Han Chinese Subjects Research Articles

Association of HLA-B*1502 allele with lamotrigine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese subjects: a meta-analysis.

Despite several studies investigating the association between the human leukocyte antigen HLA-B*1502 allele and lamotrigine-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Han Chinese subjects, the relationship remains unclear. We performed a systematic review and meta-analysis to ascertain the association between the HLA-B*1502 allele and lamotrigine-induced SJS and TEN in Han Chinese populations. We searched the biomedical literature archived in the MEDLINE, Cochrane Library, EMBASE, Chinese Biomedical, Chinese National Knowledge Infrastructure, and China Science and Technology Journal databases. Only studies investigating the association between HLA-B*1502 and lamotrigine-induced SJS/TEN were included. We then performed a meta-analysis of the data in these studies. Four studies including a total of 12 patients with SJS/TEN and 128 lamotrigine-tolerant control subjects were identified. The HLA-B*1502 allele was present in 33.3% (four of 12) of lamotrigine-induced SJS/TEN cases but in only 9.4% (12 of 128) of lamotrigine-tolerant controls. The occurrence of SJS/TEN was thus associated with the presence of the HLA-B*1502 allele (odds ratio: 4.98, 95% confidence interval 1.43-17.28; P<0.05). We found a statistical association between HLA-B*1502 and lamotrigine-induced SJS/TEN in Han Chinese subjects. Future studies with larger sample sizes are suggested to verify the results.

Associations of MTHFR C677T and MTRR A66G gene polymorphisms with metabolic syndrome: a case-control study in Northern China.

Prior evidence indicates that homocysteine plays a role in the development of metabolic syndrome (MetS). Methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase reductase (MTRR) A66G polymorphisms are common genetic determinants of homocysteine levels. To investigate the associations of the MTHFR C677T and MTRR A66G polymorphisms with MetS, 692 Chinese Han subjects with MetS and 878 controls were recruited. The component traits of MetS and the MTHFR C677T and MTRR A66G genotypes were determined. A significant association was observed between the MTHFR 677T allele and increased risk of MetS, high fasting blood glucose, high waist circumference, and increasing number of MetS components. The MTRR A66G polymorphism was associated with an increased risk of MetS when combined with the MTHFR 677TT genotype, although there was no association found between MetS and MTRR A66G alone. Furthermore, the MTRR 66GG genotype was associated with high fasting blood glucose and triglycerides. Our data suggest that the MTHFR 677T allele may contribute to an increased risk of MetS in the northern Chinese Han population. The MTRR A66G polymorphism is not associated with MetS. However, it may exacerbate the effect of the MTHFR C677T variant alone. Further large prospective population-based studies are required to confirm our findings.

IL36RN mutations define a severe autoinflammatory phenotype of generalized pustular psoriasis

Safia Hussain, BSc, Dorottya M Berki, BSc, Siew-Eng Choon, MRCP, A David Burden, MD, FRCP, Michael H Allen, PhD, Juan I Arostegui, MD, PhD, Antonio Chaves, MD, Michael Duckworth, Alan D Irvine, MD, Maja Mockenhaupt, MD, PhD, Alexander A Navarini, MD, PhD, Marieke MB Seyger, MD, PhD, Pere Soler-Palacin, MD, PhD, Christa Prins, MD, Laurence Valeyrie-Allanore, MD, M Asuncion Vicente, MD, Richard C Trembath, FMedSci, Catherine H Smith, MD, FRCP, Jonathan N Barker, MD, FRCP,* Francesca Capon, PhD,*

Association of HLA-DP/DQ and STAT4 polymorphisms with HBV infection outcomes and a mini meta-analysis.

