Population genetics of marmosets in Asian primate research centers and loci associated with epileptic risk revealed by whole-genome sequencing.

The common marmoset ( Callithrix jacchus) has emerged as a valuable nonhuman primate model in biomedical research with the recent release of high-quality reference genome assemblies. Epileptic marmosets have been independently reported in two Asian primate research centers. Nevertheless, the population genetics within these primate centers and the specific genetic variants associated with epilepsy in marmosets have not yet been elucidated. Here, we characterized the genetic relationships and risk variants for epilepsy in 41 samples from two epileptic marmoset pedigrees using whole-genome sequencing. We identified 14 558 184 single nucleotide polymorphisms (SNPs) from the 41 samples and found higher chimerism levels in blood samples than in fingernail samples. Genetic analysis showed fourth-degree of relatedness among marmosets at the primate centers. In addition, SNP and copy number variation (CNV) analyses suggested that the WW domain-containing oxidoreductase ( WWOX) and Tyrosine-protein phosphatase nonreceptor type 21 ( PTPN21) genes may be associated with epilepsy in marmosets. Notably, KCTD18-like gene deletion was more common in epileptic marmosets than control marmosets. This study provides valuable population genomic resources for marmosets in two Asian primate centers. Genetic analyses identified a reasonable breeding strategy for genetic diversity maintenance in the two centers, while the case-control study revealed potential risk genes/variants associated with epilepsy in marmosets.

Effects of Dexmedetomidine on Systemic Inflammation and Postoperative Complications in Laparoscopic Pancreaticoduodenectomy: A Double-blind Randomized Controlled Trial.

BACKGROUND: Laparoscopic pancreaticoduodenectomy (LPD) may induce intense inflammatory response which might be related to the patient's outcomes. Clinical dexmedetomidine (DEX) has been widely used for opioid-sparing anesthesia and satisfactory sedation. The objective of this study was to investigate the influence of DEX on inflammatory response and postoperative complications in LPD. METHODS: Ninety-nine patients undergoing LPD were randomly assigned to two groups: normal saline (NS) and DEX. The primary outcome was the neutrophil-to-lymphocyte ratio (NLR) differences postoperatively within 48 h. Secondary outcomes were postoperative complications, the length of postoperative hospital stay and the incidence of ICU admission. Other outcomes included anesthetics consumption and intraoperative vital signs. RESULTS: NLR at postoperative day 2 to baseline ratio decreased significantly in the DEX group (P = 0.032). Less major complications were observed in the DEX group such as pancreatic fistula, delayed gastric emptying and intra-abdominal infection (NS vs. DEX, 21.7% vs. 13.6%, P = 0.315; 10.9% vs. 2.3%, P = 0.226; 17.4% vs. 11.4%, P = 0.416, respectively) though there were no statistical differences. Three patients were transferred to the ICU after surgery in the NS group, while there was none in the DEX group (P = 0.242). The median postoperative hospital stay between groups were similar (P = 0.313). Both intraoperative propofol and opioids were less in the DEX group (P < 0.05). CONCLUSIONS: Intraoperative DEX reduced the early postoperative inflammatory response in LPD. It also reduced the use of narcotics that may related to reduced major complications, which need additional research further.

Curcumin Ameliorates the Experimental Diabetic Peripheral Neuropathy through Promotion of NGF Expression in Rats.

Increasing evidence suggested that inhibiting the apoptosis of Schwann cells (SCs) and promoting nerve growth factor (NGF) expression in sciatic nerves play key roles in preventing the onset of diabetic peripheral neuropathy (DPN). Curcumin, a primary bioactive substance in turmeric with multiple characteristics, has been shown to have many therapeutic effects in a variety of diseases. However, curcumin is poorly studied in the DPN models. We aimed to explore the therapeutic benefits and underlying mechanism of curcumin in high fat/sugar diets joint streptozotocin (STZ)-induced DPN rat models. Sprague-Dawley (SD) rats were divided into five groups (6 rats per group), control group, DPN group, Curcumin groups (50, 100, and 150 mg/kg). Curcumin was administered intragastrically once per day for 4 continuous weeks. Body weight (BW) and fasting blood glucose (FBG) were monitored in all groups. The mechanical withdraw threshold (MWT) was measured. We also assessed neuropathic change by testing nerve conductance velocity (NCV) in sciatic nerves. TEM was applied to observe the sciatic nerves ultrastructure. The SCs apoptosis in sciatic nerves was stained using TUNEL kit. NGF contents in sciatic nerves and serum were detected using western blotting and ELISA analysis. The results showed curcumin had no obvious effect on the BW and FBG change. Curcumin (100 and 150 mg/kg) attenuated the MWT, NCV, and sciatic nerves ultrastructure in DPN rats. Curcumin (50, 100 and 150 mg/kg) reduced SCs apoptosis in sciatic nerves. In addition, curcumin at 150 mg/kg had the best efficacy in increasing protein expression of NGF in sciatic nerves and serum NGF level. Our work demonstrated that curcumin has neuroprotective effects for the treatment of DPN.

