rs9515692 were associated with decreased risk of anti‐dsDNA in SLE (CT+TT vs CC: OR = 0.42, 95%CI = 0.24‐0.72, P = .002; T vs A: OR = 0.49, 95%CI = 0.31‐0.79, P = .003). Moreover, rs9515692 CT+TT genotypes had a higher level of miR‐17 as compared to CC genotype (P = .017). These findings suggest that the rs9515692 CT+TT genotypes were a protective factor for the susceptibility of SLE, probably by increasing the expression of miR‐17.     

Association between polymorphisms in the SLC27A1 gene and milk production traits in Chinese Holstein cattle

We assessed SLC27A1, a candidate gene for milk production traits in Chinese Holstein cattle. DNA was extracted from the blood of 48 top Chinese Holstein Cattle selected according to phenotypic character and mixed into DNA pool for SNP detection. We tested blood samples of these cattle for SNPs in exon 3 and the 3'-flanking region of the SLC27A1 gene by using polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) and DNA sequencing. We found 2 polymorphic sites: 112T>C, a synonymous mutation, in exon 3 (SNP(1)), and 64G>A in the 3'-UTR (SNP(2)). We also determined the genotypes of 330 Chinese Holstein cattle by using PCR-restriction fragment length polymorphism (RFLP). We found 3 genotypes each at SNP(1) (TT, TC, and CC) and SNP(2) (GG, GA, and AA). The association among the different genotypes at these 2 sites and milk production traits was analyzed using a least-squares procedure. The results showed that cows with genotype CC had higher milk yields than those with genotype TC (0.01 < p < 0.05). No significant difference was detected among the 3 SNP(2) genotypes in terms of milk production traits. Our results provide evidence that the C allele have potential effects on milk yield trait.     

Retracted: Rs11655237 polymorphism of LINC00673 affects the prognosis of cervical cancer by interfering with the interaction between LINC00673 and microRNA-1231

Single-nucleotide polymorphism (SNP) in long noncoding RNAs (lncRNAs) is known to disrupt the binding between lncRNAs and microRNAs. In this paper, we aimed to explore the role of LINC00673 rs11655237 SNP in the survival of cervical cancer (CC). Real-time polymerase chain reaction and western-blot analysis were used to detect expressions of LINC00673 and microRNA-1231 (miR-1231) in CC patients with different rs11655237 SNP genotypes. And the expression of LINC00673, miR-1231, and IFNAR1 was measured in mice and cells treated with exosomes carrying GG, GA, and AA rs11655237 genotypes. Compared with patients carrying the rs11655237 A allele of LINC00673 rs11655237 SNP, patients carrying the G allele showed higher overall survival and higher miR-1231 expression. In addition, the expression of miR-1231 was the highest in patients carrying the GG genotype and the lowest in patients carrying the AA genotype. Furthermore, the exosomes carrying GG, GA, and AA genotypes of LINC00673 rs11655237 SNP reduced tumor growth in mice, while the inhibitory effect of rs11655237 A allele was much stronger than that of the rs11655237 G allele. Additionally, exosome treatment upregulated the expression of LINC000673 and IFNAR1 while downregulating the expression of miR-1231. Interestingly, the A allele of rs11655237 generated a binding site for miR-1231 and subsequently affected the expression of IFNAR1, a target gene of miR-1231 containing a miR-1231 binding site in its 3′-untranslated region. Cells transfected with exosomes carrying GG, GA, and AA genotypes of LINC00673 rs11655237 SNP achieved higher LINC000673 and IFNAR1 expression along with lower miR-1231 expression. Therefore, rs11655237 can be used as a prognostic biomarker for CC.     

A single nucleotide polymorphism in the matrix metalloproteinase-2 promoter is associated with colorectal cancer

Matrix metalloproteinase-2 (MMP-2) is an enzyme with proteolytic activity against matrix proteins, particularly basement membrane constituents. A single nucleotide polymorphism C-->T transition at -1306, which disrupts an Sp1-type promoter site (CCACC box), displayed a strikingly lower promoter activity with T allele. Our study investigated whether the MMP-2 -1306 C-->T polymorphism contributed to the development and progression of colorectal cancer in the Chinese population. One hundred twenty-six colorectal cancer patients and 126 age- and sex-matched controls were included in this study. PCR-based denaturing high performance liquid chromatography analysis and sequencing were used to determine the MMP-2 genotypes. MMP-2 expression of each genotype was analyzed in four colorectal cancer cell lines by semi-quantitative RT-PCR. The correlation between the genotypes and clinicopathological parameters among colorectal cancer cases was investigated. The results showed that the levels of MMP-2 mRNA expression in cell lines containing CC genotype were much higher compared with cell with CT genotype. The frequency of MMP-2 CC genotype was significantly higher in colorectal cancer patients when compared with controls (OR, 1.959; 95% CI, 1.055-3.637). Colorectal cancers with CC genotype were more common with serosa/adventitia layer involvement compared with CT+TT genotypes. Our data suggest that MMP-2 -1306 C-->T polymorphism may be associated with colorectal cancer development and invasion in the Chinese population.     

