[Whole view of the immune microenvironment of biliary tract cancer].

Biliary tract cancer is a group of malignancies which originate from biliary epithelium, and adenocarcinoma is the main pathological type. Although surgical resection is the only radical treatment strategy, most biliary tract cancer patients are diagnosed at locally advanced stage or with distant metastasis. Biliary tract cancer is highly resistant to the conventional chemoradiotherapy and the emerging immunotherapy including immune checkpoint inhibitors, owing to the suppressive immune microenvironment. In a whole view, this paper discussed the anti-tumor and tumor-promoting immune responses of the various immune cells and stromal cells in the immune microenvironment of biliary tract cancer, as well as their correlation with prognosis. The understanding of the whole view of immune microenvironment in biliary tract cancer patients could further inform the design of clinical trials of immunotherapy or combination therapy.

[Preliminary study on the expression of MIF in HCC tissues and its relationship with ERK1/2 signaling pathway].

Objective: To investigate the expression of Macrophage migration-inhibitory factors (MIF) in hepatocellular carcinoma (HCC) tissues and its interaction with ERK1/2 signaling pathway, so as to establish a theoretical basis for further studying the molecular mechanism of MIF promoting HCC. Methods: From February 2020 to August 2021, 52 cases of hepatocellular carcinoma (HCC) tissues based on hepatitis B cirrhosis (HBV-LC) and 52 cases of adjacent tissues in Tianjin Medical University Cancer Hospital and 940th Hospital of Joint Logistic Support Force of PLA were collected as the experimental group, including 39 males and 13 females, aged 35-65 years. And 20 cases of normal liver tissue were selected as the control group. Immunohistochemistry was used to detect the expression of MIF, ERK1/2 and p-ERK1/2 proteins in liver tissues of the two groups, and in situ hybridization was used to detect the expression of ERK1/2 nucleic acid in liver tissues of the two groups.HepG2 HCC cells and L-02 normal hepatocytes were co-cultured with different concentrations of rMIF, the expression and phosphorylation levels of ERK1/2 and JNK1 proteins in the two kinds of liver cells were detected by Western-blot, and the expression levels of ERK1/2 nucleic acids in the two kinds of liver cells were detected by RT-PCR. One-way ANOVA was used for measurement data and χ2 test was used for counting data. Results: The expressions of MIF, ERK1/2, p-ERK1/2 and ERK1/2 mRNA were significantly increased in HCC and para-cancer tissues (the expression of MIF in HCC group was 78.8%, and that in adjacent group was 75.0%; ERK1/2 80.8% in HCC group and ERK1/2 71.8% in paracancerous group. The expression of p-ERK1/2 75.0 % in HCC group and 46.2% in paracancerous group were respectively detected. ERK1/2 mRNA was expressed in HCC group 76.9%, ERK1/2 mRNA expression in paracancerous group 78.8%), and the differences were statistically significant compared with normal liver tissues (P<0.05), but there was no significant difference between HCC and para-cancer tissues (P>0.05). The expressions of ERK1/2, p-ERK1/2 and ERK1/2 mRNA in HepG2 HCC cells were significantly increased with the increase of rMIF concentration, and the increase was most obvious when rMIF concentration was 200 ng/ml, and the difference was statistically significant compared with L-02 normal hepatocytes (P<0.05). Conclusion: MIF, ERK1/2 and p-ERK1/2 are highly expressed in HCC tissues and HepG2 HCC cells, suggesting that MIF promotes the occurrence and development of hepatocellular carcinoma through ERK1/2 signaling pathway.

Topical calcineurin inhibitors in the treatment of oral lichen planus: a systematic review and meta-analysis.

