| Depression is a common mental disorder, which usually causes severe disability andhas a large impact on individuals, families and communities. Global Burden of Disease2000estimates that by the year2020, the burden of depression will increase to5.7%of the totalburden of disease, becoming the second leading cause of disability adjusted life years lost,being second only to ischaemic heart disease worldwide. In the developed regions, depressionwill then be the highest ranking cause of burden of disease. Meanwhile, depression is anestablished risk factor for the disease predicted to be the leading cause of societal burden,ischemic heart disease. The association between depression and hypertension, the major riskfactors for cardiovascular disease, has been studied for more than a century. Plenty of clinical,epidemiological and biological studies have demonstrated the interaction between depressionand hypertension, and studies in genetics and epigenetics also have found some relevantmechanisms through which the interactions between these two diseases occur, although thereare still some inconsistent evidences between depression-hypertension association and theexact mechanisms are still unknown.Here we reviewed studies which assess the association between depression andhypertension and briefly summarized the current development in related epidemiological andbiological research and the potential genetic and epigenetic mechanisms, with emphasis onstudies, if can be retrieved, in Chinese population.The present study reviewed and summarized current research on the associationbetween depression and hypertension in epidemiology, biology, genetics and epigenetics, andhypothesized that the interaction between depression and hypertension may be influenced byboth heredity and environment, through independent or combined effect of epigeneticmodification and gene variant. The hypothesis pointed out a new aspect in studing thedepression-hypertension association and established the theoretical bases of Chapter2andChapter3. Chapter2Depression Increases the Risk of Hypertension Incidence: a Meta-analysisof Prospective Cohort StudiesBackground: It has long been known that depression is associated with hypertension butwhether depression as a risk factor for hypertension incidence is still inconclusive. Thepresent study is to assess whether depression increases the incidence of hypertension.Method: Literatures were searched from PubMed, EMBASE, Cochrane and PsycINFOwithout language restrictions. Any prospective cohort study was included, in which reportedthe correlation between depression and incidence of hypertension in apparently healthynormotensives. At baseline, the studies were selected in which have at least one self-report orinterview-based assessment on depressive symptoms/disorders. The definition ofhypertension was defined as a repeatedly elevated blood pressure exceeding140(systolic)and/or over90mmHg (diastolic) determined in interview, use of anti-hypertensivemedications, or self-reported or recorded diagnosed hypertension. Studies with cross-sectionalor case-control design were excluded. Data abstraction was conducted independently by twoauthors.Results: Seventy-five full texts were initially searched, but only9studies met ourinclusion criteria, and they were comprised of22367subjects with a mean follow-up periodof9.6years. We found that depression increased the risk of hypertension incidence (adjustedrelative risk:1.42;95%confidence interval:1.09to1.86, P=0.009) and the risk wassignificantly correlated with the length of follow-up (P=0.0002) and the prevalence ofdepression at baseline (P <0.0001).Conclusions: This is the first meta-analysis focusing on the contribution of depressionon the incident hypertension. The results indicate an approximately42%increased risk forhypertension in the depressed cohorts, supporting that depression is probably an independentrisk factor of hypertension. The present study is robust because of the prospective studydesign and minimized the selection and recall bias, so it is important to take depression intoconsideration during the process of prevention and treatment of hypertension. Further studiesare needed to exclude the effects of other confounding factors.Chapter3Role of DNA Methylation in NET Gene Promoter Region on the Depression-Hypertension AssociationBackground: Depression, a common mood disorder, has been demonstrated to beassociated with hypertension in plenty of studies. Increased sympathetic nervous systemactivities, usually measured as norepinephrine (NE) levels, and decreased NE transporter(NET) function, are thought to be plausible for the depression-hypertension association, through epigenetic modifications. The present study aims to detect the role of DNAmethylation in NET gene promoter region on the association between depression andhypertension.Methods: One hundred and sixty-two subjects, with no history of diabetes, stroke andcoronary heart disease and matched for smoking and drinking status, and physical activityfrequency and intensity, were categorized into four groups (depression-hypertension,nondepression-hypertension, depression-nonhypertension and nondepression-nonhyperte-nsion) according to their depression scores and blood pressure levels. DNA was extractedfrom peripheral white blood cell and methylation levels of9CpG sites in NET gene promoterwere investigated using pyrosequencing. Methylation differences between groups wereanalyzed using Analysis of Variance. Multiple regression models were fitted to adjust for thepotential confounding effect. The Spearman’s correlation coefficients, principle componentanalysis and hierarchical clustering analysis were used to explore the relationship among CpGsites.Results: DNA methylation levels are different from each CpG site, with a trend that thelower the DNA methylation levels, the closer the transcription start site. For each CpG siteand the average value of9CpG sites, methylation levels were lower (except for CpG2) inother three groups, compared with nondepression-nonhypertension group. However, nostatistically significant differences were found between groups. Multiple regression analysisindicated no significant difference among different groups after controlling for age and BMI.Principle component analysis and hierarchical clustering analysis found that CpG1.2-CpG5.2and CpG4are highly representable by the first principle component, and there is similarityshared by CpG1-3.Conclusion: This is the first study taking the epigenetic theory into practice in researchof depression-hypertension association, and is also the first study assessing the role of DNAmethylation in NET gene promoter region on the association between depression andhypertension. The present study found that the methylation levels of the CpG sites adjacent totranscription start site tend to be low. However, there were no significant differences in DNAmethylation levels in NET gene between groups. Further studies should modify study designs,such as characteristics of subjects and tissue heterogeneity of samples. Furthermore, studieswith prospective design or studies conducted in cell lines or animal models with interventionsare needed for mechanism research. Also it is necessary to take the role of methylation inother CpG sites and other epigenetic mechanisms in the regulation of NET gene into consideration on the association of depression and hypertension. |
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