BackgroundThough HLA-DP/DQ is regarded to associate with HBV susceptibility and HBV natural clearance, its role in hepatocellular carcinoma (HCC) development is obscure. And the role of STAT4 in HBV susceptibility and clearance as well as HCC development is still contentious. Therefore, we conducted this study, aiming to clarify these obscure relationships.MethodsWe recruited 1312 Chinese Han subjects including healthy controls, HBV carriers and HCC patients in the experiment stage. The meta-analysis included 3467 HCC patients and 5821 HBV carriers to appraise the association with HCC development.ResultsConsistent with previous studies, HLA-DP/DQ associated with HBV susceptibility and HBV natural clearance (p<0.05). However, the experiment showed that HLA-DP rs3077, rs9277535 and rs7453920 did not associate with HCC development (dominant model, rs3077, OR = 0.86, 95%CI = 0.62–1.18; rs9277535, OR = 0.94, 95%CI = 0.68–1.30; rs7453920, OR = 0.75, 95%CI = 0.44–1.27). Meta-analysis again consolidated this conclusion (allele model, rs3077, OR = 0.94, 95%CI = 0.87–1.02; rs9277535, OR = 1.04, 95%CI = 0.97–1.11; rs7453920, OR = 0.89, 95%CI = 0.76–1.02). As for STAT4 rs7574865, we did not find any significant association with HBV susceptibility (OR = 0.91, 95%CI = 0.66–1.26) or HBV natural clearance (OR = 1.13, 95%CI = 0.86–1.49). Moreover, current data failed to acquire positive connection of rs7574865 with HCC development (experiment, OR = 0.86, 95%CI = 0.62–1.19; meta-analysis, OR = 0.87, 95%CI = 0.74–1.03), which may be due to the small sample size.ConclusionsHLA-DP/DQ polymorphisms (rs3077, rs9277535, rs7453920) did not associate with HCC development, but did correlate with HBV susceptibility and HBV natural clearance. STAT4 rs7574865 seemed not to correlate with HBV susceptibility or natural clearance. And it seemed rather ambiguous in its role on HCC development at present.

Trans-omics pathway analysis suggests that eQTLs contribute to chondrocyte apoptosis of Kashin–Beck disease through regulating apoptosis pathway expression

Kashin–Beck disease (KBD) is a serious osteoarthropathia, mainly characterized by excessive chondrocyte necrosis and apoptosis. The molecular signaling pathways underlying KBD excessive chondrocyte apoptosis remain unclear, leading to a lack of effective medical interventions now. To clarify whether expression quantitative trait loci (eQTLs) contribute to excessive chondrocyte apoptosis of Kashin–Beck disease through regulating the expression of apoptosis pathways. We conducted a genome-wide eQTLs based pathway association analysis of KBD using Affymetrix Human SNP Array 6.0 in 1717 Chinese Han subjects. PLINK software was used for genome-wide association study (GWAS) of KBD. A modified gene set enrichment algorithm was applied for pathway association analysis based on GWAS results. The KBD-associated pathways were compared with abnormally expressed pathways in KBD articular cartilage, identified by microarray study of KBD. We identified 4 eQTLs pathways, which were not only significantly associated with KBD, but also abnormally expressed in KBD articular cartilage, including REACTOME_INTRINSIC_PATHWAY_FOR_APOPTOSIS (P=0.008), MAHAJAN _RESPONSE_TO_IL1A_UP (P=0.010), KEGG_PEROXISOME (P=0.005) and MARKS_HDAC_TARGETS_UP (P=0.006). Our results suggest that eQTLs contributed to KBD excessive chondrocyte apoptosis through regulating the expression of apoptosis related pathways. This study provides novel insight into the genetic susceptibility and therapeutic rationale of KBD.

Association analyses of FGFR2 gene polymorphisms with femoral neck bone mineral density in Chinese Han population

Femoral neck (FN) bone mineral density (BMD) is the most important risk phenotype for osteoporosis and has been used as a reference standard for describing osteoporosis. Identification of genetic variations associated with FN BMD may provide potential targets for therapeutic studies. Given the important biological role of FGFR2 gene involved in bone, we tested the associations between FGFR2 polymorphisms and FN BMD in 1,300 Chinese Han subjects. Of the 28 total SNPs, 2 SNPs, namely rs11200014 and rs1078806, were significantly associated with FN BMD under dominant model (P = 0.0014 and 0.0012, respectively) after conservative Bonferroni correction. The two SNPs were in complete linkage disequilibrium. In addition, haplotype-based association tests identified two haplotypes significantly associated with FN BMD, including one haplotype in block 4 where the two SNPs located. However, different from previous studies in white older men, we did not detect any significant association in sex-stratified analyses. In summary, our findings suggest that the FGFR2 gene may play an important role in variation in FN BMD in Chinese Han population, independent of gender effects. Further studies performed in multiple and large samples are needed to elucidate the underlying molecular mechanism and pathophysiology of osteoporosis.