Disruption of MAP7D1 Gene Function Increases the Risk of Doxorubicin-Induced Cardiomyopathy and Heart Failure.

Doxorubicin is a cornerstone chemotherapeutic drug widely used to treat various cancers; its dose-dependent cardiomyopathy, however, is one of the leading causes of treatment-associated mortality in cancer survivors. Patients' threshold doses leading to doxorubicin-induced cardiomyopathy (DIC) and heart failure are highly variable, mostly due to genetic variations in individuals' genomes. However, genetic susceptibility to DIC remains largely unidentified. Here, we combined a genetic approach in the zebrafish (Danio rerio) animal model with a genome-wide association study (GWAS) in humans to identify genetic susceptibility to DIC and heart failure. We firstly reported the cardiac and skeletal muscle-specific expression and sarcomeric localization of the microtubule-associated protein 7 domain-containing protein 1b (Map7d1b) in zebrafish, followed by expression validation in mice. We then revealed that disruption of the map7d1b gene function exaggerated DIC effects in adult zebrafish. Mechanistically, the exacerbated DIC are likely conveyed by impaired autophagic degradation and elevated protein aggregation. Lastly, we identified 2 MAP7D1 gene variants associated with cardiac functional decline and heart failure in cancer patients who received doxorubicin therapy. Together, this study identifies MAP7D1 as a clinically relevant susceptibility gene to DIC and heart failure, providing useful information to stratify cancer patients with a high risk of incurring severe cardiomyopathy and heart failure after receiving chemotherapy.

SNX29, a new susceptibility gene shared with major mental disorders in Han Chinese population.

OBJECTIVES: Environmental and genetic factors play important roles in the development of schizophrenia (SCZ), bipolar disorder (BPD) or major depressive disorder (MDD). Some risk loci are identified with shared genetic effects on major psychiatric disorders. To investigate whether SNX29 gene played a significant role in these psychiatric disorders in the Han Chinese population. METHODS: We focussed on 11 single-nucleotide polymorphisms (SNPs) harbouring SNX29 gene and carried out case-control studies in patients with SCZ (n = 1248), BPD (n = 1344), or MDD (n = 1056), and 1248 healthy controls (HC) recruited from the Han Chinese population. We constructed weighted gene co-expression network analysis (WGCNA) and extracted significant modules by R package. RESULTS: We found that rs3743592 was significantly associated with MDD and rs6498263 with BPD in both allele and genotype distributions. Before correction, rs3743592 showed allelic and genotypic significance with SCZ, rs6498263 showed allelic significance with SCZ. WGCNA identified top 10 modules of co-expressed genes. Gene Ontology (GO) and pathway analysis were used to examine the functions of SNX29, which revealed that SNX29 was involved in the regulation of a number of biological processes, such as TGF-beta, ErbB, and Wnt signalling pathway, etc. CONCLUSIONS: Our results supported common risk factors in SNX29 might share among these three mental disorders in the Han Chinese population.

Telomere length and type 2 diabetes: Mendelian randomization study and polygenic risk score analysis.

