Metformin use and risk of ischemic stroke in patients with type 2 diabetes: A cohort study / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between the use of metformin and the risk of ischemic stroke in patients with type 2 diabetes.@*METHODS@#A prospective cohort study was designed from the Fangshan family cohort in Beijing. According to metformin use at baseline, 2 625 patients with type 2 diabetes in Fangshan, Beijing were divided into metformin group or non-metformin group and the incidence of ischemic stroke between the different groups during follow-up was estimated and compared by Cox proportional hazard regression model. The participants with metformin were first compared with all the parti-cipants who did not use metformin, and then were further compared with those who did not use hypoglycemic agents and those who used other hypoglycemic agents.@*RESULTS@#The patients with type 2 diabetes were with an average age of (59.5±8.7) years, and 41.9% of them were male. The median follow-up time was 4.5 years. A total of 84 patients developed ischemic stroke during follow-up, with a crude incidence of 6.4 (95%CI: 5.0-7.7) per 1 000 person-years. Among all the participants, 1 149 (43.8%) took metformin, 1 476 (56.2%) were metformin non-users, including 593 (22.6%) used other hypoglycemic agents, and 883 (33.6%) did not use any hypoglycemic agents. Compared with metformin non-users, the Hazard ratio (HR) for ischemic stroke in metformin users was 0.58 (95%CI: 0.36-0.93; P = 0.024). Compared with other hypoglycemic agents, HR was 0.48 (95%CI: 0.28-0.84; P < 0.01); Compared with the group without hypoglycemic agents, HR was 0.65 (95%CI: 0.37-1.13; P=0.13). The association between metformin and ischemic stroke was statistically significant in the patients ≥ 60 years old compared with all the metformin non-users and those who used other hypoglycemic agents (HR: 0.48, 95%CI: 0.25-0.92; P < 0.05). Metformin use was associated with a lower incidence of ischemic stroke in the patients with good glycemic control (0.32, 95%CI: 0.13-0.77; P < 0.05). In the patients with poor glycemic control, and the association was not statistically significant (HR: 0.97, 95%CI: 0.53-1.79; P>0.05). There was an interaction between glycemic control and metformin use on incidence of ischemic stroke (Pinteraction < 0.05). The results of the sensitivity analysis were consistent with the results in the main analysis.@*CONCLUSION@#Among patients with type 2 diabetic in rural areas of northern China, metformin use was associated with lower incidence of ischemic stroke, especially in patients older than 60 years. There was an interaction between glycemic control and metformin use in the incidence of ischemic stroke.

Genotype-environment interaction on arterial stiffness: A pedigree-based study / 北京大学学报(医学版)

OBJECTIVE@#To utilized the baseline data of the Beijing Fangshan Family Cohort Study, and to estimate whether the association between a healthy lifestyle and arterial stiffness might be modified by genetic effects.@*METHODS@#Probands and their relatives from 9 rural areas in Fangshan district, Beijing were included in this study. We developed a healthy lifestyle score based on five lifestyle behaviors: smoking, alcohol consumption, body mass index (BMI), dietary pattern, and physical activity. The measurements of arterial stiffness were brachial-ankle pulse wave velocity (baPWV) and ankle-brachial index (ABI). A variance component model was used to determine the heritability of arterial stiffness. Genotype-environment interaction effects were performed by the maximum likelihood methods. Subsequently, 45 candidate single nucleotide polymorphisms (SNPs) located in the glycolipid metabolism pathway were selected, and generalized estimated equations were used to assess the gene-environment interaction effects between particular genetic loci and healthy lifestyles.@*RESULTS@#A total of 6 302 study subjects across 3 225 pedigrees were enrolled in this study, with a mean age of 56.9 years and 45.1% male. Heritability of baPWV and ABI was 0.360 (95%CI: 0.302-0.418) and 0.243 (95%CI: 0.175-0.311), respectively. Significant genotype-healthy diet interaction on baPWV and genotype-BMI interaction on ABI were observed. Following the findings of genotype-environment interaction analysis, we further identified two SNPs located in ADAMTS9-AS2 and CDH13 might modify the association between healthy dietary pattern and arterial stiffness, indicating that adherence to a healthy dietary pattern might attenuate the genetic risk on arterial stiffness. Three SNPs in CDKAL1, ATP8B2 and SLC30A8 were shown to interact with BMI, implying that maintaining BMI within a healthy range might decrease the genetic risk of arterial stiffness.@*CONCLUSION@#The current study discovered that genotype-healthy dietary pattern and genotype-BMI interactions might affect the risk of arterial stiffness. Furthermore, we identified five genetic loci that might modify the relationship between healthy dietary pattern and BMI with arterial stiffness. Our findings suggested that a healthy lifestyle may reduce the genetic risk of arterial stiffness. This study has laid the groundwork for future research exploring mechanisms of arterial stiffness.

