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Human DOC-2/DAB2 interactive protein (hDAB2IP) gene is a novel member of the Ras GTPase-activating family and has been demonstrated to be a tumor-suppressor gene that inhibits cell survival and proliferation and induces cell apoptosis. It was reported that the expression level of hDAB2IP in gastric cancer tissue was highly correlated with tumor progression, however, whether hDAB2IP genetic variants are associated with the risk of gastric cancer remains yet unknown. In this case-control study, we conducted a genetic analysis for hDAB2IP variants in 311 patients with gastric cancer and 425 controls from the Chinese Han population. We found that the SNP rs2243421 of hDAB2IP gene with the minor allele C significantly revealed strong association with decreased gastric cancer susceptibility (P=0.007, adjusted odds ratio [OR]=0.734, 95%CI=0.586-0.919). Haplotypes rs2243421 and rs10985332 (HaploType: CC, P=0.012, aOR=0.760) and haplotypes rs2243421 and rs555996 (HaploType: CG, P=0.034, aOR=0.788) represented the decreased risk of gastric cancer, respectively. On the contrary, rs2243421 and rs555996 showed an elevated susceptibility (HaploType: TG, P=0.010, aOR=1.320). Our results for the first time provided new insight into susceptibility factors of hDAB2IP gene variants in carcinogenesis of gastric cancer.

Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04×10(-4), OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (P(correction) = 3.60×10(-10), OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, P(correction) = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population.

Enhancer of zeste 2 (EZH2) gene encodes a histone methyltransferase that constitutes the catalytic component of the polycomb repressive complex-2 (PRC2) to initiate epigenetic silencing of genes. It is reported that the expression level of EZH2 in gastric cancer tissue was highly correlated with tumor progression, however, whether EZH2 genetic variants were associated with the risk of gastric cancer remains yet unknown. In this study, we conducted a genotyping analysis for EZH2 in 311 cases of gastric cancer and 425 controls from the Chinese Han population. We found five single nucleotide polymorphisms (SNP; rs12670401, rs6464926, rs2072407, rs734005, and rs734004) of EZH2 gene were significantly associated with the risk of gastric cancer. Of which, the rs12670401 with the minor allele C and rs6464926 with the minor allele T revealed strong associations with increased gastric cancer risk [P = 0.009, adjusted odds ratio (aOR) = 1.327, 95% CI = 1.075–1.683 and P = 0.012, aOR = 1.310, 95% CI = 1.059–1.619]. The other three SNPs, rs2072407, rs734005, and rs734004 contributed to significantly reduced risk of gastric cancer (P = 0.033, aOR = 0.787, 95% CI = 0.633–0.981, P = 0.045, aOR = 0.799, 95% CI = 0.642–0.995 and P = 0.048, aOR = 0.803, 95% CI = 0.645–0.999), respectively. We further found that rs12670401 and rs6464926 were in a strong LD while rs2072407, rs734005, and rs734004 were in another. Haplotype analysis of the five SNPs showed that haplotype CCTCT reduced the risk of gastric cancer (P = 0.031 and aOR = 0.784), while haplotype GTCTC significantly elevated the risk of gastric cancer (P = 0.011 and aOR = 1.310). We concluded that EZH2 variants were significantly associated with gastric cancer risk. Our results for the first time provided new insight into susceptibility factors of EZH2 gene variants in carcinogenesis of gastric cancer of the Chinese Han population. © 2012 Wiley Periodicals, Inc.