Recent epidemiological studies suggest an association between shorter telomere length and higher risk for type 2 diabetes (T2D). However, results from observational studies are susceptible to confounding and reverse causation, and it is not clear whether there is a causal association between telomere length and T2D. Using Mendelian randomization (MR) and polygenic risk score (PRS) approaches, we had evaluated the causal effect of telomere length on T2D in the Chinese Han population. Using 8 telomere-length associated genetic variants as instrumental variables, an analysis of genetically predicted telomere length and T2D risk was performed in the MR study based on data from a T2D genome-wide association study (GWAS) in 2632 individuals (1318 cases and 1314 controls). We also applied a PRS approach to investigate the causal relationship using Chinese GWAS data. The inverse-variance weighted, MR-Egger regression, simple median, and weighted median methods yielded no evidence of association between genetically predicted longer telomere length and risk of T2D (OR = 0.78, 95% CI: 0.36 ~ 1.68, P = 0.522; OR = 0.23, 95% CI: 0.01 ~ 7.64, P = 0.412; OR = 0.60, 95% CI: 0.28 ~ 1.28, P = 0.185; OR = 0.64, 95% CI: 0.31 ~ 1.33,P = 0.233; respectively). Further, PRS analysis did not produce consistent genetic overlap between telomere length and T2D. Accordingly, this study found no evidence supporting a causal association between telomere length and T2D. Further studies with larger cohorts could yield more reliable results and conclusions.

The YWHAE gene confers risk to major depressive disorder in the male group of Chinese Han population.

Schizophrenia and major depressive disorder are two major psychiatric illnesses that may share specific genetic risk factors to a certain extent. Increasing evidence suggests that the two disorders might be more closely related than previously considered. To investigate whether YWHAE gene plays a significant role in major depressive disorder in Han Chinese population, we recruited 1135 unrelated major depressive disorder patients (485 males, 650 females) and 989 unrelated controls (296 males, 693 females) of Chinese Han origin. Eleven common SNPs were genotyped using TaqMan® technology. In male-group, the allele and genotype frequencies of rs34041110 differed significantly between patients and control (Pallele=0.036486, OR[95%CI]: 1.249442(1.013988-1.539571); Pgenotype=0.045301). Also in this group, allele and genotype frequencies of rs1532976 differed significantly (Pallele=0.013242, OR[95%CI]: 1.302007(1.056501-1.604563); genotype: P=0.039152). Haplotype-analyses showed that, in male-group, positive association with major depressive disorder was found for the A-A-C-G haplotype of rs3752826-rs2131431-rs1873827-rs12452627 (χ2=20.397, P=6.38E-06, OR[95%CI]: 7.442 [2.691-20.583]), its C-A-C-G haplotype (χ2=19.122, P=1.24E-05, OR and 95%CI: 0.402 [0.264-0.612]), its C-C-T-G haplotype (χ2=9.766, P=0.001785, OR[95%CI]: 5.654 [1.664-19.211]). In female-group, positive association was found for the A-A-C-G haplotype of rs3752826-rs2131431-rs1873827-rs12452627 (χ2=78.628, P=7.94E-19, OR[95%CI]: 50.043 [11.087-225.876]), its A-C-T-G haplotype (χ2=38.806, P=4.83E-10, OR[95%CI]: 0.053 [0.015-0.192]), the C-A-C-G haplotype (χ2=18.930, P=1.37E-05, OR[95%CI]: 0.526 [0.392-0.705]), and the C-C-T-G haplotype (χ2=38.668, P=5.18E-10, OR[95%CI]: 6.130 [3.207-11.716]). Our findings support YWHAE being a risk gene for Major Depressive Disorder in the Han Chinese population.

Cell Culture System for Analysis of Genetic Heterogeneity Within Hepatocellular Carcinomas and Response to Pharmacologic Agents.