GW25-e1584 COL4A1 gene polymorphism is related to arterial pulse wave velocity in healthy Han Chinese subjects

GW25-e1584 COL4A1 gene polymorphism is related to arterial pulse wave velocity in healthy Han Chinese subjects

Synergistic effect of smoking with genetic variants in the AMPKα1 gene on the risk of coronary artery disease in type 2 diabetes

Increasing evidence suggests that adenosine monophosphate-activated protein kinase (AMPK) plays a critical physiological role in the cardiovascular system. The objective of this study was to assess the possible correlation between the genetic variability of the AMPKα1 (PRKAA1) gene and the risk of cardiovascular disease, as well as the interactive effects of the genetic variations and environmental factors, on the risk in Chinese patients with type 2 diabetes. Five haplotype-tagging single nucleotide polymorphisms (SNPs) at the AMPKα1 locus and 404 unrelated Chinese Han subjects with type 2 diabetes were studied; 260 individuals with coronary artery disease and 144 non-coronary artery disease controls were genotyped using the polymerase chain reaction-restriction fragment length polymorphism assay. Minor allele C at rs3805489 was protective from coronary artery disease in type 2 diabetic subjects compared with allele A (OR 0.67, 95% CI 0.48-0.92, p = 0.015). There was no significant correlation between the genotypes at five SNPs and the risk of coronary artery disease. In addition, a significant interaction was identified between smoking status and rs3805489 (p = 0.018 for interaction). The smokers with genotype AA at the SNP had a three-fold higher risk of coronary artery disease compared with non-smokers with genotypes AC or CC (OR' 3.02, 95% CI' 1.39-6.57, p' = 0.005, after adjustment for other known coronary artery disease risk factors). The genetic variability at the AMPKα1 locus has synergetic effects with smoking to increase the risk of coronary artery disease in the Chinese Han population with type 2 diabetes.

Leber's hereditary optic neuropathy caused by the homoplasmic ND1 m.3635G>A mutation in nine Han Chinese families

In this report, we investigated the molecular mechanism underlying Leber's hereditary optic neuropathy (LHON)-associated mitochondrial m.3635G>A (p.S110N, ND1) mutation. A mutational screening of ND1 gene in a cohort of 1070 Han Chinese subjects LHON identified the m.3635G>A mutation in nine Chinese families with suggestively maternally transmitted LHON. Thirty-eight (22 males/16 females) of 162 matrilineal relatives in these families exhibited the variable severity and age-at-onset of optic neuropathy. Molecular analysis of their mitochondrial genomes identified the homoplasmic m.3635G>A mutation and distinct sets of polymorphisms belonging to the Asian haplogroups G2a1, R11a, D4, R11a, M7b2, G1a, F1a1, B4, and N9a3, respectively. Using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from one Chinese family into mtDNA-less (ρ0) cells, we showed ~27% decrease in the activity of NADH:ubiquinone oxidoreductase (complex I) in mutant cybrids carrying the m.3635G>A mutation, compared with control cybrids. The respiratory deficiency caused by the m.3635G>A mutation results in decreased efficiency of mitochondrial ATP synthesis. These mitochondrial dysfunctions caused an increase in the production of reactive oxygen species in the mutant cybrids. The data provide the direct evidence for the m.3635G>A mutation leading to LHON. Our findings may provide new insights into the understanding of pathophysiology of LHON.