Host immune responses are critical steps for carcinogenesis. Single nucleotide polymorphisms (SNPs) in immunoregulatory genes may influence gastric cancer risk. We performed a genotyping analysis for immunoregulatory genes in 311 gastric cancer cases and 425 controls from a Chinese population. We found that there were significant differences of E-selectin variant rs5361 (AC) and FCGR2A variant rs1801274 (TC) between cases and controls (P = 0.022 and P = 0.0001, respectively). Logistic regression analysis indicated that genotype of E-selectin rs5361AC increased the risk of gastric cancer significantly (P = 0.026, adjusted Odds ratio (OR) = 2.84, 95% confidence interval (CI) = 1.13-7.12). C allele of E-selectin rs5361 showed a significant increased frequency in cases (P = 0.023). However, the E-selectin variant did not affect the protein expression. E-selectin protein was observed not only in tumor interstitial vascular endothelial cells, but also in gastric cancer cells at primary and metastatic sites. The protein was associated with clinicopathological characteristics of gastric cancer, such as age (P = 0.008), tumor size (P = 0.027), differentiation (P = 0.000), and tumor-node-metastasis (TNM) stage (P = 0.006). CT and CC + CT genotypes of FCGR2A variant rs1801274 increased gastric cancer risk (P = 0.000, adjusted OR = 1.92, 95%CI = 1.36-2.72; P = 0.003, adjusted OR = 1.68, 95%CI = 1.20-2.35, respectively). Interleukin-4 receptor (IL-4R) variant rs2107356 presented negative correlations to E-selectin variant rs5361 and FCGR2A variant rs1801274 (P = 0.035 and P = 0.023) in conferring susceptibility to gastric cancer. We concluded E-selectin variant rs5361 and FCGR2A variant rs1801274 were significantly associated with gastric cancer risk. Expression of E-selectin protein would promote progression of gastric cancer.

Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disease. Clinically, no efficient assay protocols have been available. In this study, we aimed to develop an oligonucleotide biochip specialized for detection of known base substitution mutations in mitochondrial DNA causing LHON and to investigate frequencies of LHON relevant variants in Anhui region of China. Thirty-two pairs of oligonucleotide probes matched with the mutations potentially linked to LHON were covalently immobilized. Cy5-lablled targets were amplified from blood DNA samples by a multiplex PCR method. Two kinds of primary mutations 11778 G > A and 14484 T > C from six confirmed LHON patients were interrogated to validate this biochip format. Further, fourteen Chinese LHON pedigrees and twenty-five unrelated healthy individuals were investigated by the LHON biochip, direct sequencing and pyrosequencing, respectively. The biochip was found to be able efficiently to discriminate homoplasmic and heteroplasmic mtDNA mutations in LHON. Biochip analysis revealed that twelve of eighteen LHON symptomatic cases from the 14 Chinese pedigree harbored the mutations either 11778G > A, 14484T > C or 3460G > A, respectively, accounting for 66.7%. The mutation 11778G > A in these patients was homoplasmic and prevalent (55.5%, 10 of 18 cases). The mutations 3460G > A and 3394T > C were found to co-exist in one LHON case. The mutation 13708G > A appeared in one LHON pedigree. Smaller amount of sampling and reaction volume, easier target preparation, fast and high-throughput were the main advantages of the biochip over direct DNA sequencing and pyrosequencing. Our findings suggested that primary mutations of 11778G > A, 14484T > C or 3460G > A are main variants of mtDNA gene leading to LHON in China. The biochip would easily be implemented in clinical diagnosis.

About 15% of the couples at reproductive age worldwide suffer from infertility. It is estimated that 50% of the entity result from male itself. The mechanism of male infertility is quite complicated, attributing to inherent and environment factors of the infertility patients, of which defects of fertility-related genes are of importance for its occurrence. The clinical features of male infertility vary from azoospermia to oligoasthenoteratozoospermia. This paper presents the relationship between the known defects in genes and male infertility.

Summary Epidermolysis bullosa simplex (EBS) is a group of inherited skin diseases, characterized by the formation of intraepidermal blisters. We performed genetic analysis of the keratin 5 (KRT5) gene in two Chinese pedigrees. One novel missense mutation was identified in a patient with sporadic EBS (general, non-Dowling–Meara). Sequence analysis showed a heterozygous T > A transition at nucleotide 1730 of KRT5, changing phenylalanine (Phe) to tyrosine (Tyr) at position 577 of the keratin 5 (K5). In addition, two recurrent mutations c.1649delG (p.Gly550AlafsX77) and c.508G > (p.Glu170Lys) in KRT5 were identified in Chinese patients with mottled pigmentation EBS and localized EBS, respectively. None of the mutations were found in any unaffected family members or in an additional 100 unrelated control samples. These results suggest that these mutations are pathogenic and might be one of the potential causes of EBS in these Chinese patients.

