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.

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.

Incidence and risk factors of ischemic stroke in patients with type 2 diabetes among urban workers in Beijing, China / 北京大学学报(医学版)

OBJECTIVE@#To explore the incidence of ischemic stroke after the onset of type 2 diabetes, and further analyze the risk factors, so as to provide a basis for further research.@*METHODS@#The data were obtained from the database of the Beijing Urban Employee Basic Medical Insurance Database. The study used a prospective design to describe the incidence of ischemic stroke in patients with type 2 diabetes. In our study, these patients were followed up for seven years. Multivariate Logistic regression models were used to analyze the risk factors of ischemic stroke in patients with type 2 diabetes.@*RESULTS@#A total of 185 813 newly diagnosed type 2 diabetes patients were enrolled, with an average age of (58.5±13.2) years, and 49.0% of them were males. A total of 10 393 patients with newly diagnosed ischemic stroke occurred in 7 years, with a cumulative incidence of 5.6% and an incidence density of 8.1/1 000 person-years. Ischemic stroke occurred in all age groups in patients with type 2 diabetes. The cumulative incidence was 1.5% (95%CI: 1.3%-1.6%) in group ≤44 years old, 3.6% (95%CI: 3.4%-3.7%) in group 45-54 years old, 5.4% (95%CI: 5.2%-5.5%) in group 55-64 years old, and 9.2% (95%CI: 9.0%-9.4%) in group ≥65 years old, and the cumulative incidence increased with age (P < 0.05). Cumulative incidence rate of the males (6.8%, 95%CI: 6.7%-7.0%) was higher than the females (4.4%, 95%CI: 4.3%-4.6%). Among the patients < 80 years old, the cumulative incidence rate of the males was higher than that of the females in all the age groups. In the patients ≥80 years of age, the cumulative incidence was higher in the females (9.2%) than in the males (7.9%). Further analysis revealed that complications, such as coronary heart disease (OR=3.18, 95%CI: 2.72-3.72), heart failure (OR=1.53, 95%CI: 1.32-1.79) and kidney failure (OR=1.45, 95%CI: 1.20-1.75) were associated with ischemic stroke in the patients with type 2 diabetes.@*CONCLUSION@#The incidence level of ischemic stroke in patients with type 2 diabetes is high. It is necessary to strengthen the management of risk factors in elderly patients, screen the complications of type 2 diabetes as early as possible, and take active preventive and control measures.

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>

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>

Clinical observation of physiological and psychological reactions to electric stimulation of the amygdaloid nucleus and the nucleus accumbens in heroin addicts after detoxification / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Stereotactic surgery has been used to treat heroin abstinence in China since 2000 by ablating the amygdaloid nucleus (AMY) and the nucleus accumbens (NAc), which also provides opportunity to identify the relationship between these nuclei and addiction. Our study aimed to explore the physiological and psychological effects of electrically stimulating the AMY and the NAc in heroin addicts after detoxification by observing changes of heart rate, arterial pressure and occurrence of euphoria similar to heroin induced euphoria.</p><p><b>METHODS</b>A total of 70 heroin addicts after detoxification were recruited, and 61 of them were eligible to be given stereotactic surgery for heroin abstinence. The operation was carried out after determining the coordinates of all target nucleuses, and stimulation was performed at the AMY and the NAc solely or jointly. Heart rate, arterial pressure and occurrence of euphoria similar to heroin induced euphoria were recorded and analyzed.</p><p><b>RESULTS</b>The average heat rate was (66 ± 10) beats/min before electric stimulation, and significantly increased to (84 ± 14) beats/min during stimulation, and changed to (73 ± 12) beats/min 10 minutes after stimulation. There was a significant elevation of the average arterial pressure from 83 mmHg before stimulation to 98 mmHg during the stimulation, and it then decreased to 90 mmHg after stimulation. Forty-three of the 61 patients showed intense euphoria similar to heroin induced euphoria. The largest number (118/186) of euphoric responses occurred when the AMY and the NAc were stimulated at the same time. Odds ratio was 5.4 (95%CI: 2.4 - 11.9, P < 0.0001) to quantify the association. Results from a Logistic regression model showed a positive correlation between unilateral stimulation of either the AMY or NAC and induction of euphoria (OR > 1), especially when the left AMY or left NAc was stimulated (P < 0.05).</p><p><b>CONCLUSIONS</b>Our data are consistent with existing results that the AMY and the NAc are related to addiction. Different roles in drug dependence would be suggested according to the location of the AMY and NAc.</p>

A community-based epidemiologic study on gastroesophageal reflux disease in Haidian district of Beijing / 中华预防医学杂志