Interaction between ischemic stroke risk loci identified by genome-wide association studies and sleep habits / 北京大学学报(医学版)

OBJECTIVE@#To explore the relationship between sleep habits (sleep duration, sleep efficiency, sleep onset timing) and ischemic stroke, and whether there is an interaction between sleep habits and ischemic stroke susceptibility gene loci.@*METHODS@#A questionnaire survey, physical examination, blood biochemical testing and genotyping were conducted among rural residents in Beijing, and the gene loci of ischemic stroke suggested by previous genome-wide association studies (GWAS) were screened. Multivariable generalized linear model was used to analyze the correlation between sleep habits, sleep-gene interaction and ischemic stroke.@*RESULTS@#A total of 4 648 subjects with an average age of (58.5±8.7) years were enrolled, including 1 316 patients with ischemic stroke. Compared with non-stroke patients, stroke patients with sleep duration ≥9 hours, sleep efficiency < 80%, and sleep onset timing earlier than 22:00 accounted for a higher proportion (P < 0.05). There was no significant association between sleep duration and risk of ischemic stroke (OR=1.04, 95%CI: 0.99-1.10, P=0.085). Sleep efficiency was inversely associated with the risk of ischemic stroke (OR=0.18, 95%CI: 0.06-0.53, P=0.002). The risk of ischemic stroke in the subjects with sleep efficiency < 80% was 1.47-fold (95%CI: 1.03-2.10, P=0.033) of that in the subjects with sleep efficiency ≥80%. Falling asleep earlier than 22:00 was associated with 1.26 times greater risk of stroke than falling asleep between 22:00 and 22:59 (95%CI: 1.04-1.52, P=0.017). Multifactorial adjustment model showed that rs579459 on ABO gene had an interaction with sleep time (P for interaction =0.040). When there were two T alleles for rs579459 on the ABO gene, those who fell asleep before 22:00 had 1.56 times (95%CI: 1.20-2.04, P=0.001) the risk of stroke compared with those who fell asleep between 22:00 and 22:59, and there was no significant difference when the number of pathogenic alleles was 0 or 1. In the model adjusted only for gender, age and family structure, sleep duration and the number of T allele rs2634074 on PITX2 gene had an interaction with ischemic stroke (P for interaction=0.033).@*CONCLUSION@#Decreased sleep efficiency is associated with increased risk of ischemic stroke, and falling asleep earlier than 22:00 is associated with higher risk of ischemic stroke. Sleep onset timing interacted with rs579459 in ABO gene and the risk of ischemic stroke. Sleep duration and PITX2 rs2634074 may have a potential interaction with ischemic stroke risk.

Exploring the association between de novo mutations and non-syndromic cleft lip with or without palate based on whole exome sequencing of case-parent trios / 北京大学学报(医学版)