BACKGROUND & AIMS: No targeted therapies have been found to be effective against hepatocellular carcinoma (HCC), possibly due to the large degree of intratumor heterogeneity. We performed genetic analyses of different regions of HCCs to evaluate levels of intratumor heterogeneity and associate alterations with responses to different pharmacologic agents. METHODS: We obtained samples of HCCs (associated with hepatitis B virus infection) from 10 patients undergoing curative resection, before adjuvant therapy, at hospitals in China. We collected 4-9 spatially distinct samples from each tumor (55 regions total), performed histologic analyses, isolated cancer cells, and carried them low-passage culture. We performed whole-exome sequencing, copy-number analysis, and high-throughput screening of the cultured primary cancer cells. We tested responses of an additional 105 liver cancer cell lines to a fibroblast growth factor receptor (FGFR) 4 inhibitor. RESULTS: We identified a total of 3670 non-silent mutations (3192 missense, 94 splice-site variants, and 222 insertions or deletions) in the tumor samples. We observed considerable intratumor heterogeneity and branched evolution in all 10 tumors; the mean percentage of heterogeneous mutations in each tumor was 39.7% (range, 12.9%-68.5%). We found significant mutation shifts toward C>T and C>G substitutions in branches of phylogenetic trees among samples from each tumor (P < .0001). Of note, 14 of the 26 oncogenic alterations (53.8%) varied among subclones that mapped to different branches. Genetic alterations that can be targeted by existing pharmacologic agents (such as those in FGF19, DDR2, PDGFRA, and TOP1) were identified in intratumor subregions from 4 HCCs and were associated with sensitivity to these agents. However, cells from the remaining subregions, which did not have these alterations, were not sensitive to these drugs. High-throughput screening identified pharmacologic agents to which these cells were sensitive, however. Overexpression of FGF19 correlated with sensitivity of cells to an inhibitor of FGFR 4; this observation was validated in 105 liver cancer cell lines (P = .0024). CONCLUSIONS: By analyzing genetic alterations in different tumor regions of 10 HCCs, we observed extensive intratumor heterogeneity. Our patient-derived cell line-based model, integrating genetic and pharmacologic data from multiregional cancer samples, provides a platform to elucidate how intratumor heterogeneity affects sensitivity to different therapeutic agents.

Common variants predict recurrence after nonfamilial atrial fibrillation ablation in Chinese Han population.

BACKGROUND: Genome-wide association studies (GWAS) have identified several loci associated with atrial fibrillation (AF) and have been reportedly associated with response to catheter ablation for AF in patients of European ancestry; however, associations between susceptibility loci and clinical recurrence of AF after catheter ablation have not been examined in Chinese Han populations. To the personalization of catheter ablation for AF, we examined whether these single nucleotide polymorphisms (SNPs) can predict clinical outcomes after catheter ablation for AF in Chinese Han population. METHODS AND RESULTS: The association between 8 SNPs and AF was studied in 1418 AF patients and 1424 controls by the unconditional logistic regression analysis. The survival analyses were used to compare AT/AF recurrence differences among 438 AF patients, which were classified by the genotype of rs2200733. rs2200733 and rs6590357 were significantly associated with AF in Chinese Han population. In addition, rs2200733 was associated with clinical recurrence of AF after catheter ablation. In Kaplan-Meier survival analysis, the recurrence-free rates for AF with TT and with TC+CC were 35.5% and 61.9%, respectively (P=0.0009). In multivariate Cox regression analysis, rs2200733 was strong independent risk factor for recurrence. CONCLUSION: rs2200733 risk allele at the 4q25 predicted impaired clinical response to catheter ablation for AF in Chinese Han population. Our findings suggested rs2200733 polymorphism may be used as a clinical tool for selection of patients for AF catheter ablation.

Polymorphisms in GCKR, SLC17A1 and SLC22A12 were associated with phenotype gout in Han Chinese males: a case-control study.

BACKGROUND: Gout is a common arthritic disease resulting from elevated serum uric acid (SUA) level. A large meta-analysis including 28,141 individuals identified nine single nucleotide polymorphisms (SNPs) associated with altered SUA level in a Caucasian population. However, raised SUA level alone is not sufficient for the development of gout arthritis and most of these SNPs have not been studied in a Han Chinese population. Here, we performed a case-control association analysis to investigate the relationship between these SUA correlated SNPs and gout arthritis in Han Chinese. METHODS: A total of 622 ascertained gout p9atients and 917 healthy controls were genotyped. Genome-wide significant SNPs, rs12129861, rs780094, rs734553, rs742132, rs1183201, rs12356193, rs17300741 and rs505802 in the previous SUA study, were selected for our analysis. RESULTS: No deviation from the Hardy-Weinberg equilibrium was observed either in the case or control cohorts (corrected p > 0.05). Three SNPs, rs780094 (located in GCKR, corrected p = 1.78E(-4), OR = 0.723), rs1183201 (located in SLC17A1, corrected p = 1.39E(-7), OR = 0.572) and rs505802 (located in SLC22A12, corrected p = 0.007, OR = 0.747), were significantly associated with gout on allelic level independent of potential cofounding traits. While the remaining SNPs were not replicated. We also found significant associations of uric acid concentrations with these three SNPs (rs780094 in GCKR, corrected p = 3.94E(-5); rs1183201 in SLC17A1, corrected p = 0.005; rs505802 in SLC22A12, corrected p = 0.003) and of triglycerides with rs780094 (located in GCKR, corrected p = 2.96E(-4)). Unfortunately, SNP-SNP interactions for these three significant SNPs were not detected (rs780094 vs rs1183201, p = 0.402; rs780094 vs rs505802, p = 0.434; rs1183201 vs rs505802, p = 0.143). CONCLUSIONS: Three SUA correlated SNPs in Caucasian population, rs780094 in GCKR, rs1183201 in SLC17A1 and rs505802 in SLC22A12 were confirmed to be associated with gout arthritis and uric acid concentrations in Han Chinese males. Considering genetic differences among populations and complicated pathogenesis of gout arthritis, more validating tests in independent populations and relevant functional experiments are suggested in future.

