| Part 1:Association of Fasting Glucose Levels with Incident Atherosclerotic Cardiovascular Disease:a Prospective Study in Chinese PopulationBackground and objective:Cardiovascular diseases (CVDs) have been the leading cause of death and years of life lost worldwide and identification of high-risk population for CVDs is very important for target prevention. Diabetes increases the risk of CVD, but some uncertainties still exist regarding the relation between fasting glucose levels in the normal range and CVD risk. The prediction of fasting glucose levels on incident atherosclerotic cardiovascular disease (ASCVD) in large-scale general Chinese population remained unclear. Considering the limited healthcare resources, the identification of the association is critical to determine whether to conduct primary prevention for ASCVD in population with different fasting glucose levels. The objective of the current study was to examine the association of fasting glucose levels with incident ASCVD and provide evidence for primary prevention of ASCVD in high-risk Chinese population.Subjects and methods:This prospective study included 19 687 participants aged 35 to 74 years at baseline from China Multicenter Collaborative Study of Cardiovascular Epidemiology (ChinaMUCA) and the International Collaborative Study of Cardiovascular Disease in Asian (InterAsia) study. Baseline information was collected using a standardized questionnaire, physical examination or laboratory test in 1998 and 2000-2001, respectively. During the follow-up examination conducted during 2007 and 2008, disease status and vital information were updated. Cox proportional hazards regression analysis was used to estimate the association of fasting glucose levels with incident ASCVD, with fasting glucose level of 85-99 mg/dL as the reference group and further investigate the combined effect of blood pressure, blood lipid and physical activity with fasting glucose levels on incident ASCVD.Results:During 7.9 years of follow-up (154520 person-years),534 incident ASCVD [129 coronary heart disease (CHD) and 405 stroke] cases were identified.The age-standardized incidence of ASCVD was 5.61/1000 person-years, 6.63/1000person-years and 4.59/1000 person-years in total population, males and females, respectively. After adjustment of age, gender, body mass index, smoking status, drinking status, physical activity, education, family history of ASCVD and other traditional cardiovascular risk factors, a potential J-shape association has been identified. However, only participants with diabetes had a significantly higher risk of developing ASCVD, with the hazard ratio (HR) and corresponding 95% confidence interval of 1.58 (1.18,2.11),1.17 (0.78,1.77) and 2.19 (1.43,3.33) in total population, males and females, respectively. Region and area difference in the prediction of diabetes on ASCVD was also identified. For example, the association was significant in participants from northern China other than those from southern China, with the multivariable-adjusted HR of 1.62 (1.14,2.30) and 1.50 (0.89,2.51), respectively, while the association was significant in participants from urban areas other than those from rural areas, with the multivariable-adjusted HR of 1.89 (1.26,2.83) and 1.38 (0.90,2.11), respectively. In addition, hypertension and abnormal lipid levels might increase the risk of incident ASCVD, while physical activity might decrease the risk.Conclusion:Individuals with diabetes are at an increased risk of developing ASCVD, independent of other cardiovascular risk factors. Primary prevention to reduce the impact of diabetes on incident ASCVD is highly needed, especially for females or population from northern China or urban areas of China. Furthermore, the management of blood pressure, blood lipid and physical activity is also very important in prevention of ASCVD in diabetic population. females, respectively. After adjustment of age, gender, body mass index, smoking status, drinking status, physical activity, education, family history of ASCVD and other traditional cardiovascular risk factors, a potential J-shape association has been identified. However, only participants with diabetes had a significantly higher risk of developing ASCVD, with the hazard ratio (HR) and corresponding 95% confidence interval of 1.58 (1.18,2.11),1.17 (0.78,1.77) and 2.19 (1.43,3.33) in total population, males and females, respectively. Region and area difference in the prediction of diabetes on ASCVD was also identified. For example, the association was significant in participants from northern China other than those from southern China, with the multivariable-adjusted HR of 1.62 (1.14,2.30) and 1.50 (0.89,2.51), respectively, while the association was significant in participants from urban areas other than those from rural areas, with the multivariable-adjusted HR of 1.89 (1.26,2.83) and 1.38 (0.90,2.11), respectively. In addition, hypertension and abnormal lipid levels might increase the risk of incident ASCVD, while physical activity might decrease the risk.Conclusion:Individuals with diabetes are at an increased risk of developing ASCVD, independent of other cardiovascular risk factors. Primary prevention to reduce the impact of diabetes on incident ASCVD is highly needed, especially for females or population from northern China or urban areas of China. Furthermore, the management of blood pressure, blood lipid and physical activity is also very important in prevention of ASCVD in diabetic population.Part 2:Associations of Endothelial System Genes with Longitudinal Blood Pressure Changes:the GenSalt StudyBackground and objective:Several reports have highlighted the importance of the endothelium on relaxing vascular smooth muscle and regulating vasomotor tone and such findings suggest a potential role of endothelial dysfunction in the pathogenesis of hypertension. Several studies have already identified associations between genes encoding components of the endothelial system and prevalent hypertension. However, genomic research on longitudinal BP phenotypes, such as blood pressure (BP) change over time and hypertension incidence, is limited. In the current study, we used single-marker and novel gene-based methods to examine the associations of endothelial system genes with BP changes and hypertension in a longitudinal family study.Subjects and methods:The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) follow-up study was conducted among 1768 Chinese participants from 633 families. Mean systolic BP (SBP) and diastolic BP (DBP) were calculated using nine BP measurements, which were obtained at baseline and at 2 follow-up visits using a random-zero sphygmomanometer. Mixed-effect models were used to assess the additive associations of 206 SNPs in 15 endothelial system genes with longitudinal BP changes and incident hypertension. Gene-based analyses were conducted using the truncated product method. The Bonferroni method was used to adjust for multiple testing in all analyses. Software Haploview, PLINK, SAS and R were used to conduct the analyses.Results:On average, participants were 39.0 years of age, had a mean body mass index of 23.4 kg/m2, and mean baseline SBP and DBP of 116.9 mmHg and 73.8 mmHg, respectively. A total of 173 (9.8%) participants had hypertension at baseline. During the average 7.2 years of follow-up, SBP and DBP increased 1.8 mmHg and 1.2 mmHg per year, respectively. In addition, among those free from hypertension at baseline,512 participants (32.1%) developed hypertension. In single-marker analyses, each copy of the minor alleles of correlated SELE markers rs4656704, rs6427212 and rs5368 were associated with increased risk of developing hypertension (Pfor trend=1.48×10-4,6.69×10-5 and 7.64×10-5, respectively). In addition, the minor allele of the SELE marker rs3917436 was associated with smaller diastolic BP (DBP) increases over time. Results of gene-based analyses confirmed associations of the SELE gene with the longitudinal BP phenotypes (P values<1.00×10-6 for DBP change and incident hypertension). Furthermore, the DDAH1 and COL18A1 genes were associated with SBP change (P<1.00×10-6 and P=4.00×10-6, respectively), while EDNRA was associated with incident hypertension (P=2.39×10-4).Conclusion:The current study provides strong evidence of a role of endothelial system genes in BP progression and incident hypertension.
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