OBJECTIVE@#To explore the association between de novo mutations (DNM) and non-syndromic cleft lip with or without palate (NSCL/P) using case-parent trio design.@*METHODS@#Whole-exome sequencing was conducted for twenty-two NSCL/P trios and Genome Analysis ToolKit (GATK) was used to identify DNM by comparing the alleles of the cases and their parents. Information of predictable functions was annotated to the locus with SnpEff. Enrichment analysis for DNM was conducted to test the difference between the actual number and the expected number of DNM, and to explore whether there were genes with more DNM than expected. NSCL/P-related genes indicated by previous studies with solid evidence were selected by literature reviewing. Protein-protein interactions analysis was conducted among the genes with protein-altering DNM and NSCL/P-related genes. R package "denovolyzeR" was used for the enrichment analysis (Bonferroni correction: P=0.05/n, n is the number of genes in the whole genome range). Protein-protein interactions among genes with DNM and genes with solid evidence on the risk factors of NSCL/P were predicted depending on the information provided by STRING database.@*RESULTS@#A total of 339 908 SNPs were qualified for the subsequent analysis after quality control. The number of high confident DNM identified by GATK was 345. Among those DNM, forty-four DNM were missense mutations, one DNM was nonsense mutation, two DNM were splicing site mutations, twenty DNM were synonymous mutations and others were located in intron or intergenic regions. The results of enrichment analysis showed that the number of protein-altering DNM on the exome regions was larger than expected (P < 0.05), and five genes (KRTCAP2, HMCN2, ANKRD36C, ADGRL2 and DIPK2A) had more DNM than expected (P < 0.05/(2×19 618)). Protein-protein interaction analysis was conducted among forty-six genes with protein-altering DNM and thirteen genes associated with NSCL/P selected by literature reviewing. Six pairs of interactions occurred between the genes with DNM and known NSCL/P-related genes. The score measuring the confidence level of the predicted interaction between RGPD4 and SUMO1 was 0.868, which was higher than the scores for other pairs of genes.@*CONCLUSION@#Our study provided novel insights into the development of NSCL/P and demonstrated that functional analyses of genes carrying DNM were warranted to understand the genetic architecture of complex diseases.

Association of obesity and brachial-ankle pulse wave velocity among type 2 diabetes patients / 中华疾病控制杂志

Objective The aim of this study was to investigate associations of overall obesity (OO) and abdominal obesity (AO) with brachial-ankle pulse wave velocity (baPWV) among type 2 diabetes(T2DM) patients. Methods A community-based study for T2DM patients was conducted in rural communities in Beijing．Every patient completed a questionnaire to collect demography, lifestyle and diseases history, and underwent physical examinations, baPWV assessments and blood biochemical tests. Multivariate linear regression was used to assess the relationship between obesity index and baPWV. Abnormal baPWV was defined as patients with baPWV≥1,700 cm/s. Logistic regression model was performed to explore the risk of abnormal baPWV after adjusting for poetential confounders step by step. Results A total of 2 048 T2DM patients were recruited. The average age was (59.2±8.3) years and total prevalence of abnormal baPWV was 49.7%. After multivariable adjustment, linear regression showed that there was a negative correlation between body mass index(BMI) and baPWV and a positive correlation between waist-to-hip ratio (WHR) and baPWV. Compared to normal weight group, those with BMI≥28 kg/m2 had lower risk of abnormal baPWV (OR=0.59, 95% CI: 0.44-0.78，P<0.001), but there was an increased risk of 46% among patients with obesity in WHR (OR=1.46, 95% CI:1.07-2.00，P=0.018). Compared to those without OO and AO, patients without OO but with AO had a 1.67-fold increasesd risk of abnormal baPWV (OR=1.67, 95% CI: 1.19-2.35，P=0.003). Conclusions Abdominal obesity is related with arterial stiffnening among T2DM patients, and it is critical to evaluate arterial stiffness of T2DM patients with abdmonal obesity and normal BMI in order to reduce future risk of cardiovascular diseases.

Associations between sleep duration and different ischemic stroke subtypes / 中华疾病控制杂志

