Searching across-cohort relatives in 54,092 GWAS samples via encrypted genotype regression.

Explicitly sharing individual level data in genomics studies has many merits comparing to sharing summary statistics, including more strict QCs, common statistical analyses, relative identification and improved statistical power in GWAS, but it is hampered by privacy or ethical constraints. In this study, we developed encG-reg, a regression approach that can detect relatives of various degrees based on encrypted genomic data, which is immune of ethical constraints. The encryption properties of encG-reg are based on the random matrix theory by masking the original genotypic matrix without sacrificing precision of individual-level genotype data. We established a connection between the dimension of a random matrix, which masked genotype matrices, and the required precision of a study for encrypted genotype data. encG-reg has false positive and false negative rates equivalent to sharing original individual level data, and is computationally efficient when searching relatives. We split the UK Biobank into their respective centers, and then encrypted the genotype data. We observed that the relatives estimated using encG-reg was equivalently accurate with the estimation by KING, which is a widely used software but requires original genotype data. In a more complex application, we launched a finely devised multi-center collaboration across 5 research institutes in China, covering 9 cohorts of 54,092 GWAS samples. encG-reg again identified true relatives existing across the cohorts with even different ethnic backgrounds and genotypic qualities. Our study clearly demonstrates that encrypted genomic data can be used for data sharing without loss of information or data sharing barrier.

Genomic analyses of 10,376 individuals in the Westlake BioBank for Chinese (WBBC) pilot project.

We initiate the Westlake BioBank for Chinese (WBBC) pilot project with 4,535 whole-genome sequencing (WGS) individuals and 5,841 high-density genotyping individuals, and identify 81.5 million SNPs and INDELs, of which 38.5% are absent in dbSNP Build 151. We provide a population-specific reference panel and an online imputation server ( https://wbbc.westlake.edu.cn/ ) which could yield substantial improvement of imputation performance in Chinese population, especially for low-frequency and rare variants. By analyzing the singleton density of the WGS data, we find selection signatures in SNX29, DNAH1 and WDR1 genes, and the derived alleles of the alcohol metabolism genes (ADH1A and ADH1B) emerge around 7,000 years ago and tend to be more common from 4,000 years ago in East Asia. Genetic evidence supports the corresponding geographical boundaries of the Qinling-Huaihe Line and Nanling Mountains, which separate the Han Chinese into subgroups, and we reveal that North Han was more homogeneous than South Han.

Starchy vegetable intake in the first trimester is associated with a higher risk of gestational diabetes mellitus: a prospective population-based study.

OBJECTIVE: The purpose of this study was to evaluate the association between starchy vegetable consumption and subgroup consumption in the first trimester and the risk of gestational diabetes mellitus (GDM). METHODS: A prospective study (n = 1444) was conducted in China. Dietary information was assessed by 24-hour dietary recalls for three days and then we calculated the consumption of total starchy vegetable and its subgroups, including (1) potato and (2) other starchy vegetable (pumpkin, lotus root, yam, taro, water chestnut, pea, and cowpea). GDM was diagnosed according to the results of 75-g two-hour oral glucose tolerance test (OGTT) at 24-28 weeks of gestation. A modified log-binomial regression was used to estimate RRs and 95% CIs of GDM risk. RESULTS: Among the 1444 participants in our study, 520 were diagnosed with GDM. The adjusted RRs (95% CIs) for GDM from the lowest to the highest quartiles of total starchy vegetable consumption were 1.00 (reference), 1.29 (1.06, 1.57), 1.13 (0.93, 1.40), and 1.26 (1.02, 1.56), respectively; p for trend = .032. For potato, the RR of GDM risk was 1.32 for the highest potato intake quartile compared with the lowest quartile (95% CI 1.07-1.64, p for trend = .003). In addition, we did not observe an association between other starchy vegetable intakes and GDM risk. CONCLUSIONS: A higher consumption of total starchy vegetables and potatoes in the first trimester is associated with a greater risk of GDM.

Serum epidermal growth factor-like domain 7 serves as a novel diagnostic marker for early hepatocellular carcinoma.