Polymorphisms of renin-angiotensin-aldosterone system gene in chinese han patients with nonfamilial atrial fibrillation.

BACKGROUND: Atrial fibrillation(AF) is the most common arrhythmia in the adult population. The activated renin-angiotensin-aldosterone system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation. The aim of this study was to investigate the association between nonfamilial AF and polymorphisms in RAS gene. METHODS: A total of 931 patients with nonfamilial AF, 663 non-AF heart disease patients and 727 healthy subjects were selected. 10 tagSNPs (tSNPs) (ACE gene rs8066114, AGT gene rs7539020, rs3789678, rs2478544, rs11568023, rs2478523, rs4762, rs699 and CYP11B2 rs3802230, rs3097) were chosen and genotyped in our study. Single-locus analysis and haplotype analysis were used in this study. RESULTS: In single-locus analysis, we found rs11568023 and rs3789678 in AGT gene were associated with nonfamilial AF in Chinese Han population. AF risk was associated with rs3789678 between the AF group and control groups. Under dominant model, the significant AF risk was observed in rs3789678 between the AF group and non AF heart control group; And the protective effect was found in rs11568023, compared with the non-AF heart disease control group. In multilocus haplotype analysis, the association between frequencies of the haplotypes and AF risk was showed in AGT gene (rs7539020-rs3789678), compared 'TT' haplotype with the common 'TC' haplotype, adjusted for age, gender, LVEF, LVEDD, LAD and frequency of hypertension and diabetes. The diplotype with 'TC', carrying rs3789678-C-allele, was associated with reduced risk of AF between the AF group and the healthy control group. The diplotype with 'TT' haplotype in the same block, carrying rs3789678-T-allele, was associated with increased risk of AF. CONCLUSIONS: Via a large-scale case-control study, we found that rs3789678 site was potential susceptible locus of AF whereas rs11568023 was protective factor.

Recurrent gain-of-function USP8 mutations in Cushing's disease.

Cushing's disease, also known as adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas (PAs) that cause excess cortisol production, accounts for up to 85% of corticotrophin-dependent Cushing's syndrome cases. However, the genetic alterations in this disease are unclear. Here, we performed whole-exome sequencing of DNA derived from 12 ACTH-secreting PAs and matched blood samples, which revealed three types of somatic mutations in a candidate gene, USP8 (encoding ubiquitin-specific protease 8), exclusively in exon 14 in 8 of 12 ACTH-secreting PAs. We further evaluated somatic USP8 mutations in additional 258 PAs by Sanger sequencing. Targeted sequencing further identified a total of 17 types of USP8 variants in 67 of 108 ACTH-secreting PAs (62.04%). However, none of these mutations was detected in other types of PAs (n = 150). These mutations aggregate within the 14-3-3 binding motif of USP8 and disrupt the interaction between USP8 and 14-3-3 protein, resulting in an elevated capacity to protect EGFR from lysosomal degradation. Accordingly, PAs with mutated USP8 display a higher incidence of EGFR expression, elevated EGFR protein abundance and mRNA expression levels of POMC, which encodes the precursor of ACTH. PAs with mutated USP8 are significantly smaller in size and have higher ACTH production than wild-type PAs. In surgically resected primary USP8-mutated tumor cells, USP8 knockdown or blocking EGFR effectively attenuates ACTH secretion. Taken together, somatic gain-of-function USP8 mutations are common and contribute to ACTH overproduction in Cushing's disease. Inhibition of USP8 or EGFR is promising for treating USP8-mutated corticotrophin adenoma. Our study highlights the potentially functional mutated gene in Cushing's disease and provides insights into the therapeutics of this disease.