BACKGROUND: TCS (topical corticosteroids) are the first-line drug in the treatment of oral lichen planus (OLP). However, the value of topical calcineurin inhibitors (TCI) including tacrolimus, pimecrolimus and ciclosporin for OLP is still controversial. OBJECTIVES: To compare the efficacy and safety of TCI vs. TCS for OLP. METHODS: The authors searched PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science and four Chinese databases from 1950 to May 2018. The randomized controlled trials comparing TCI and TCS for OLP reported at least one of the following outcomes: improvement of clinical signs and/or symptoms, relapse, blood levels of TCI and adverse events. RESULTS: Twenty-one trials involving 965 patients were included in the analysis. For the treatment of OLP (3-8 weeks), TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy. Tacrolimus-TCS resulted in similar outcomes, with relapse at 3 weeks to 6 months. Blood levels of TCI were usually undetectable. In addition, tacrolimus showed a statistically higher incidence of local adverse events than TCS for short-term treatment. A few systemic adverse events occurred in the tacrolimus and ciclosporin groups, but they were not serious. CONCLUSIONS: The evidence for tacrolimus (n = 12), pimecrolimus (n = 3) and ciclosporin (n = 6) demonstrated that treatment with TCI may be an alternative approach when OLP does not respond to the standard protocols. Tacrolimus 0·1% should be the first drug of choice when selecting TCI for short-term treatment in recalcitrant OLP. Further well-designed trials are warranted to evaluate the long-term efficacy and safety of TCI. What's already known about this topic? The main topical drug for oral lichen planus (OLP) is topical corticosteroids (TCS). Patients with OLP who are not responsive to TCS or are at risk of adverse events from TCS need other alternative drugs. Topical calcineurin inhibitors (TCI), including tacrolimus, pimecrolimus and ciclosporin, have become a hot topic in a variety of mucocutaneous immune-mediated diseases. What does this study add? TCI including tacrolimus, pimecrolimus and ciclosporin were similar to TCS in efficacy for the short-term treatment of OLP. The local adverse events of tacrolimus were higher than with TCS. A few systemic adverse events were reported with TCI, but they were all tolerable and not serious. The limited evidence for pimecrolimus (three trials) and ciclosporin (six trials) requires further studies to evaluate the short-term and long-term efficacy and safety of TCI compared with TCS.

Effect of dietary supplements of biotin, intramuscular injections of vitamin B12, or both on postpartum lactation performance in multiparous dairy cows.

The current study was conducted to investigate the effects of dietary supplementation of biotin, intramuscular injections of vitamin B12 (VB12), or both beginning at the prepartum period on feed intake and lactation performance in postpartum dairy cows. Forty-eight dairy cows were allocated into 12 blocks, based on parity and milk yield of the previous lactation cycle, and randomly assigned to 1 of 4 treatments. Supplementation of VB12 (weekly intramuscular injections of 0 or 10 mg) and biotin (dietary supplements of 0 or 30 mg/d) were used in a 2 × 2 factorial arrangement in a randomized complete block design of 12 blocks with repeated measures. The study started at 3 wk before the expected calving date and ended at 8 wk after calving. Feed intake and lactation performance (milk yield and composition) were recorded weekly after calving. Blood variables were measured on d -10, 0, 8, 15, 29, 43, and 57 relative to calving. When VB12 was given, the cows had greater feed intake, better lactation performance and lower body weight loss in the postpartum period compared with animals without injection of VB12. The VB12-injected cows had lower plasma nonesterified fatty acids and ß-hydroxybutyrate concentrations but higher plasma superoxide dismutase activity compared with cows without VB12. Cows fed a biotin supplement had higher milk protein yield (6 and 8 wk) and lactose yield (6-8 wk), compared with animals without biotin. However, under the present experimental conditions, we found no additive effect of a combined supplement of biotin and vitamin B12 on lactation performance of dairy cows.

Short communication: Effects of dietary 5,6-dimethylbenzimidazole supplementation on vitamin B12 supply, lactation performance, and energy balance in dairy cows during the transition period and early lactation.