Objective To explore the relationship between sleep duration and different ischemic stroke (IS) subtypes. Methods Participants in the study were recruited from rural communities in Beijing. The survey questionnaires, physical examination and biochemical tests were performed. Sleep duration was categorized into 5 groups, namely ≤5 hours/day, 6 hours/day (5.5-6.5 h/d), 7 hours/day (6.5-7.5 h/d), 8 hours/day (7.5-8.5 h/d) and ≥9 hours/day(≥8.5 h/d). Classification of ischemic stroke was based on Trial of org 10172 in acute stroke treatment(TOAST)classification. Logistic models were used to evaluate the associations between sleep duration and different IS subtypes. Results A total of 6 370 participants were recruited. The average age was (58.34±9.37) years old. Logistic regression analysis showed that after adjusting for age, sex, behavioral lifestyle, socioeconomic status and health status, compared to subjects with 7 hours/day, subjects with sleep duration ≤5 hours/day was significantly associated with increased risk of IS (OR=1.75, 95% CI: 1.42-2.15, P<0.001), large-artery atherosclerosis (OR=1.98, 95% CI:1.46-2.70, P<0.001), small-artery occlusion lacunar (OR=5.73, 95% CI:3.34-9.83, P<0.001) and stroke of undetermined etiology (OR=4.43, 95% CI:1.86-10.53, P=0.001). Subjects with sleep duration 8 hours/day and ≥9 hours/day was only found to be significantly associated with IS and large-artery atherosclerosis (P<0.05). Conclusions Short sleep duration is associated with increased risk of IS, large-artery atherosclerosis, small-artery occlusion lacunar and stroke of undetermined etiology. But long sleep duration is only associated with increased risk of IS and large-artery atherosclerosis.

CDH13 Genetic Polymorphisms, Adiponectin and Ischemic Stroke: a Chinese Family-based Sib-pair Study / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To understand the relationships between CDH13 (T-cadherin) genetic polymorphisms, adiponectin levels and ischemic stroke, and possible interactions between CDH13 polymorphisms and other risk factors.</p><p><b>METHODS</b>We recruited 342 Chinese ischemic stroke sib pairs. We genotyped rs4783244 and rs7193788 on CDH13 using time-of-flight mass spectrometry genotyping technology and measured total and high-molecular weight (HMW) adiponectin levels. We investigated associations between SNPs and ischemic stroke, and interactions between SNPs and other risk factors using multi-level mixed-effects regression model.</p><p><b>RESULTS</b>In individuals without ischemic stroke, CDH13 rs4783244 was associated with total adiponectin levels (per T: Coef = -0.257, P = 0.001). CDH13 rs7193788 was associated with total adiponectin levels (per A: Coef = -0.221, P = 0.001) and HMW adiponectin levels (per A: Coef = -0.163, P = 0.003). rs7193788 was significantly associated with ischemic stroke (GA/AA vs. GG: OR = 1.55, 95% CI: 1.07 to 2.24, P = 0.020) after Bonferroni correction (α = 0.025). There was an interaction between rs7193788 and diabetes (P = 0.036). Compared to diabetes-free individuals with rs7193788 GG genotype, diabetes patients with rs7193788 GA/AA genotypes had higher risks for ischemic stroke (OR = 2.64, 95% CI: 1.58-4.40, P < 0.001).</p><p><b>CONCLUSION</b>CDH13 genetic polymorphisms are associated with adiponectin levels and ischemic stroke. An interaction is found between CDH13 SNP and diabetes for ischemic stroke.</p>

Profile and Correlates of Health-related Quality of Life in Chinese Patients with Coronary Heart Disease / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Although coronary heart disease (CHD) is one of the major cardiovascular diseases, risk factors associated with the health-related quality of life (HRQoL) of CHD patients remain unclear. The present study was designed to determine the profile and significant factors of the HRQoL in CHD patients.</p><p><b>METHODS</b>A cross-sectional study was conducted in rural communities of Fangshan District, Beijing, China. Socio-demographic, lifestyle, and comorbidity information of CHD patients were collected by a structured questionnaire and medical records. HRQoL was measured using European Quality of Life 5-dimensions (EQ-5D) scale and EQ Visual Analog Scale (EQ-VAS). Multiple linear and logistic regressions were performed to explore the association of potential risk factors with HRQoL scores and each EQ-5D, respectively.</p><p><b>RESULTS</b>Totally, 1928 CHD patients (mean age 61.64 ± 9.24 years; female:male = 2.4:1) were enrolled in the study. The mean score of EQ-5D index and EQ-VAS were 0.889 ± 0.172 and 71.56 ± 17.65, respectively. Multiple linear regression revealed that marital status, physical activity, moderate alcohol drinking, and family's population were positive independent correlates of EQ-VAS, whereas diabetes mellitus and stroke were negative independent correlates (all P < 0.05). Age and stroke were negatively while physical activity, moderate alcohol drinking, family's population and household income were positively correlated with EQ-5D index (all P < 0.05) independently. In addition, each of the five HRQoL dimensions had various specific determinants, including obesity, underweight, smoking or education.</p><p><b>CONCLUSIONS</b>Findings of the study highlight certain socio-demographic, lifestyle factors, and comorbid stroke or diabetes mellitus as correlates of HRQoL in Chinese CHD patients. Large-scale cohort studies should be carried out to confirm our results in the future.</p>