The relationships between type 2 diabetic retinopathy and VEGF-634G/C and VEGF-460C/T polymorphisms in Han Chinese subjects

ObjectiveTo investigate how VEGF-634G/C and VEGF-460C/T SNPs are related to diabetic retinopathy (DR) in Han Chinese subjects from the Shijiazhuang region of China. MethodsTotally 376 DM cases were divided into non-proliferative diabetic retinopathy (NPDR) group (n=124), proliferative diabetic retinopathy (PDR) group (n=108), and diabetes without retinopathy (DWR) group (n=144). PCR/LDRwas utilised to detect and assess the genotypes and allele distribution frequencies at the VEGF-634G/C and VEGF-460C/T loci in each group. ResultsThe differences between NPDR, PDR and DWR groups were not significant in genotypes and allele distribution frequencies at VEGF-634G/C locus (P>0.05). But there were significant differences between NPDR and DWR groups in genotypes (P=0.013) and allele distribution frequencies (P=0.002) at VEGF-460C/T locus, at which CT+CC genotypes were associated with a reduced risk of developing NPDR. There were no significant differences in genotypes (P=0.759) or allele distribution frequencies (P=0.433) at VEGF-460C/T locus between PDR and DWR groups. ConclusionsAmong Chinese Han individuals with type-2 DM, polymorphism −634G/C of the VEGF gene was not correlated with NPDR or PDR; however, polymorphism-460C/T of the VEGF gene was correlated with NPDR, and C allele was associated with lower NPDR risk than T allele.

IGF2BP2 and obesity interaction analysis for type 2 diabetes mellitus in Chinese Han population.

BackgroundThe objective of this study was to systematically evaluate the contribution of the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) to type 2 diabetes mellitus (T2DM) and its interaction with obesity to T2DM susceptibility.MethodsTo clarify whether IGF2BP2 is an independent risk factor for T2DM in Chinese population, we conducted a study with a total of 2,301 Chinese Han subjects, including 1,166 T2DM patients and 1,135 controls, for the genotype of a most common and widely studied polymorphism—rs4402960 of IGF2BP2. Genotyping was performed by iPLEX technology. Gene and environment interaction analysis was performed by using multiple logistic regression models.ResultsThe repeatedly confirmed association between IGF2BP2 (rs4402960) and T2DM had not been replicated in this cohort (P = 0.182). Interestingly, we found that obese subjects (body mass index (BMI) ≥ 28.0 kg/m2) bearing the minor A allele had an increased risk to develop T2DM (P = 0.008 for allele analysis and P < 0.001 for genotype analysis).ConclusionsThe present study provided data suggesting that the wild C allele of IGF2BP2 (rs4402960) had a protective effect against T2DM in obese subjects of Chinese Han population.

Polymorphisms in CISH gene are associated with persistent hepatitis B virus infection in Han Chinese population.

Background and AimCytokine-inducible SRC homology 2 domain protein (CISH) is the first member of the suppressors of cytokine signaling (SOCS) protein family. An association between multiple CISH polymorphisms and susceptibility to infectious diseases has been reported. This study aimed to investigate the possible association of these single nucleotide polymorphisms (SNPs) in CISH gene with different outcomes of Hepatitis B virus (HBV) infection.Methods1019 unrelated Chinese Han subjects, including 240 persistent asymptomatic HBV carriers, 217 chronic hepatitis B patients, 137 HBV-related liver cirrhosis patients, and 425 cases of spontaneously recovered HBV as controls, were studied. Four SNPs (rs622502, rs2239751, rs414171 and rs6768300) in CISH gene were genotyped with the snapshot technique. Transcriptional activity of the CISH promoter was assayed in vitro using the dual-luciferase reporter assay system.ResultsAt position rs414171, A allele and AA genotype frequencies were significantly higher in the HBV-resolved group as compared to the persistent HBV infection group. At position rs2239751, TT genotype was further observed in the HBV-resolved group. Using asymptomatic HBV carriers as controls, our results indicated that the rs414171 and rs2239751 polymorphisms were unrelated to HBV progression. The other two SNPs (rs622502 and rs6768300) showed no association with persistent HBV infection. Haplotype analysis revealed that the GGCA haplotype was associated with spontaneous clearance of HBV in this population. Moreover, luciferase activity was significantly higher in the PGL3-Basic-rs414171T construct as compared to the PGL3-Basic-rs414171A construct (p<0.001).ConclusionTwo SNPs (rs414171 and rs2239751) in the CISH gene were associated with persistent HBV infection in Han Chinese population, but not with HBV progression.