We developed an oligonucleotide biochip for synchronous multiplex detection of 31 known mitochondrial DNA mutations associated with MELAS (Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) and MERRF (Myoclonic epilepsy with ragged red fibers). Allele-specific oligonucleotide probes were covalently immobilized on aldehyde modified glass slides, and then hybridized with Cy5-labled DNA fragments amplified from sample DNAs by a multiplex asymmetric PCR (MAP) method. Five patients with MELAS, 5 patients with MERRF and 20 healthy controls were investigated using the oligonucleotide biochip. The results showed that all the cases with MELAS had an A3243G mutation in the MT-TL1 gene. In the MERRF group, 4 cases were found to be an A8344G mutation and 1 case was a T8356C mutation, and both mutations were in the MT-TK gene. In the healthy controls, none of the 31 related mutations was found. The results of the DNA biochip were consistent with those by DNA sequencing. Clearly, the DNA biochip combined with MAP method would become a valuable tool in multiplex detecting of the point mutations in mtDNA leading to MELAS and/or MERRF syndrome. Moreover, this biochip format could be modified to extend to the screening scope of SNPs for any other human mitochondrial diseases.

Summary To study the clinical and epidemiological profile of Pityriasis versicolor (PV) and to determine the possible genetic model for PV in Chinese Han, we investigated 503 patients with PV who were recruited by a questionnaire method. Statistical analysis, heritability and complex segregation analysis were performed using EPI INFO 6.0, SPSS 10.0, the Falconer method and the SAGE-REGTL programs. In the total 503 PV patients, the mean age of onset was 22.85 ± 10.36 years. For male and female patients, the peak ages of initial onset were both 20‐29 years. A total of 106 (21.1%) patients were reported to have a positive family history of PV. The mean age of onset in males with positive family history was earlier than those with negative family history (t = 3.58, P < 0.01). Higher rate of recurrence and longer duration were seen in the patients with positive family history than those with negative family history. The heritability of PV in first-, second- and third-degree relatives was 48.13%, 40.11% and 27.20% respectively. Based on the REGTL results, the best model was a polygenic additive model for PV.

In the past two decades, it has been found that mitochondrial DNA (mtDNA) mutations are associated with a wide range of human diseases, from those affecting single organ to those with multi-system involvement. The purpose of this review is to explore the relationship between mtDNA mutations and human diseases. Four aspects are highlighted: characteristics of mitochondrial genetics, mtDNA mutations in human inherited diseases, role of somatic mtDNA mutations in aging and tumor, as well as diagnosis and treatment of mtDNA diseases.

Background Linkage and association studies suggest that the human leucocyte antigen (HLA) region may be involved in the genetic susceptibility of vitiligo. HLA-A2 has been reported to be associated with vitiligo in some, but not all, studies. Objective To identify sources of the heterogeneity among studies and to quantify effect estimates, we examined the association of HLA-A2 with vitiligo in a meta-analysis of all observational studies comparing the frequencies of HLA-A2 between vitiligo individuals and controls during 1966–2005. Methods The summary odds ratio (OR) was calculated by using a fixed- or a random-effects model. Meta-regression analysis was undertaken to investigate the effects of study characteristics on the pooled OR. Results Eleven case-controlled studies fulfilled our inclusion criteria. The studies identified a total of 777 patients and 4820 controls. Meta-analysis showed a significantly increased frequency of HLA-A2 in vitiligo among cases [OR = 2.07, 95% confidence interval (CI) 1.67–2.58]. Heterogeneity was explained by the quality of the study and the ethnic background of the participants. Meta-regression analysis further showed that the percentage of familial vitiligo among the subjects had a significant effect on the pooled OR (P = 0.008). No study had a significant effect on the pooled OR and no publication bias presented in the studies analysed (P = 0.688). Conclusion These findings strongly suggest an association between HLA-A2 and vitiligo.