Recurrent deletions of ULK4 in schizophrenia: a gene crucial for neuritogenesis and neuronal motility.

Although many pathogenic copy number variations (CNVs) are associated with neuropsychiatric diseases, few of them have been functionally characterised. Here we report multiple schizophrenia cases with CNV abnormalities specific to unc-51-like kinase 4 (ULK4), a serine/threonine kinase gene. Deletions spanning exons 21-34 of ULK4 were present in 4 out of 3391 schizophrenia patients from the International Schizophrenia Consortium, but absent in 3181 controls. Deletions removing exons 33 and 34 of the large splice variant of ULK4 also were enriched in Icelandic schizophrenia and bipolar patients compared with 98,022 controls (P = 0.0007 for schizophrenia plus bipolar disorder). Combining the two cohorts gives a P-value less than 0.0001 for schizophrenia, or for schizophrenia plus bipolar disorder. The expression of ULK4 is neuron-specific and developmentally regulated. ULK4 modulates multiple signalling pathways that include ERK, p38, PKC and JNK, which are involved in stress responses and implicated in schizophrenia. Knockdown of ULK4 disrupts the composition of microtubules and compromises neuritogenesis and cell motility. Targeted Ulk4 deletion causes corpus callosum agenesis in mice. Our findings indicate that ULK4 is a rare susceptibility gene for schizophrenia.

Polymorphisms and haplotypes in the YWHAE gene increase susceptibility to bipolar disorder in Chinese Han population.

BACKGROUND: Schizophrenia and bipolar disorder are 2 major psychiatric illnesses sharing some specific genetic risk factors. Increasing evidence suggests the 2 illnesses might be more closely related than previously considered. OBJECTIVE: To test this hypothesis, we investigated the allele and genotype frequencies of 11 single nucleotide polymorphisms (SNPs) and the haplotypes in these SNPs of the YWHAE gene. METHOD: 1,982 patients were interviewed by 2 independent, experienced psychiatrists. Bipolar disorder diagnoses were made in strict accordance with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria using the Structured Clinical Interview for DSM-IV Axis I Disorders. In 2011, we conducted this genetic association analysis between 11 SNPs in YWHAE and bipolar disorder, involving a male group and a female group. RESULTS: In the analysis of allele and genotype frequencies, the SNP rs1873827 increased susceptibility to bipolar disorder in the male group. The haplotype analysis of CAC in rs3752826, rs2131431, and rs1873827 in the male group (χ2 = 25.744, P = 3.97E-07, OR = 0.478 [95% CI, 0.358-0.639]) and of ACT and CAC in rs3752826, rs2131431, and rs1873827 in the female group (for ACT, χ2 = 30.365, P = 3.67E-08, OR = 0.040 [95% CI, 0.007-0.218]; for CAC, χ2 = 16.874, P = 4.04E-05, OR = 0.597 [95% CI, 0.466-0.765]) showed they are protective factors for bipolar disorder. However, the haplotype analysis of CAT in the male group (χ2 = 19.874, P = 8.39E-06, OR = 2.314 [95% CI, 1.587-3.374]) and of AAC and CAT in the female group (for AAC, χ2 = 38.561, P = 5.47E-10, OR = 7.104 [95% CI, 3.471-14.540]; for CAT, χ2 = 25.497, P = 4.52E-07, OR = 2.076 [95% CI, 1.556-2.770]) showed they are risk factors for bipolar disorder. CONCLUSIONS: Considering the size of our sample, the results suggest that YWHAE does play a major role in bipolar disorder in the Han Chinese population.

ZNF804A and schizophrenia susceptibility in Asian populations.