Genome Wide Association Study: Searching for Genes Underlying Body Mass Index in the Chinese

ObjectiveObesity is becoming a worldwide health problem. The genome wide association (GWA) study particularly for body mass index (BMI) has not been successfully conducted in the Chinese. In order to identify novel genes for BMI variation in the Chinese, an initial GWA study and a follow up replication study were performed. MethodsAffymetrix 500K SNPs were genotyped for initial GWA of 597 Northern Chinese. After quality control, 281 533 SNPs were included in the association analysis. Three SNPs were genotyped in a Southern Chinese replication sample containing 2 955 Chinese Han subjects. Association analyses were performed by Plink software. ResultsEight SNPs were significantly associated with BMI variation after false discovery rate (FDR) correction (P=5.45×10−7−7.26×10−6, FDR q=0.033–0.048). Two adjacent SNPs (rs4432245 & rs711906) in the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) gene were significantly associated with BMI (P=6.38×10−6 & 4.39×10−6, FDR q=0.048). In the follow-up replication study, we confirmed the associations between BMI and rs4432245, rs711906 in the EIF2AKE gene (P=0.03 & 0.01, respectively). ConclusionOur study suggests novel mechanisms for BMI, where EIF2AK4 has exerted a profound effect on the synthesis and storage of triglycerides and may impact on overall energy homeostasis associated with obesity. The minor allele frequencies for the two SNPs in the EIF2AK4 gene have marked ethnic differences between Caucasians and the Chinese. The association of the EIF2AK4 gene with BMI is suggested to be ‘ethnic specific’ in the Chinese.

Validation of type 2 diabetes risk variants identified by genome-wide association studies in Han Chinese population: a replication study and meta-analysis.

BackgroundSeveral genome-wide association studies (GWAS) involving European populations have successfully identified risk genetic variants associated with type 2 diabetes mellitus (T2DM). However, the effects conferred by these variants in Han Chinese population have not yet been fully elucidated.MethodsWe analyzed the effects of 24 risk genetic variants with reported associations from European GWAS in 3,040 Han Chinese subjects in Taiwan (including 1,520 T2DM cases and 1,520 controls). The discriminative power of the prediction models with and without genotype scores was compared. We further meta-analyzed the association of these variants with T2DM by pooling all candidate-gene association studies conducted in Han Chinese.ResultsFive risk variants in IGF2BP2 (rs4402960, rs1470579), CDKAL1 (rs10946398), SLC30A8 (rs13266634), and HHEX (rs1111875) genes were nominally associated with T2DM in our samples. The odds ratio was 2.22 (95% confidence interval, 1.81-2.73, P<0.0001) for subjects with the highest genetic score quartile (score>34) as compared with subjects with the lowest quartile (score<29). The incoporation of genotype score into the predictive model increased the C-statistics from 0.627 to 0.657 (P<0.0001). These estimates are very close to those observed in European populations. Gene-environment interaction analysis showed a significant interaction between rs13266634 in SLC30A8 gene and age on T2DM risk (P<0.0001). Further meta-analysis pooling 20 studies in Han Chinese confirmed the association of 10 genetic variants in IGF2BP2, CDKAL1, JAZF1, SCL30A8, HHEX, TCF7L2, EXT2, and FTO genes with T2DM. The effect sizes conferred by these risk variants in Han Chinese were similar to those observed in Europeans but the allele frequencies differ substantially between two populations.ConclusionWe confirmed the association of 10 variants identified by European GWAS with T2DM in Han Chinese population. The incorporation of genotype scores into the prediction model led to a small but significant improvement in T2DM prediction.