Risk Factors for Anxiety in Major Depressive Disorder Patients

OBJECTIVE: To analyze the sociodemographic and clinical factors related to anxiety in patients with major depressive disorder (MDD). METHODS: This study involved a secondary analysis of data obtained from the Diagnostic Assessment Service for People with Bipolar Disorders in China (DASP), which was initiated by the Chinese Society of Psychiatry (CSP) and conducted from September 1, 2010 to February 28, 2011. Based on the presence or absence of anxiety-related characteristics, 1,178 MDD patients were classified as suffering from anxious depression (n=915) or non-anxious depression (n=263), respectively. RESULTS: Compared with the non-anxious group, the anxious-depression group had an older age at onset (t=-4.39, p<0.001), were older (t=-4.69, p<0.001), reported more lifetime depressive episodes (z=-3.24, p=0.001), were more likely to experience seasonal depressive episodes (chi2=6.896, p=0.009) and depressive episodes following stressful life events (chi2=59.350, p<0.001), and were more likely to have a family history of psychiatric disorders (chi2=6.091, p=0.014). Their positive and total scores on the Mood Disorder Questionnaire (MDQ) and the 32-item Hypomania Checklist (HCL-32) (p<0.05) were also lower. The logistic regression analysis indicated that age (odds ratio [OR]=1.03, p<0.001), a lower total MDQ score (OR=0.94, p=0.011), depressive episodes following stressful life events (OR=3.04, p<0.001), and seasonal depressive episodes (OR=1.75, p=0.039) were significantly associated with anxious depression. CONCLUSION: These findings indicate that older age, fewer subclinical bipolar features, an increased number of depressive episodes following stressful life events, and seasonal depressive episodes may be risk factors for anxiety-related characteristics in patients with MDD.

The impact of lipid-metabolizing genetic polymorphisms on body mass index and their interactions with soybean food intake: a study in a Chinese population / 生物医学与环境科学（英文）

<p><b>OBJECTIVE</b>To evaluate the association of known polymorphisms in the lipid metabolic pathway with body mass index (BMI), and estimate their interactions with soybean food intake.</p><p><b>METHODS</b>A community-based cross-sectional survey was conducted in a Chinese Han population. BMI, soybean food intake, and single nucleotide polymorphisms of rs599839, rs3846662, rs3846663, rs12916, rs174547, rs174570, rs4938303, and rs1558861 were measured in 944 subjects. A multivariate logistic regression was used to analyze the association of the studied polymorphisms with BMIs. The expectation-maximization algorithm was employed to evaluate the extent of linkage disequilibrium between pairwise polymorphisms. The gene-environment interaction was assessed in the general multifactor dimensionality reduction model.</p><p><b>RESULTS</b>The polymorphisms of rs3846662 and rs3846663 were associated with 10% highest BMIs when comparing to the 10% lowest values both in individuals and haplotype-based association tests. Although no statistically significant gene-environment interactions were found, people with the haplotype composed of C allele in rs3846662 and T allele in rs3846663 and low frequency of soybean intake had significantly higher risk to overweight and obesity as compared with those with the haplotype consisting of T allele in rs3846662 and C allele in rs3846663 and highly frequent soybean food intake, with an odds ratio of 1.64 (95% confidence interval: 1.15-2.34, P<0.01) after adjusting for the common confounders.</p><p><b>CONCLUSION</b>Our study has suggested that rs3846662 and rs3846663 may be the potential candidate polymorphisms for obesity, and their effect on the pathogenesis could be mediated by the frequency of soybean food intake.</p>