ZNF804A, a recently identified risk gene for schizophrenia, has been extensively investigated and the principle finding for this locus has been the association with SNP rs1344706 in populations of European ancestries. However, in Asian populations, only a few studies have been conducted for rs1344706 and the results were inconsistent. Here, we studied rs1344706 and schizophrenia susceptibility in multiple Asian case-control samples (10 Chinese and 2 Japanese samples; N = 21,062), and the meta-analyses indicated non-significant association of rs1344706 with schizophrenia (P = 0.26), suggesting the same SNP identified in European samples is not predisposing risk in Asians. Further genotyping and association analyses of a set of SNPs spanning the entire genomic region of ZNF804A (520 kb) identified no association except for SNP rs359895 (P = 7.8 x 10(-5) , N = 5,172), a newly reported risk SNP located in the ZNF804A promoter region with functional implications. This suggests that ZNF804A may also contribute to schizophrenia susceptibility in Asians although the risk SNP is different from that in Europeans, and it was supported by the detected up-regulation of ZNF804A mRNA expression in the blood cells of Chinese schizophrenia patients compared with normal controls (P = 0.004). Additionally, the linkage disequilibrium (LD) structure analyses using data from HapMap indicated distinct LD blocks across ZNF804A between Chinese and Europeans, which may explain the different association patterns between them, and also highlight the compounding difficulty of genetic studies of complex diseases like schizophrenia when studying multiple ethnic populations.

[Current status of studies on genome-wide gene-gene interactions].

Complex diseases have affected human's health throughout the world. Hundreds of studies show that complex diseases are caused by multiple loci. Currently, genome-wide association studies(GWAS) only focus on the single locus that contributes to the susceptibility of a certain disease. However, the interaction between genes could be one of the main factors that lead to complex traits. This fact has initiated scientists to propose some algorithms to detect these interactions, such as the penalized logistic regression model, multifactor dimensionality reduction method, set association analysis method, Bayesian networks analysis method and random forest. However, these algorithms are of high complexity, hypothesis-driven, causing over fitting of data, or not sensible of data at low dimensions. In this paper, we reviewed these algorithms, and then demonstrated a new algorithm based on GPU to provide a powerful strategy to analyze gene-gene interaction in genome-wide association datasets. This algorithm is of low computing complexity, free of hypothesis, not affected by single locus marginal effect, and also of high stability and speed.

[Effects of different fluid resuscitation regimes on lung injury and expression of pulmonary aquaporin 1 and aquaporin 5 in uncontrolled hemorrhagic shock in rats].

OBJECTIVE: To investigate the effects of different fluid resuscitation regimes on lung injury and expression of pulmonary aquaporin 1 (AQP1) and AQP5 in rats with uncontrolled hemorrhagic shock. METHODS: Sixty Sprague-Dawley (SD) rats were randomly assigned to the following five groups: control group (C group), no fluid resuscitation group (NF group), lactated Ringer's solution group (LRS group), 7.5%NaCl group (HS group) and hydroxyethyl starch group (hydroxyethyl starch 130/0.4, HES group). A four-phased uncontrolled hemorrhagic shock model was reproduced. Uncontrolled hemorrhagic shock phase began with blood withdrawal extended over 15 minutes, in which animals were subjected to massive hemorrhage [mean arterial pressure (MAP)=40 mm Hg (1 mm Hg=0.133 kPa)] for 60 minutes and followed by intratracheal lipopolysaccharide 2 mg/kg and continuous bleeding with amputation of the tail. Then, animals were partially resuscitated with LRS of 3 times the volume of shed blood (LRS group), followed by a bolus dose of 4 ml/kg body weight of 7.5%NaCl (HS), or hydroxyethyl starch (a volume equal to that of the shed blood), respectively, during different fluid resuscitation regimes. After that, comprehensive resuscitation phase of 60 minutes began with hemostasis, and transfusion of all the shed blood plus same amount of normal saline. Observation phase was continued for 3.5 hours. At the end the experiment, the lung tissue was sampled to measure wet-to-dry lung weight ratio (W/D), and the expression of AQP1 and AQP5 were determined with immunohistochemistry. The paraffin-embedded lungs were stained with hematoxylin and eosin for pathological analysis. RESULTS: When compared with NF and LRS groups, the lung W/D ratio was significantly decreased, and the shock induced decreased expression of AQP1 and AQP5 in lung tissue were attenuated in HES group, but these beneficial effects were blunted in the HS group. CONCLUSION: Uncontrolled hemorrhagic shock may induce lung injury and pulmonary edema as well as down regulation of the expression of AQP1 and AQP5 in rats. Resuscitation with hypertonic fluids, especially with HES, can reduce lung damage and pulmonary edema in this kind of shock. The cause may be due in part to maintenance of the expression of AQP1 and/or AQP5 in the lung. Pulmonary AQP1 and AQP5 play an important role in fluid transportation.