The current study was conducted to investigate the effects of 5,6-dimethylbenzimidazole (DMB) supplementation to the feed during the transition period and early lactation on the vitamin B12 supply, lactation performance, and energy balance in postpartum cows. Twenty-four prepartum Holstein dairy cows were divided into 12 blocks based on their parity and milk yield at the last lactation and were then randomly allocated to 1 of 2 treatments: a basal diet without DMB (control) or a treatment diet that contained 1.5 g of DMB/d per cow. The study started at wk 3 before the expected calving day and ended at wk 8 postpartum. The feed intake and the lactation performance were measured weekly after calving. Blood parameters were measured on d -10, 0, 8, 15, 29, 43, and 57 relative to the calving day. Body weight was measured on the calving day and on d 57 after calving. The yields of milk, protein, and lactose in cows fed DMB were higher than in the control throughout the whole postpartum stage. On wk 8 postpartum, the vitamin B12 content in the milk and sera was greater in cows fed DMB than in the control. The overall body weight loss from wk 1 to 8 postpartum was less in cows fed DMB than in the control. The plasma content of nonesterified fatty acids and ß-hydroxybutyric acid was significantly lower in cows fed DMB than in the control throughout the whole experimental stage. In conclusion, dietary DMB fed during the transition period and early lactation improved the vitamin B12 supply, milk production, and energy balance of postpartum dairy cows.

[Association between serum lipid level and depression in patients with chronic heart failure].

Objective: To investigate the association between serum lipid level and depression in patients with chronic heart failure (CHF). Methods: A total of 348 patients with CHF from the First department of Cardiology of the people's hospital of Shaanxi province from September 2016 to June 2017 were included.The Hamilton Depression Scale (HAMD) was used to evaluate the degree of depression and some related clinical data were tested.The serum lipid level and depression scores in the patients were analyzed using Pearson correlation analysis, and Logistic regression analysis was used to analyze the confounding factors of depression. Results: There was significant difference in the proportion of depression between normal serum lipid group and dyslipidemia group (P=0.044). Pearson correlation analysis showed that depression score was linearly related to total cholesterol (r=0.326, P<0.001) and low density lipoprotein cholesterol (r=0.354, P<0.001), and Logistic regression analysis showed that after adjusting for age, BMI, triglyceride, low density lipoprotein cholesterol, creatinine, total bilirubin, albumin, B type natriuretic peptide, total cholesterol (OR=3.523, P=0.007) and high density lipoprotein cholesterol (OR=0.205, P=0.041) were associated with depression in CHF patients. Conclusion: Total cholesterol can increase the risk of depression, and high density lipoprotein cholesterol can reduce the risk of depression in CHF patients.

Characterization of miRNAs involved in response to poly(I:C) in porcine airway epithelial cells.

MicroRNAs (miRNA) have been implicated in a variety of pathological conditions including infectious diseases. Knowledge of the miRNAs affected by poly(I:C), a synthetic analog of viral double-stranded RNA, in porcine airway epithelial cells (PAECs) contributes to understanding the mechanisms of swine viral respiratory diseases, which bring enormous economic loss worldwide every year. In this study, we used high throughput sequencing to profile miRNA expression in PAECs treated with poly(I:C) as compared to the untreated control. This approach revealed 23 differentially expressed miRNAs (DEMs), five of which have not been implicated in viral infection before. Nineteen of the 23 miRNAs were down-regulated including members of the miR-17-92 cluster, a well-known polycistronic oncomir and extensively involved in viral infection in humans. Target genes of DEMs, predicted using bioinformatic methods and validated by luciferase reporter analysis on two representative DEMs, were significantly enriched in several pathways including transforming growth factor-ß signaling. A large quantity of sequence variations (isomiRs) were found including a substitution at position 5, which was verified to redirect miRNAs to a new spectrum of targets by luciferase reporter assay together with bioinformatics analysis. Twelve novel porcine miRNAs conserved in other species were identified by homology analysis together with cloning verification. Furthermore, the expression analysis revealed the potential importance of three novel miRNAs in porcine immune response to viruses. Overall, our data contribute to clarifying the mechanisms underlying the host immune response against respiratory viruses in pigs, and enriches the repertoire of porcine miRNAs.