BACKGROUND: Epidermal growth factor-like domain 7 (Egfl7), a recently identified secreted protein, was significantly increased in patients with HCC by our previous studies. However, its efficacy in the diagnosis of early HCC remains unknown. In this study, we therefore evaluate the efficacy of serum Egfl7 for early HCC diagnosis and compare it with alpha-fetoprotein (AFP). METHODS: Serum Egfl7 levels in testing cohort (1081 participants) and validation cohort (476 participants) were measured by a sandwich enzyme-linked immunoassay (ELISA). The cut-off value of Egfl7 was determined by Youden's index and the efficacies of Egfl7 and AFP in diagnosing early HCC were estimated by receiver operating characteristic (ROC). RESULTS: Serum Egfl7 was significantly elevated in patients with early HCC than all non-HCC controls in whatever Testing Cohort or Validation Cohort. In the Testing Cohort, ROC curves showed the optimum cut-off value of Egfl7 was 2610 ng/mL and Egfl7 showed a significantly higher sensitivity than AFP in discriminating early HCC from healthy individuals (77.4% vs. 65.3%, P = 0.0013) but the area under ROC (AUROC) and accuracy of Egfl7 and AFP were similar (0.860 vs. 0.868, P = 0.704; 80.2% vs. 83.8%, P = 0.184). In distinguishing patients with early HCC from patients with chronic liver disease (CLD), the AUROC, sensitivity, specificity and accuracy of Egfl7 were 0.800, 75.2, 71.7 and 73.5%, which were all significantly higher than AFP (0.675, 61.8, 62.0 and 61.9% in order). Egfl7 also showed a significant higher sensitivity and accuracy than AFP (76.6% vs. 64.0%, P = 0.0031; 79.9% vs. 66.1%, P < 0.0001) in differentiating early HCC patients from non-HCC individuals. Additionally, 70.8% of early HCC patients with negative AFP could be diagnosed by Egfl7 and the combined use of Egfl7 and AFP increased the sensitivity to 91.0%. These results were confirmed by a validation cohort. CONCLUSION: Egfl7 is a valuable serum marker in the diagnosis of early HCC and could complement the efficacy of AFP, especially in distinguishing early HCC from CLD and identifying patients with AFP-negative early HCC.

[A Prospective Study of the Relationship Between Dietary Patterns during the Second Trimester of Pregnancy and Gestational Weight Gain].

OBJECTIVE: To study dietary patterns during the second trimester of pregnancy and to investigate the relationship between dietary patterns and gestational weight gain (GWG). METHODS: A prospective cohort study was conducted to select healthy singleton pregnant women at 8-14 weeks of gestation in a maternal and child health care institution in Chengdu city. Food items and quantities were collected at 8-14, 24-28, 32-36 weeks of gestation by using the 3-day 24-hour dietary recall and energy intakes were calculated. Dietary patterns during the second trimester were established by factor analysis and factor scores were calculated. The weight of pregnant women was measured at 8-14, 24-28 weeks of gestation and 1 week before delivery, and the total GWG and the GWG rates in the second and third trimesters were calculated. Multiple linear regression analyses were used to analyze the association between dietary patterns and GWG. RESULTS: A total of 1 004 samples were included. Three dietary patterns were identified: Milk-egg-whole grain pattern, Beverage-dessert pattern and Traditional pattern. The average total GWG was (13.2±4.5) kg. The average weight gain rate was (0.4±0.2) kg/week in the second trimester. The average weight gain rate was (0.5±0.3) kg/week in the third trimester. After adjusting for confounding factors including maternal age, body mass index before pregnancy, dietary energy intake, physical activity, multiple linear regression analysis showed that the factor score of Beverage-dessert pattern was positively associated with the total GWG and the weight gain rate in the third trimester ( ß=0.370, 95% confidence interval ( CI): (0.103, 0.636), P=0.007; ß=0.014, 95% CI: (0.000, 0.027), P=0.049, respectively), and the factor score of Traditional pattern was negatively associated with the total GWG ( ß=-0.285, 95% CI: (-0.555, -0.015), P=0.039). There was no association between the Milk-egg-whole grain pattern and GWG. CONCLUSION: Dietary patterns during the second trimester of pregnancy are associated with GWG. The Beverage-dessert pattern may increase the total GWG and weight gain rate in the third trimester. The traditional pattern may help control the total GWG.