Influence of functional genetic polymorphism (-590C/T) in non-small cell lung cancer (NSCLC) development: the paradoxal role of IL-4

Lung cancer is the leading cause of death by cancer in the world, originating about 17.5% of total deaths from cancer (1.18 million). Inflammation plays an important role in the pathogenesis of lung cancer. IL-4 is an anti-inflammatory cytokine, which reduces the production of proinflammatory cytokines by monocytes and with direct antiproliferative effects in some tumors. The polymorphism -590C/T SNP is a C to T transition in the -590 position of the promoter region of the IL-4 gene. The aim of this study was to evaluate the influence of this polymorphism in the susceptibility to NSCLC. DNA was extracted from peripheral blood of 1060 individuals (391 patients diagnosed with NSCLC and a control group of 669 individuals without cancer). The characterization of IL-4 -590C/T genotypes was performed by PCR-RFLP (BsmFI). The -590C/T polymorphism genotypes were classified as low (CC) and high expression (TT). The frequencies obtained for the CC and TT genotypes were 90.1% and 9.9%, respectively, in the control group and 92.9% and 7.1%, respectively, in the case group. The analysis of the TT and CC genotype frequencies in the two groups showed a statistically significant difference in its distribution, indicating a protection of 80% for the development of NSCLC, type epidermoid in individuals with the TT genotype when compared with individuals with CC genotype (P=0.024, OR=0.221: 95% CI=0.053-0.928). We present for the first time that increased expression of IL-4 associated with the TT genotype may contribute to immune surveillance during NSCLC development.     

Methylenetetrahydrofolate reductase (MTHFR-677 and MTHFR-1298) genotypes and haplotypes and plasma homocysteine levels in patients with occlusive artery disease and deep venous thrombosis

The aim was to investigate different genotypes and haplotypes of methylenetetrahydrofolate reductase (MTHFR-677, -1298) and plasma concentration of total homocysteine (tHcy) in Macedonian patients with occlusive artery disease (OAD) and deep venous thrombosis (DVT). Investigated groups consists of 80 healthy, 74 patients with OAD, and 63 patients with DVT. Plasma tHcy was measured with Microplate Enzyme Immunoassay. Identification of MTHFR genotypes and haplotypes was done with CVD StripAssay. The probability level (P-value) was evaluated by the Student's t-test. Plasma concentration of tHcy in CC and CT genotypes of MTHFR C677T was significantly increased in patients with OAD and in patients with DVT. Plasma concentration of tHcy in AC genotype of MTHFR A1298C was increased in patients with OAD and in patients with DVT. Plasma concentration of tHcy was significantly increased in AA genotype of patients with OAD, but not in patients with DVT. We found a significant increase of plasma tHcy in patients with OAD in comparison with healthy respondents for normal:heterozygote (CC:AC), heterozygote:normal (CT:AA), and heterozygote:heterozygote (CT:AC) haplotypes. Plasma concentration of tHcy in patients with DVT in comparison with healthy respondents was significantly increased for normal:normal (CC:AA), normal heterozygote (CC:AC), and heterozygote:heterozygote (CT:AC) haplotypes. We conclude that MTHFR C677T and MTHFR A1289C genotypes and haplotypes are connected with tHcy plasma levels in Macedonian patients with OAD and DVT.     