Effects of Supplemental Levels of Saccharomyces cerevisiae Fermentation Product on Lactation Performance in Dairy Cows under Heat Stress.

The objectives of this study were to evaluate the effects of different supplemental levels of Saccharomyces cerevisiae fermentation product (SCFP; Original XP; Diamond V) on lactation performance in Holstein dairy cows under heat stress. Eighty-one multiparous Holstein dairy cows were divided into 27 blocks of 3 cows each based on milk yield (23.6±0.20 kg/d), parity (2.88±0.91) and day in milk (204±46 d). The cows were randomly assigned within blocks to one of three treatments: 0 (control), 120, or 240 g/d of SCFP mixed with 240, 120, or 0 g of corn meal, respectively. The experiment was carried out during the summer season of 2014, starting from 14 July 2014 and lasting for 9 weeks with the first week as adaption period. During the experimental period, average daily temperature-humidity index (measured at 08:00, 14:00, and 20:00) was above 68, indicating that cows were exposed to heat stress throughout the study. Rectal temperatures tended to decrease linearly (p = 0.07) for cows supplemented with SCFP compared to the control cows at 14:30, but were not different at 06:30 (p>0.10). Dry matter intake was not affected by SCFP supplementation (p>0.10). Milk yield increased linearly (p<0.05) with increasing levels of SCFP. Feed efficiency (milk yield/dry matter intake) was highest (p<0.05) for cows fed 240 g/d SCFP. Cows supplemented with SCFP gained (p<0.01) body weight, while cows in the control lost body weight. Net energy balance also increased linearly (p<0.01) with increasing levels of SCFP. Concentrations of milk urea nitrogen (p<0.01) decreased linearly with increasing levels of SCFP, while no difference (p>0.10) was observed among the treatments in conversion of dietary crude protein to milk protein yield. In summary, supplementation of SCFP alleviated the negative effect of heat stress in lactating Holstein dairy cows and allowed cows to maintain higher milk production, feed efficiency and net energy balance. Effects of SCFP were dose-dependent and greater effects were observed from higher doses.

Effects of Replacement of Concentrate Mixture by Broccoli Byproducts on Lactating Performance in Dairy Cows.

The objective of the present study was to determine the effects of feeding pelletized broccoli byproducts (PBB) on milk yield and milk composition in dairy cows. In Trial 1, an in vitro gas test determined the optimal replacement level of PBB in a concentrate mixture in a mixed substrate with Chinese wild ryegrass hay (50:50, w/w) at levels of 0, 10%, 20%, 30%, or 40% (dry matter basis). When the concentrate was replaced by PBB at a level of 20%, no adverse effects were found on the gas volume or its rate constant during ruminal fermentation. In trial 2, 24 lactating cows (days in milk = 170.4±35; milk yield = 30±3 kg/d; body weight = 580 ±13 kg) were divided into 12 blocks based on day in milk and milk yield and randomly allocated to two dietary treatments: a basic diet with or without PBB replacing 20% of the concentrate mixture. The feeding trial lasted for 56 days; the first week allowed for adaptation to the diet. The milk composition was analyzed once a week. No significant difference in milk yield was observed between the two groups (23.5 vs 24.2 kg). A significant increase was found in milk fat content in the PBB group (p<0.05). Inclusion of PBB did not affect milk protein, lactose, total solids or solids-not-fat (p>0.05). These results indicated that PBB could be included in dairy cattle diets at a suitable level to replace concentrate mixture without any adverse effects on dairy performance.

Effects of alfalfa and cereal straw as a forage source on nutrient digestibility and lactation performance in lactating dairy cows.