[Associations of Dairy Consumption during Pregnancy and Neonatal Birth Body Mass: a Prospective Study].

OBJECTIVE: To investigate the dairy product intake during pregnancy in Southwest China and to explore its relationship with neonatal birth body mass. METHODS: A prospective study was conducted to select healthy singleton pregnant women at 8-14 weeks of gestation in a maternal and fetal health care institution in Chengdu City. Dairy product consumption during the first, second, third trimester of pregnancy were collected by 24-hour dietary recalls at 8-14 weeks, 24-28 weeks and 32-36 weeks of pregnancy, respectively, and the total milk intake and milk consumption rate were calculated. According to the dietary guidelines for Chinese pregnant women (2016), the recommended amount of milk (300 g/d) was used as the standard to calculate the compliance rate. The respondents were divided into three groups: no dairy consumption group, insufficient dairy consumption group and suitable dairy consumption group. The gestational age at delivery and neonatal birth body mass were collected by the hospital information system. Logistic regression model was used to analyze the association between milk intake during pregnancy and neonatal birth body mass. RESULTS: A total of 962 pregnant women were included. The average milk intake in the first, second and third trimester of pregnancy were 125.0 (0, 236.1) g/d, 208.3 (0, 284.7) g/d and 250.0 (150.0, 416.7) g/d, respectively, with the compliance rates of 12.6%, 33.2% and 48.4%, respectively. The average neonatal birth body mass was (3 225.0±399.8) g. The incidence of small for gestational age (SGA) and large for gestational age (LGA) was 8.3% and 3.9%, respectively. Compared with no dairy consumption group in the second trimester of pregnancy, the risk of SGA was lower in suitable dairy consumption group (odds ratio (OR)=0.786, 95% confidence interval (CI): 0.385-0.976). Compared with no dairy consumption group in the third trimester of pregnancy, the risk of SGA was lower in insufficient dairy consumption group and suitable dairy consumption group (OR=0.672, 95%CI: 0.477-0.821 and OR=0.497, 95%CI: 0.116-0.807, respectively). No association was observed between milk intake in the first trimester and neonatal birth body mass, and milk intake in the second and third trimester of pregnancy was not associated with the risk of LGA. CONCLUSION: Insufficient milk intake of pregnant women is a significant problem in southwest China and needs to be improved. Milk intake during pregnancy is associated with neonatal birth body mass, and increased milk intake in the second and third trimester of pregnancy may reduce the risk of SGA.

Captivity Influences Gut Microbiota in Crocodile Lizards (Shinisaurus crocodilurus).

Captivity is an important measure for conservation of an endangered species, and it is becoming a hot topic in conservation biology, which integrates gut microbiota and endangered species management in captivity. As an ancient reptile, the crocodile lizard (Shinisaurus crocodilurus) is facing extreme danger of extinction, resulting in great significance to species conservation in the reserve. Thus, it is critical to understand the differences in gut microbiota composition between captive and wild populations, as it could provide fundamental information for conservative management of crocodile lizards. Here, fecal samples of crocodile lizards were collected from two wild and one captive populations with different ages (i.e., juveniles and adults) and were analyzed for microbiota composition by 16S ribosomal RNA (rRNA) gene amplicon sequencing. This study showed that the lizard gut microbiota was mainly composed of Firmicutes and Proteobacteria. The gut microbiota composition of crocodile lizard did not differ between juveniles and adults, as well as between two wild populations. Interestingly, captivity increased community richness and influenced community structures of gut microbiota in crocodile lizards, compared with wild congeners. This was indicated by higher abundances of the genera Epulopiscium and Glutamicibacter. These increases might be induced by complex integration of simple food resources or human contact in captivity. The gut microbiota functions of crocodile lizards are primarily enriched in metabolism, environmental information processing, genetic information processing, and cellular processes based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. This study provides fundamental information about the gut microbiota of crocodile lizards in wild and captive populations. In the future, exploring the relationship among diet, gut microbiota, and host health is necessary for providing animal conservation strategies.