Adhesional inhibiton of polyclonal anti-porin I antibody / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the blockness effects of purified polyclonal anti-porin I antibody on N. gonorrhoeae adherence to genitourinary tract epithelia of BALB/c mouse.</p><p><b>METHODS</b>Polyclonal anti GST-PI antibody was generated by immunizing rabbit with GST-PI fusion protein which was constructed and expressed by ourselves. The purified immunoglobulin G was obtained by ammonium sulphate deposition and DEAE cellulose chromatography. Mice model of gonorrhea was established. In order to evaluate the effects of PI-IgG on gonococcus adhesion to vagina mucus, the macroscopic and pathological assessing as well as gonococcus culture was employed after gonococcus challenge on PI-IgG immunized mice.</p><p><b>RESULT</b>No pus and pathological inflammation were observed on mice vagina mucus treated with 1 mg/ml PI-IgG 3 hours before gonococcus challenge. Gonococcus could not be detected in the smears and washing solutions from vagina. Pathological inflammation was found in mice treated with anti PI-IgG, in which the concentrations were lower than 1 mg/ml or the treated time was longer than 3 hours prior to gonococcus challenge.</p><p><b>CONCLUSION</b>The purified anti PI-IgG can effectively inhibit the adherence and infection of gonococci to genitourinary tract epithelia of BALB/c mice. In addition, the blocking duration of anti PI-IgG is associated with antibody concentration.</p>

Identification of gene-gene interactions related to the etiology of complex disease: a multifactor dimensionality reduction-genotype pedigree disequilibrium test / 中华流行病学杂志

<p><b>UNLABELLED</b>To introduce the application of a multifactor dimensionality reduction-genotype pedigree disequilibrium test (MDR-PDT) for detecting gene-gene interactions in the etiology of complex disease. A brief overview on the basic theory, implementing steps and features of MDR-PDT were described, and a practical research case was demonstrated to application of MDR-PDT in nuclear family studies. The MDR-PDT approach was the extension or development of conventional MDR method which could be used for detecting gene-gene interactions in families of diverse structure.</p><p><b>CONCLUSION</b>MDR-PDT was a new nonparametric and model-free method which might use additional family members in the nuclear families and had a good power to identify gene-gene interactions.</p>

Effects of lower fluence pulsed dye laser irradiation on production of collagen and the mRNA expression of collagen relative gene in cultured fibroblasts in vitro / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Lower fluence of 585-nm flashlamp-pumped pulsed dye laser has been successfully used as a nonablative technique in the treatment of wrinkles. The objective of this study was to evaluate the effect of the pulsed dye laser (585 nm) on the production of collagen and the mRNA expression of collagen related gene in fibroblasts in vitro.</p><p><b>METHODS</b>Cultured fibroblasts were treated with a 585-nm flashlamp-pumped pulsed dye laser (fluence 3 J/cm(2), 4 J/cm(2), spot size 7 mm, pulse duration 450 micros). The production of collagen and the mRNA expression of transforming growth factor (TGF)-beta1, SMAD2, SMAD3, SMAD4, SMAD7 and type I procollagen alpha1, alpha2 in fibroblasts were investigated by colorimetry or real time polymerase chain reaction.</p><p><b>RESULTS</b>The production of collagen was significantly up-regulated after treatment with a 585-nm flashlamp-pumped pulsed dye laser with a fluence of 3 J/cm(2) (P < 0.001). The mRNA expression of TGF-beta1, SMAD2, SMAD3, SMAD4, SMAD7 and procollagen I was significantly up-regulated after treatment with a 585-nm flashlamp-pumped pulsed dye laser with a fluence of 3 J/cm(2) (P < 0.001). No significant difference of mRNA expression of SMAD2, SMAD3, SMAD4, SMAD7 and type I procollagen was found between controls and fibroblasts treated with pulsed dye laser with a fluence of 4 J/cm(2) (P > 0.05).</p><p><b>CONCLUSIONS</b>Lower fluence (3 J/cm(2)) pulsed dye laser increased the collagen production in fibroblasts by up-regulating TGF-beta1, SMAD2, SMAD3, SMAD4, SMAD7 and type I procollagen mRNA expression. These may be the reason it can be effectively used in the treatment of wrinkles.</p>