This study was conducted to investigate the nutrient digestibility and lactation performance when alfalfa was replaced with rice straw or corn stover in the diet of lactating cows. Forty-five multiparous Holstein dairy cows were blocked based on days in milk (164 ± 24.8 d; mean ± standard deviation) and milk yield (29.7 ± 4.7 kg; mean ± standard deviation) and were randomly assigned to 1 of 3 treatments. Diets were isonitrogenous, with a forage-to-concentrate ratio of 45:55 [dry matter (DM) basis] and contained identical concentrate mixtures and 15% corn silage, with different forage sources (on a DM basis): 23% alfalfa hay and 7% Chinese wild rye hay (AH), 30% corn stover (CS), and 30% rice straw (RS). The experiment was conducted over a 14-wk period, with the first 2 wk for adaptation. The DM intake of the cows was not affected by forage source. Yield of milk, milk fat, protein, lactose, and total solids was higher in cows fed diets of AH than diets of RS or CS, with no difference between RS and CS. Contents of milk protein and total solids were higher in AH than in RS, with no difference between CS and AH or RS. Feed efficiency (milk yield/DM intake) was highest for cows fed AH, followed by RS and CS. Cows fed AH excreted more urinary purine derivatives, indicating that the microbial crude protein yield may be higher for the AH diet than for RS and CS, which may be attributed to the higher content of fermentable carbohydrates in AH than in RS and CS. Total-tract apparent digestibilities of all the nutrients were higher in cows fed the AH diet than those fed CS and RS. The concentration of rumen volatile fatty acids was higher in the AH diet than in CS or RS diets, with no difference between CS and RS diets. When the cereal straw was used to replace alfalfa as a main forage source for lactating cows, the shortage of fermented energy may have reduced the rumen microbial protein synthesis, resulting in lower milk protein yield, and lower nutrient digestibility may have restricted milk production.

Differentiation of bacteria cell wall using Raman scattering enhanced by nanoparticle array.

We have fabricated surface-enhanced Raman scattering (SERS) substrates based on arrays of silver nanoparticles grown on porous anodic alumina templates. Using this nanotechnology platform, label-free and high-speed detection of bacteria are achieved. SERS spectra of various bacteria including Staphylococcus Aureus (Gram-positive bacterium), Klebsiella Pneumoniae (Gram-negative bacterium), and Mycobacterium Smegmatis (Mycobacterium) were recorded. The highly reproducible SERS-based technological platform is capable of differentiating different kinds of bacteria by PCA, LDA, clustering analysis, and SVM methods, which provides promising opportunity for biosensing of clinical microbes.

Association of the genes for tumor necrosis factor-α and myelin basic protein with delayed encephalopathy after acute carbon monoxide poisoning.

There is structural damage to myelin and secondary immune injury in the development of delayed encephalopathy after acute carbon monoxide (CO) poisoning (DEACMP). In order to assess the role of genetic factors in this mechanism, we studied the association between tumor necrosis factor-α308 (TNF-α308) and myelin basic protein (MBP) 5'-side tetranucleotide repetitive sequence (TGGA) n gene polymorphism and DEACMP. We selected 109 DEACMP patients from the Han population in the Northern Henan Province as the case group, and 115 patients without delayed encephalopathy (called the acute CO poisoning group or the control group). There were no significant differences in TNF-α308 and MBP 5'-side TGGA n genotype distribution and allele frequency between the DEACMP group and the acute CO poisoning group (all P > 0.05). When the population was stratified by gender, only the MBP 5'-side TGGA n allele frequency was significantly different, and the frequency of allele L in the DEACMP group was significantly higher than that of the acute CO poisoning group in males (χ(2) = 4.089, P = 0.043, odds ratio = 2.103, 95% confidence interval = 1.014-4.363). The results showed that there was association between MBP 5'-side TGGA n gene polymorphism and DEACMP, and that allele L could increase the risk of occurrence in male patients with DEACMP. DEACMP may be the result of interaction of environmental and genetic factors.