Validated HILIC–MS/MS assay for determination of vindesine in human plasma: Application to a population pharmacokinetic study

The first HILIC–tandem mass spectrometry (MS/MS) method for determination of vindesine (VDS) in human plasma using vinorelbine as an internal standard (IS) has been developed and validated. Plasma samples clean-up consisted of solid phase extraction with a strata™-X column. The compounds were separated on a HILIC column with an isocratic mobile phase consisting of acetonitrile and 15mM ammonium acetate buffer containing 0.15% formic acid (80:20, v/v). The detection was performed on a triple quadrupole tandem mass spectrometer via electrospray positive ionization (ESI+). The ion transitions recorded in multiple reaction monitoring mode were m/z 754.6→123.8 for VDS and 779.4→323.3 for IS, respectively. Linear calibration curves were obtained in the concentration range of 0.3–28ng/ml and the lower limit of quantification for VDS was 0.3ng/ml. The coefficient of variation of the assay precision was less than 13%, and the accuracy exceeded 96%. The developed assay method was successfully applied for the evaluation of population pharmacokinetics of VDS after intravenous infusion of Xi Ai Ke Vial® (3mg of Vindesine Sulfate for Injection) to Chinese Han subjects with hematological malignant disorders.

A potential ethnic difference in the association between 5-HTTLPR polymorphisms and the brain default mode network

The serotonin-transporter-linked polymorphic region (5-HTTLPR) is associated with mood disorders. This association is thought to be due to amygdala hyperresponsiveness to negative emotional stimuli as a result of reduced frontal cortical control. In Caucasians, the short form is associated with this effect, but in Han Chinese we recently found that the long form is involved. Serotonin receptors have rich expression in default mode network (DMN) regions and the recent studies have found an association between the short form of the 5-HTTLPR and DMN functional connectivity (FC) in Caucasians. The present study has investigated whether there may also be an ethnic difference in this influence of 5-HTTLPR on the DMN. We recruited 233 young Han Chinese subjects and calculated the resting-state default-network FC. Our study found that the L carriers had decreased FC in the bilateral medial prefrontal cortex, right parahippocampal gyrus, left middle temporal gyrus, and increased FC in left precuneus (Pcu) compared to SS. The PCC-Pcu FC in L carriers was significantly negatively correlated with the depression scores. Our findings, therefore, suggest that there is also a difference between Caucasian and Han Chinese subjects in the association between the different forms of the 5-HTTLPR and DMN functional connectivity.

Frequency and Spectrum of MitochondrialND6Mutations in 1218 Han Chinese Subjects With Leber's Hereditary Optic Neuropathy

To investigate the molecular pathogenesis of Leber's hereditary optic neuropathy (LHON) in Chinese families. A cohort of 1218 Han Chinese subjects with LHON and 316 control subjects underwent the clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. The age at onset of optic neuropathy in these subjects ranged from 5 to 55 years, with the average of 18 years. Mutational analysis of ND6 gene identified 92 (73 known and 19 novel) variants in these subjects. These variants included 29 (9 novel and 20 known) missense mutations and 63 silence variants. A total of 94 subjects carrying one of the known T14484C, T14502C, and G14459A mutations accounted for 7.7% cases of this cohort, particularly 4.4% for T14484C mutation. Furthermore, eight putative LHON-associated ND6 mutations accounted for 1.1% case of this cohort. Thus, 106 subjects carrying one of ND6 mutations accounted for 8.7% cases of this cohort. Low penetrance of optic neuropathy in pedigrees carrying one of eight putative mutations indicated that the mutation(s) is necessary, but itself insufficient to produce a clinical phenotype. Mitochondrial DNAs in 98 probands carrying the ND6 mutation(s) were widely dispersed among 12 Eastern Asian subhaplogroups. In particular, the occurrences of haplogroups M9, M10, M11, and H2 in patients carrying the ND6 mutations were higher than those in controls. These data further support that the ND6 gene is the hot spot for mutations associated with LHON. Thus, our findings may provide valuable information for the further understanding of pathophysiology and management of LHON.