AIM: To observe the therapeutic efficacy of high-dose Vitamin C (Vit. C) on acute pancreatitis (AP), and to explore its potential mechanisms. METHODS: Eghty-four AP patients were divided into treatment group and control group, 40 healthy subjects were taken as a normal group. In the treatment group, Vit. C (10 g/d) was given intravenously for 5 d, whereas in the control group, Vit. C (1 g/d) was given intravenously for 5 d. Symptoms, physical signs, duration of hospitalization, complications and mortality rate were monitored. Meanwhile, serum amylase, urine amylase and leukocyte counts were also determined. The concentration of plasma vitamin C (P-VC), plasma lipid peroxide (P-LPO), plasma vitamin E (P-VE), plasma β-carotene (P-β-CAR), whole blood glutathione (WB-GSH) and the activity of erythrocyte surperoxide dimutase (E-SOD) and erythrocyte catalase (E-CAT) as well as T lymphocyte phenotype were measured by spectrophotometry in the normal group and before and after treatment with Vit. C in the treatment and the control group. RESULTS: Compared with the normal group, the average values of P-VC, P-VE, P-β-CAR, WB-GSH and the activity of E-SOD and E-CAT in AP patients were significantly decreased and the average value of P-LPO was significantly increased, especially in severe acute pancreatitis (SAP) patients (P < 0.05. P-VC, P = 0.045; P-VE, P = 0.038; P = 0.041; P-β-CAR, P = 0.046; WB-GSH, P = 0.039; E-SOD, P = 0.019; E-CAT, P = 0.020; P-LPO, P = 0.038). Compared with the normal group, CD3 and CD4 positive cells in AP patients were significantly decreased. The ratio of CD4/CD8 and CD4 positive cells were decreased, especially in SAP patients (P < 0.05. CD4/CD8, P = 0.041; CD4, P = 0.019). Fever and vomiting disappeared, and leukocyte counts and amylase in urine and blood become normal quicker in the treatment group than in the control group. Moreover, patients in treatment group also had a higher cure rate, a lower complication rate and a shorter in-ward days compared with those in he control group. After treatment, the average value of P-VC was significantly higher and the values of SIL-2R, TNF-α, IL-6 and IL-8 were significantly lower in the treatment group than in the control group (P < 0.05 P-VC, P = 0.045; SIL-2R, P = 0.012; TNF-α, P = 0.030; IL-6, P = 0.015; and IL-8, P = 0.043). In addition, the ratio of CD4/CD8 and CD4 positive cells in the patients of treatment group were significantly higher than that of the control group after treatment (P < 0.05. CD4/CD8, P = 0.039; CD4, P = 0.024). CONCLUSION: High-dose vitamin C has therapeutic efficacy on acute pancreatitis. The potential mechanisms include promotion of anti-oxidizing ability of AP patients, blocking of lipid peroxidation in the plasma and improvement of cellular immune function.

AIM:To find out the relationship between the gene transcription of different types of procollagen and the deposition of the relevant collagens in the liver tissue and to confirm the types of collagen producing cells in liver fibrogenesis.METHODS:Dynamic changes of the expression of alpha1(I), alpha1(III) and alpha1(IV) procollagen mRNA and relevant collagens and the distribution of collagen producing cells during liver fibrogenesis of rat induced by CCl(4) (20 weeks) were investigated with Northern blot analysis, in situ hybridization and immunohistochemical techniques.RESULTS: The increased expression of alpha 1(III) procollagen mRNA by Northern blot analysis was the most predominant one among the three mRNAs during fibrogenesis. However, the enhanced expression of alpha1(IV) procollagen mRNA occurred very early while the expression of alpha1(I) mRNA was not enhanced much until the middle stage of the experiment. Desmin (Dm) positive hepatic stellate cells (HSCs) and few myofibroblasts (MFs) in and around the necrotic areas expressed alpha1(I), alpha1(III) and alpha1(IV) procollagen mRNA signals detected by in situ hybridization at the early stage of the experiment. All the three procollagen mRNA signals thereafter mainly localized in fibroblasts (Fbs) and MFs in fibrotic septa during the middle and late stages of fibrosis, which distributed parallel to the corresponding collagens detected by immunohistochemical study. In addition, the endothelial cells of sinusoids and the small blood vessels within the septa also showed alpha1(IV) procollagen mRNA and type IV collagen expression.CONCLUSION:It is considered that "HSC-MF-Fb effect cell system is the major cellular source of collagen production in liver fibrosis, in which HSCs are collagen producing precursor cells in the early liver fibrogenesis, thereafter the synthesis of type I, III and IV collagens (Col I, Col III and Col IV) mainly derives from MFs and Fbs, which play a very important role in the progress of liver fibrosis. The endothelial cells along sinusoids, as another source of Col IV production, might participate in the capillization of liver sinusoids.