Fatty Acid Profiles and Stearoyl-CoA Desaturase Gene Expression in Longissimus dorsi Muscle of Growing Lambs Influenced by Addition of Tea Saponins and Soybean Oil.

This study was conducted to determine the effects of dietary addition of tea saponins (TS) and soybean oil (SO) on fatty acid profile and gene expression of stearoyl-CoA desaturase (SCD) in longissimus dorsi (LD) muscle of growing lambs. Thirty-two Huzhou lambs were assigned to four dietary treatments in a 2×2 factorial arrangement with main effects of TS (0 or 3 g/d) and SO (0 or 30 g/kg of diet DM). The diet without additives was considered as NTNS (no TS or SO). After a feeding trial for 60 d, four lambs of each treatment were slaughtered to collect the samples of LD muscle. Percentage of trans-11 vaccenic acid was enhanced (p<0.05) in muscle of lambs fed TS and SO. The proportion of total conjugated linoleic acid (CLA) was increased (p<0.05) by SO, but decreased (p<0.05) by TS in LD muscle. The percentage of total saturated fatty acids in muscle was decreased (p<0.05) by addition of TS and SO, while addition of SO increased (p<0.05) the percentage of total polyunsaturated fatty acids. The ratio of cis-9, trans-11 CLA to tran-11 vaccenic acid was decreased (p<0.05) by TS, but increased (p<0.05) by SO. The same effects were observed in SCD mRNA expression. From these results it is indicated that including TS and SO in the diet of growing lambs affect the fatty acid profiles of LD muscle and that the proportion of cis-9, trans-11 CLA in the muscle influenced by TS and SO may be related to the SCD gene expression.

Prediction of active ingredients and mechanism of Siwei Jianbu decoction in the treatment of atherosclerosis by network pharmacology.

OBJECTIVE: Siwei Jianbu Decoction (SJD) has been shown to be effective in treating atherosclerosis (AS). However, its mechanism is still unclear. MATERIALS AND METHODS: The active compounds and targets of SJD were identified from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. The target genes of AS were obtained from the Online Mendelian Inheritance in Man (OMIM), GeneCards, DrugBank, and Therapeutic Target (TTD) databases. Interactions between drug and disease targets were analyzed to obtain common targets. Subsequently, "herb-compound-target" and protein-protein interaction (PPI) networks were constructed and analyzed using the Cytoscape software. Thereafter, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed by DAVID online database. Then, the results were visualized by R software. Finally, molecular docking was performed using AutoDockTools and PyMOL software. RESULTS: A total of 61 active compounds and 377 target genes were identified for SJD, as well as 726 target genes for AS. Interactive analyses revealed 126 common genes between SJD and AS. Quercetin, ellagic acid, baicalein, and kaempferol were the 4 key compounds in SJD. Moreover, eight key targets, namely TNF, SRC, RELA, AKT1, STAT3, JUN, MAPK1 and FOS were found. Results from enrichment analysis indicated that the MAPK pathway may play an important role. The analysis of molecular docking revealed that the key compounds formed strong bonds with their corresponding key targets. CONCLUSIONS: These findings indicate that SJD could prevent AS by inhibiting the expression of genes associated with MAPK pathway such as MAPK1, RELA, and FOS.

Optimizing electromagnetic enhancement of flexible nano-imprinted hexagonally patterned surface-enhanced Raman scattering substrates.

The production of inexpensive, large-scale, uniform substrates for surface-enhanced Raman scattering (SERS) is a key to popularize its usage in chemical and biological detection. We demonstrate a flexible nano-imprinted hexagonally patterned SERS-active substrate. Its electromagnetic enhancement factor was optimized by the thickness adjustment of its silver over-coated film. The experimental data show a good correspondence with the theoretical prediction. Such substrate was shown to exhibit high uniformity and reproducibility with a variation of less than 2%, offering a potential of greatly exploiting such substrate in infield biocide monitoring.