Genetic polymorphisms of XRCC1 gene and susceptibility to hepatocellular carcinoma in Chinese population

Hepatocellular carcinoma (HCC) is a common cancer in the worldwide. Accumulated evidences indicate that genetic polymorphisms of human X-ray repair complementing group 1 gene (XRCC1) are associated with the susceptibility to HCC. This study aims to investigate the potential association between XRCC1 c.482C>T and c.1178G>A genetic polymorphisms and the susceptibility to HCC. A total of 1,069 Chinese Han subjects consisting of 530 HCC patients and 539 cancer-free controls were recruited in this case-control study. The created restriction site-polymerase chain reaction and directly DNA sequencing methods were utilized to analyze the genotyping of XRCC1 genetic polymorphisms. Our data suggested that the XRCC1 c.482C>T and c.1178G>A genetic polymorphisms were statistically associated with the increased risks of HCC [for c.482C>T, TT vs. CC: OR 2.05, 95% CI 1.26-3.32, P = 0.003; T vs. C: OR 1.26, 95% CI 1.04-1.51, P = 0.017; for c.1178G>A, AA vs. GG: OR 2.15, 95% CI 1.26-3.67, P = 0.004; A vs. G: OR 1.33, 95% CI 1.10-1.61, P = 0.004]. The allele-T and genotype-TT of c.482C>T and allele-A and genotype-AA of c.1178G>A genetic polymorphisms may enhance the susceptibility to HCC. Our findings indicate that the studied XRCC1 genetic polymorphisms may influence the risk of HCC in Chinese populations and might be used as molecular markers for assessing the risk of HCC.

Dosage Effects of BDNF Val66Met Polymorphism on Cortical Surface Area and Functional Connectivity

The single nucleotide polymorphism (SNP) that leads to a valine-to-methionine substitution at codon 66 (Val66Met) in BDNF is correlated with differences in cognitive and memory functions, as well as with several neurological and psychiatric disorders. MRI studies have already shown that this genetic variant contributes to changes in cortical thickness and volume, but whether the Val66Met polymorphism affects the cortical surface area of healthy subjects remains unclear. Here, we used multimodal MRI to study whether this polymorphism would affect the cortical morphology and resting-state functional connectivity of a large sample of healthy Han Chinese human subjects. An SNP-wise general linear model analysis revealed a "dosage effect" of the Met allele, specifically a stepwise increase in cortical surface area of the right anterior insular cortex with increasing numbers of the Met allele. Moreover, we found enhanced functional connectivity between the anterior insular and the dorsolateral prefrontal cortices that was linked with the dosage of the Met allele. In conclusion, these data demonstrated a "dosage effect" of BDNF Val66Met on normal cortical structure and function, suggesting a new path for exploring the mechanisms underlying the effects of genotype on cognition.

ABCC4copy number variation is associated with susceptibility to esophageal squamous cell carcinoma

Esophageal squamous cell carcinoma (ESCC) is the eighth most common cause of cancer-related death worldwide. However, previous genome-wide single nucleotide polymorphism association analyses have not explained the high heritability associated with ESCC. In this study, we performed genome-wide copy number variation (CNV) analysis on 128 discordant sibling pairs to identify novel genes that contribute to ESCC susceptibility. A total of 57 774 individual CNVs were identified, and an interactive network of common CNV-associated genes was constructed, which showed that several ABC transporter genes contain CNVs in ESCC patients. Independent validation of a CNV at 13q32.1 in 1048 northern Chinese Han subjects demonstrated that the amplification of ABCC4 significantly correlated with ESCC risk [odds ratio: 3.36 (1.65-7.93), P = 0.0013]. Immunohistochemistry staining suggested that high copy numbers correlated with increased protein levels. High expression of ABCC4 was an independent poor prognostic factor for ESCC [relative risk: 1.73 (1.10-2.73), P = 0.0181]. The CNV region showed strong enhancer activity. Furthermore, inhibition of ABCC4 protein in ESCC cells decreased cell proliferation and motility via the inhibition of COX-2, PGE2 receptors and c-Myc expression; AKT, extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation; and β-catenin nuclear translocation in ESCC cells. In conclusion, the CNV at 13q32.1 is associated with ESCC susceptibility, and a gene within this locus, ABCC4, activates the oncogenic pathways in ESCC and thus facilitates cancer cell development and progression. A direct genetic contribution of ESCC risk through CNV common variants was determined in this study, and ABCC4 might therefore have predictive and therapeutic potential for ESCC.