Effects of the polymorphisms of Mx1, BAT2 and CXCL12 genes on immunological traits in pigs

It is necessary that genetic markers or biomarkers can be used to predict resistance towards a wide range of infectious diseases. In the present study, we estimated the potential markers and measured their relationship with heritabilities of a wide range of immune traits. Polymorphisms in exon 13 of Mx1, intron 25 of BAT2 and intron 3 of CXCL12 were identified by sequencing, and the genotypes were analyzed by PCR-RFLP in a resource population composed of 352 pure breed Landrace piglets at days 0, 17 and 32 after birth. Associations of single-nucleotide polymorphisms (SNPs) in these genes with a variety of immunological traits and antibody levels for pig reproduction and porcine respiratory syndrome virus (PRRSV), pseudorabies virus (PRV) and classical swine fever virus (CSFV) were performed. The performance of GG genotype of BAT2 on hemoglobin concentration (HBG) and hematocrit (HCT) of piglets at day 0 was significantly higher than that of the AA and AG individuals. For Mx1, compared with CT genotype, the pigs with TT or CC generated more PRRS antibody at day 0. The piglets with CT genotype had highly significant difference of PRV antibody from those with CC and TT genotypes at day 0. And the piglets with CC genotype had higher level red blood cell count (RBC), hemoglobin concentration (HBG) and hematocrit (HCT) than those with CT and TT genotypes at day 17. For the C7462G SNP in the intron 3 of CXCL12, the PRV antibody level of piglets with the CG genotype were higher than that of piglets with CC and GG genotypes at day 17, and the mean corpuscular volume (MCV) of GG piglets were larger than that of CC and CG individuals at day 0. At the locus 7331?bp in the intron 3 of CXCL12, there were significantly differences of mean corpuscular hemoglobin concentrations (MCHC) at day 0 and white blood cell count (WBC) at day 32, which showed the trend GG or AG>AA, AA>AG or GG, respectively. The pigs with AA or GG genotype had more platelet distribution width (PDW), mean platelet volume (MPV) and platelet-large cell ratio (PLR) at day 17 than those with AG. The results of this study indicated that polymorphisms in Mx1, BAT2 and CXCL12 genes were significantly associated with the immunological traits in Landrace piglets and had potential application value for marker-assisted selection of pig breeding with disease resistance.     

Lymph node metastasis of gastric cancer is associated with the interaction between poly (ADP-ribose) polymerase 1 and matrix metallopeptidase 2

Poly (ADP-ribose) polymerase 1 (PARP1), which plays a critical role in the base excision DNA repair mechanism, and matrix metallopeptidase 2 (MMP2), a member of the matrix metalloprotease family, are involved in tumor formation and metastasis, respectively. In the present study, the possible association of single nucleotide polymorphisms (SNPs) and gene-gene interaction between PARP1 and MMP2 with the increased incidence of gastric cancer (GC) development and lymph node metastasis (LNM) was investigated in a Korean population. Samples were obtained from 326 patients with chronic gastritis and 153 patients with GC and genotyped using the GoldenGate? method. The PARP1 rs1136410 genotype showed a significant association with the frequency of LNM of GC (odds ratio [OR]?=?2.19, p?=?0.02), LNM stage (p?=?0.035), and tumor invasion (p?=?0.035). The allele frequency of MMP2 rs243865 was not associated with the development of GC or with the development of LNM of GC. Epistasis between the PARP1 SNP and the MMP2 SNP was associated with the development of LNM of GC. The combination of the MMP2 rs243865 CC genotype and the PARP1 rs1136410 CC or CC+CT genotypes showed a high risk of LNM of GC (OR?=?2.47, p?=?0.01; OR?=?2.28, p?=?0.01, respectively). In summary, PARP1 is associated with the risk of LNM of GC and the stage of LNM and tumor invasion. Epistasis between PARP1 rs1136410 and MMP2 rs243865 increased the risk of LNM of GC.     

Abnormal methylation does not prevent X inactivation in ICF patients.

DNA undermethylation is a characteristic feature of ICF syndrome and has been implicated in the formation of the juxtacentromeric chromosomal abnormalities of this rare syndrome. We have previously shown that in female ICF patients the inactive X chromosome (Xi) is also undermethylated. This result was unexpected since female ICF patients are not more severely affected than male patients. Here we show that CpG island methylation is abnormal in some ICF patients but in other ICF patients, the difference in methylation pattern between Xi and Xa (active X) is maintained. The consequences of Xi undermethylation on gene expression were investigated by enzyme assays. They showed that significant gene expression did not correlate with CpG island methylation status. The widespread Xi undermethylation does not affect overall Xi replication timing and does not prevent Barr body formation suggesting that a normal methylation pattern is not required for normal chromatin organization of Xi. Molecular investigation of some X-chromosome intron regions showed that the methylation changes in ICF female patients extend to non CpG islands sequences. Our results suggest that the genetic alteration of DNA methylation in ICF syndrome has little consequence on X chromosome gene expression and chromatin organization.     