Protamine genes play important roles in DNA packaging within the sperm nucleus. In order to evaluate the association of PRM1, PRM2, KIT and KITLG variants with susceptibility to severely defective spermatogenesis, 309 male infertility patients (199 cases with non-obstructive azoospermia and 110 cases with severe oligozoospermia) and 377 controls were recruited in the Chinese Han population. This study genotyped 38 single-nucleotide polymorphisms (SNP) in PRM1, PRM2, KIT and KITLG using Sequenom iplex. The results showed that PRM1 variant rs35576928 (p.R34S) was significantly associated with severe oligozoospermia and played a protective role against the disease (P = 0.0079, Bonferroni correction, OR 0.426). The dominant model (variant-containing genotypes) of the SNP was confirmed to protect against the occurrence of oligozoospermia (P = 0.0078, Bonferroni correction, OR 0.387). Haplotype analysis of PRM1 and PRM2 in combination exhibited that haplotype TACCGGC exhibited a significant protective effect against the occurrence of oligozoospermia when compared with controls (P = 0.002, Bonferroni correction, OR 0.602). Hap- lotype TACCTGC was strongly associated with risk of the clinical phenotype severe oligozoospermia (P = 0.002, Bonferroni correc- tion, OR 2.716). The findings indicated that PRM1 variant rs35576928 (p.R34S) was associated with severely defective spermatogenesis in the Chinese Han population. RBMOnline

e18088 Background: Combinations of anti-angiogenic drugs with chemotherapeutics are widely used for cancers control. Whether can better efficacy of such a combinated modality be achieved and predicted earlier is a great challenge. Circulating endothelial cells (CECs) and cytokeratins (CKs) might have a role in tumour angiogenesis and in tumour cell death. Measurement of CECs and CKs in the blood of patients with tumors could be a simple, non-invasive approach to monitor or predict responses and survival to treatment. Methods: One hundred and seven patients with primary advanced non-small cell lung cancer (NSCLC) were enrolled, randomly assigned to either the endostatin treatment group (paclitaxel+ carboplatin+ endostatin) or the control group (paclitaxel+carboplatin). CEC count and serum CK8, caspase-cleaved CK18 (ccCK18) and uncleaved CK18 (CK18) were measured in the 107 subjects at before treatment (baseline), week 3, and week 6 of treatment, respectively. Results: Higher baseline CEC count was observed in patients with good tumor response (p=0.002 for all the 107 patents; p=0.000 in the treatment group). When compared with the baseline level, after 6 weeks therapy in the endostatin group, CECs decreased significantly (p=0.000), but the CKs levels increased. The increased levels of ccCK18 and CK18 at week 6 reached significance in the treatment group (p=0.001 and p=0.048, respectively). Tumor response showed strong correlation with the reduction extent of CECs (p=0.000) and the increase value of ccCK18 (p=0.040) after endostatin therapy. The best cut-off values of the changes of CECs and ccCK18 for prediction of survival were designed being 0.58/ul and 19.6ng/ml, respectively. Furthermore, obvious reduction of CECs and more rise of ccCK18 significantly correlated with the longer median survival (p= 0.013 and p = 0.016 for PFS, p = 0.009 and p=0.012 for OS, respectively). Conclusions: CECs and CKs would be the impressive biomarkers to explore for selecting NSCLC patients who might benefit from endostain in combination with paclitaxel plus carboplatin treatment.