<p><b>OBJECTIVE</b>To explore the prevalence of gastroesophageal reflux disease (GERD) and its symptoms in Haidian district of Beijing, identify its associated risk factors and analyze the relations between GERD and history of other diseases.</p><p><b>METHODS</b>2615 residents of 18-80 years old were selected to participate in the study by multi-stage sampling from Haidian district from June and September in 2008. Questionnaires were distributed to obtain the information on demographic characteristics, diseases history and the reflux disease questionnaire (RDQ).</p><p><b>RESULTS</b>The prevalence of GERD in the population was 8.4% (220/2615), and the prevalence of heartburn, reflux, both heartburn and reflux were 1.0% (25/2615), 6.2% (163/2615) and 1.2% (32/2615), respectively. Multi-factor analysis showed rural area (OR = 2.237, 95%CI: 1.422 - 3.517), female (OR = 1.456, 95%CI: 1.085 - 1.955), high education (OR = 1.242, 95%CI: 1.001 - 1.542), pressure (OR = 1.277, 95%CI: 1.089 - 1.497), bad emotional status (OR = 1.320, 95%CI: 1.046 - 1.665), and family history of gastrointestinal disorders (OR = 1.594, 95%CI: 1.075 - 2.365) were significantly associated with GERD. Rural area (OR = 2.481, 95%CI: 1.278 - 4.818), female (OR = 1.747, 95%CI: 0.902 - 3.386), drinking (OR = 1.838, 95%CI: 0.916 - 3.690), no exercise (OR = 2.091; 95%CI: 1.131 - 3.867) and bad emotional status (OR = 1.657, 95%CI: 1.123 - 2.446) were significant risk factors for heartburn. Rural area (OR = 2.171, 95%CI: 1.326 - 3.556), female (OR = 1.505, 95%CI: 1.102 - 2.056), high education (OR = 1.347, 95%CI: 1.063 - 1.706), pressure (OR = 1.317, 95%CI: 1.113 - 1.558), bad emotional status (OR = 1.266, 95%CI: 0.992 - 1.616), and family history of gastrointestinal disorders (OR = 1.739, 95%CI: 1.163 - 2.600) were significantly associated with reflux symptom. History of diseases such as inflammatory bowel disease, anxiety, depression, peptic ulcer, gastritis, and renal diseases were found to be significantly related to GERD and its symptoms.</p><p><b>CONCLUSION</b>This area has epidemic of GERD, which was related to mental problems and unhealthy life style, and should be paid more attention by conducting effective community-based interventions.</p>

Study on the long-term efficacy and safety of medicine named 'Beijing Hypertensive No. 0' in patients with primary hypertension / 中华流行病学杂志

<p><b>OBJECTIVE</b>To assess the antihypertensive effect and safety on medicine named 'Beijing Hypertensive No. 0' in a three-year treatment of primary hypertension.</p><p><b>METHODS</b>A community-based intervention study was conducted. The antihypertensive effects and adverse events were observed.</p><p><b>RESULTS</b>4000 patients with primary hypertension were randomly divided into two groups with 1529 patients treated with 'Beijing Hypertensive No. 0' and 976 patients treated with other antihypertensive drugs, among which 946 and 853 patients in the two groups completed the three-year study. After treatment, the systolic blood pressure decreased 13 mm Hg and 7 mm Hg while diastolic blood pressure decreased 8 mm Hg and 4 mm Hg in the 'No. 0' group and controlled group respectively. After three years of treatment, 90.0% and 79.5% in the 'No.0' group and in the control group had reached the BP 'fulfillment criteria', which were much higher than the baseline data. Side effects occurred in 33/1274 (2.6%) cases during three years' treatment with most commonly seen as dizziness, headache, palpitation and weakness. No serious adverse reactions occurred. There were some positive effects after treated by 'No. 0', including 0.13 mmol/L decrease of TC, 0.70 mmol/L decrease of LDL-C and an average 0.12 mmol/L increase of HDL-C. All of these changes were statistically significant. There were also opposite effects as 0.13 mmol/L increase of TG, 0.24 mmol/L increase of K+, and 0.88 mmol/L increase of Na+ on average, which were also statistically significant.</p><p><b>CONCLUSION</b>Compared with the conventional treatment, this treatment of 'Beijing Hypertensive No.0' was more convenient, safe and effective in treating mild to moderate primary hypertension in the community.</p>

Cost-effectiveness analysis on compound anti-hypertensive tablets for primary hypertension / 中华流行病学杂志

Objective To compare the cost-effectiveness of two anti-hypertensive therapy regimens,Compound anti-hypertensive tablets and other common anti-hypertensive agents,in the treatment program of Primary Hypertension.Methods We conducted a cost-effectiveness analysis based on a community trial.Two communities'primary hypertensive patients were enrolled to receive different therapy drugs:Compound anti-hypertensive tablets(Group A)or other common anti-hypertensive agents(Group B).Blood pressure,medicine used,and adverse drug reactions were observed and recorded for one year,and then costeffectiveness ratio of the two groups and incremental ratio were calculated.We considered a 30%drug price fluctuating load to make the sensitivity analysis.Results 2505 cases were enrolled with 1529 cases in group A and 976 cases in group B.The cost-effectiveness ratios were 418.1 and 1057.7 for Group A and B respectively while the incremental cost-effectiveness of Group B vs.Group A was 19 202.2.The results were insensitive to variation in the costs of drugs over clinically reasonable ranges.Conclusion Compound anti-hypertensive tablets appeared to be relatively cost-effective when compared to common drugs for the treatment of primary hypertension.