MDR1 single nucleotide polymorphism C3435T in Turkish patients with non-small-cell lung cancer

We assessed whether single nucleotide polymorphisms (SNPs) in MDR1 gene C3435T predicted the outcome of platinum-based chemotherapies and survival in our non small cell lung cancer (NSCLC) patients. A total of 79 non-small cell lung cancer patients were enrolled to study. We determined the MDR1 C3435T single nucleotide gene polymorphisms. Median age was 60years: 91.7% male, 8.9% female. We found that CC, CT, TT genotype and T, C allele frequencies in lung cancer patients as 24.1%, 62%, 13.9% and 44.3%, 55.7%, respectively. Patients with CT genotype had a higher response rate (11.4%) than the other genotypes. However, this difference is not statistically significant (p=0.743). Cox regression analysis for overall survival showed that ECOG PS status 0 (HR PS 1 vs. 0, 5.68 p=0.002; HR of PS 2 vs. 0 is 21.579, p=0.001; HR of PS 3 vs. 0 is 35.35, p=0.001), stage ≤II (HR of stage III vs. I+II is 17.77; p=0.016, HR of stage IV vs. I+II is 26.97, p=0.006), and albumin level ≥3g/dl (HR of albumin <3g/dl vs. ≥3g/dl is 2.46, p=0.044) were the most important prognostic factors (also, time to progression was related to these factors). There was no significant association between the genotypes and clinicopathologic parameters; however, good performance status, early stage and ≥3g/dl albumin level were found to be the most important prognostic factors for overall survival and progression-free survival.     

Placental FKBP5 Genetic and Epigenetic Variation Is Associated with Infant Neurobehavioral Outcomes in the RICHS Cohort

Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function. FK506 binding protein (FKBP5) is a negative regulator of cortisol response, FKBP5 methylation has been linked to brain morphology and mental disorder risk, and genetic variation of FKBP5 was associated with post-traumatic stress disorder in adults. We hypothesized that placental FKBP5 methylation and genetic variation contribute to gene expression control, and are associated with infant neurodevelopmental outcomes assessed using the Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scales (NNNS). In 509 infants enrolled in the Rhode Island Child Health Study, placental FKBP5 methylation was measured at intron 7 using quantitative bisulfite pyrosequencing. Placental FKBP5 mRNA was measured in a subset of 61 infants by quantitative PCR, and the SNP rs1360780 was genotyped using a quantitative allelic discrimination assay. Relationships between methylation, expression and NNNS scores were examined using linear models adjusted for confounding variables, then logistic models were created to determine the influence of methylation on membership in high risk groups of infants. FKBP5 methylation was negatively associated with expression (P = 0.08, r = −0.22); infants with the TT genotype had higher expression than individuals with CC and CT genotypes (P = 0.06), and those with CC genotype displayed a negative relationship between methylation and expression (P = 0.06, r = −0.43). Infants in the highest quartile of FKBP5 methylation had increased risk of NNNS high arousal compared to infants in the lowest quartile (OR 2.22, CI 1.07–4.61). TT genotype infants had increased odds of high NNNS stress abstinence (OR 1.98, CI 0.92–4.26). Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta’s ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.     

The Relationship between Gene Polymorphism and CRP Level in a Chinese Han Population

We investigated the relationships among the +1444C/T polymorphism in the C-reactive protein (CRP) gene and the concentration of CRP and the risk of coronary heart disease. Using polymerase chain reaction-restriction fragment length polymorphism, we analyzed the frequency distribution of genotypes and alleles of the +1444C/T polymorphism in samples from 128 patients with coronary heart disease (coronary stenosis more than 50%) and 119 unrelated normal individuals. The plasma levels of CRP and lipids in the subjects were also measured. The frequencies of the genotypes were CC 89.1%, CT 10.9%, and TT 0% in patients and CC 89.9%, CT 10.1%, and TT 0% in controls. The frequency of allele C was 94.5% in patients and 95.0% in controls, and allele T was 5.5% in patients and 5.1% in controls. The distribution of genotypes and alleles in the Chinese Han population was significantly different from that of the Caucasian population. There were no significant differences between frequencies of genotype and allele of controls and those of patients (P>0.05), but in controls the concentrations of CRP in the CC genotype subgroup were significantly higher than those in the CT genotype subgroup (P<0.05). This suggests that the +1444C/T variant in the CRP gene influences the basal CRP level in normal people. These findings imply that there may eventually be a need to establish genotype-specific risk thresholds of the CRP level.