Genetic evidence for domestic raccoon dog rabies caused by Arctic-like rabies virus in Inner Mongolia, China.

An outbreak of rabies affected domestic raccoon dogs on an animal farm in Inner Mongolia, China in 2007. A study was conducted to characterize the aetiological agent and clarify the origin of the rabies virus. Brain tissues were obtained from five rabid raccoon dogs. Viral nucleoprotein antigen was detected in the brain tissues and five rabies viruses were isolated from these rabid animals. Phylogenetic analysis of the N and G gene sequences showed that these isolates were closely related to Arctic-like rabies viruses isolated from the far-eastern region of Russia and South Korea, but distinct from the rabies viruses that are widely distributed in endemic areas in China. Epidemiological data suggested that the likely source of infection was from one wild raccoon dog that was captured and placed in the same type of pen used for domestic raccoon dogs.

Molecular ruler based on concurrent measurements of enhanced Raman scattering and fluorescence.

We report a way to assess the separation between a molecule and a metal surface on account of both Raman scattering and fluorescence intensities measured simultaneously. This approach has no need for an accurate quantity of molecules and bears 1 nm resolution. Its distance sensitivity is experimentally demonstrated in the case of dye molecules lying on a gold surface with a polymer spacer layer in between and is compared with theoretical prediction.

Red blood cell transfusion in the treatment and management of anaemia: the search for the elusive transfusion trigger.

Therapeutic red blood cell (RBC) transfusion is widely utilized in the management of anaemia. Critically ill intensive care unit (ICU) patients in particular, as well as medical and haematology-oncology patients, are among the largest groups of users of RBC products. While anaemia is common in these patients, its treatment and management, including appropriate thresholds for RBC transfusion, remain controversial. We review here the function of RBCs in oxygen transport and physiology, with a view to their role in supporting and maintaining systemic tissue oxygenation. Adaptive and physiological compensatory mechanisms in the setting of anaemia are discussed, along with the limits of compensation. Finally, data from clinical studies will be examined in search of evidence for, or against, a clinically relevant transfusion trigger.

Association of haplotypes spanning PDZ-GEF2, LOC728637 and ACSL6 with schizophrenia in Han Chinese.

BACKGROUND: Schizophrenia is a complex genetic disorder caused by multiple genetic and environmental factors. Several lines of linkage and association studies have repeatedly suggested that the chromosome 5q22-33 region is implicated in the aetiology of schizophrenia. However, most of the previous studies on the linkage of 5q22-33 with schizophrenia were from European populations, and it was not well characterised in other populations. METHODS: We analysed eight single nucleotide polymorphisms (SNPs) located in the 5q23.3 region in a cohort of 506 schizophrenia patients and 672 control subjects from south western China. Single marker association, haplotypic association, sex-specific association and molecular evolutionary analysis were performed. RESULTS: Single marker analysis indicated that SNP5 (rs1355095) in LOC728637 is associated with schizophrenia. When males and females were analysed separately, SNP4 (rs31251) in PDZ-GEF2 is associated with schizophrenia in females. Further analysis using haplotypes demonstrated that a haplotype block spanning PDZ-GEF2, LOC728637 and ACSL6 is highly associated with schizophrenia and several haplotypes in this haploblock have about twofold to 10-fold increase in the affected subjects. In addition, molecular evolutionary analysis suggests that PDZ-GEF2 has undergone adaptive evolution due to Darwinian positive selection in the human lineage. CONCLUSION: Our data provide evidence of the association of 5q22-33 with schizophrenia in Han Chinese. This chromosomal region is likely responsible for genetic susceptibility to schizophrenia, supporting previous data from European patients. In addition, our evolutionary analysis is consistent with the hypothesis that genes contributing to schizophrenia are likely under positive selection during human evolution.