Downregulation of castor zinc finger 1 predicts poor prognosis and facilitates hepatocellular carcinoma progression via MAPK/ERK signaling.

BACKGROUND: Castor zinc finger 1 (CASZ1) plays critical roles in various biological processes and pathologic conditions, including cancer. However, the prognostic importance and biologic functions of CASZ1 in hepatocellular carcinoma (HCC) are still unclear. METHODS: qRT-PCR, western blot and immunohistochemistry analyses were used to determine CASZ1 expression in HCC samples and cell lines. The clinical significance of CASZ1 was assessed in two independent study cohorts containing 232 patients with HCC. A series of in vitro and in vivo experiments were performed to explore the role and molecular mechanism of CASZ1 in HCC progression. RESULTS: Here we report that CASZ1 expression was downregulated in HCC tissues and cell lines. Low CASZ1 expression was closely correlated with aggressive clinicopathological features, poor clinical outcomes and early recurrence of HCC patients. Moreover, overexpression of CASZ1 in HCCLM3 cells significantly inhibited cell proliferation, migration, invasion in vitro and tumor growth and metastasis in vivo, whereas silencing CASZ1 significantly enhanced the above abilities of PLC/PRF/5 cells. Further mechanism study indicated that these phenotypic changes were mediated by MAPK/ERK signaling pathway and involved altered expression of MMP2, MMP9 and cyclinD1. Finally, we proved that CASZ1 exerted its tumor-suppressive effect by directly interacting with RAF1 and reducing the protein stability of RAF1. CONCLUSIONS: Our study for the first time demonstrated that CASZ1 is a tumor suppressor in HCC, which may serve as a novel prognostic predictor and therapeutic target for HCC patients.

miR-148a-mediated estrogen-induced cholestasis in intrahepatic cholestasis of pregnancy: Role of PXR/MRP3.

Intrahepatic cholestasis of pregnancy (ICP) is an idiopathic liver disease while the biochemical characteristic is the elevated level of total bile acid (TBA). The present study investigated whether miR-148a mediates the induced effect of estrogen on the development of ICP and the proper mechanism: PXR/MRP3 signal pathway. mRNA expression was detected by qPCR, protein expression was detected by western blotting, the concentration of estrogen and TBA were detected by reagent kit respectively. In the cinical research, it was found that miR-148a expression was positive related with the concentration of TBA in the serum of ICP patients. In in vitro research, estradiol (500 nmol/L, 12 h) significantly upregulated miR-148a expression and LV-148a-siRNA inhibited the function of estradiol (500 nmol/L, 48 h) on TBA secretion. In addition, gene silence of miR-148a upregulated PXR expression which was inhibited by estradiol in LO2 cells. Pretreatment of rifampin (10 µmol/L), the agonist of PXR alleviated the TBA secretion induced by estradiol (500 nmol/L, 48 h). miR-148a-siRNA and PXR had a synergistic action on TBA secretion of LO2. Both of miR-148a-siRNA and rifampin (10 µmol/L) inhibited the upregulated effect of estradiol on MRP3 expression. This research has demonstrated that miR-148a may be involved in the induction of estrogen on ICP via PXR signal pathway, and MRP3 may be involved.

[Appropriate application of statistical methods in physiological research].

OBJECTIVE: To offer a series of efficient methods to physiologists in appropriate selection, and application of statistical techniques. METHODS: We bring about two questions as follows:What's the role of statistics in the process of a physiological research? How to make sure the results produced in a physiological research can be repeatable in practice in the long run. From the answers to these two questions, we highlight the importance of the discipline of statistics to research work, explain why it is difficult, how to choose a suitable statistical method in a specific situation, and offer the critical methods to use statistics accurately and appropriately. RESULTS: We abstract three core sections from the discipline of statistics:how to make the design of a study impeccable; How to strictly follow the protocol of a study, and How to draw conclusions well reasoned and strongly supported by evidence. By elaborating these sections, it is feasible to correctly use statistical methods for data analysis and results interpretation. CONCLUSIONS: In physiological research, conclusion can stand with time and repeatable in practice only when researchers strictly and rigorously follow the rule of scientific research.