한국인의 치주질환에 대한 전장유전체연관분석

학위논문 (박사)-- 서울대학교 대학원 : 치의과학과 예방치학전공, 2016. 2. 김현덕.Objective: This study aims to locate the genes related to periodontitis through genome-wide association study (GWAS) in Korean population. Methods: Total of 677 adults aged 44-88 years were recruited from the Yangpyeong cohort in Korea. The participants did not have self-reported metabolic diseases, cardiovascular diseases or cancer. Periodontitis was assessed using alveolar bone loss from a digital panoramic radiograph and classified into three groups: normal to mild, moderate and severe periodontitis. DNA from blood samples were genotyped using the Illumina Human 1M-duo Beadchip. Multivariable logistic regression analysis in PLINK was applied to examine the SNPs related to periodontitis after controlling for various confounders. Results: Associations of three SNPs suggested TENM2 (rs4242220) and LDLRAD4 (rs12969041, rs2027756) as putative risk genes of chronic periodontitis (p-values< 1 × 10-5). The odds ratio (95% confidence interval [CI]) of TENM2 was 0.53 (0.40-0.70) for moderate periodontitis and that of LDLRAD4 was 2.86 (1.92-4.27) for severe periodontitis. Two nonsynonymous SNPs of protein coding region and seven SNPs selected from previous reports showed nominal association. Conclusion: Our GWAS supports a previously reported gene of TENM2 and newly suggests LDLRAD4. These two genes role on lipid metabolism may play a part in the molecular etiology of periodontitis.1. INTRODUCTION 1 2. METHODS 2 3. RESULTS 7 4. DISCUSSION 9 5. CONCLUSIONS 13 TABLE 14 FIGURE 16 REFERENCES 17 KOREAN ABSTRACT 20Docto

Blood-based omic profiling supports female susceptibility to tobacco smoke-induced cardiovascular diseases

We recently reported that differential gene expression and DNA methylation profiles in blood leukocytes of apparently healthy smokers predicts with remarkable efficiency diseases and conditions known to be causally associated with smoking, suggesting that blood-based omic profiling of human populations may be useful for linking environmental exposures to potential health effects. Here we report on the sex-specific effects of tobacco smoking on transcriptomic and epigenetic features derived from genome-wide profiling in white blood cells, identifying 26 expression probes and 92 CpG sites, almost all of which are affected only in female smokers. Strikingly, these features relate to numerous genes with a key role in the pathogenesis of cardiovascular disease, especially thrombin signaling, including the thrombin receptors on platelets F2R (coagulation factor II (thrombin) receptor; PAR1) and GP5 (glycoprotein 5), as well as HMOX1 (haem oxygenase 1) and BCL2L1 (BCL2-like 1) which are involved in protection against oxidative stress and apoptosis, respectively. These results are in concordance with epidemiological evidence of higher female susceptibility to tobacco-induced cardiovascular disease and underline the potential of blood-based omic profiling in hazard and risk assessment

Expanding the Membership of a Stem Cell-Related Blood Transcriptional Module Containing Biomarkers of Cardiovascular Function by a Novel “Bottom-up” Bioinformatics Approach

Background: The circulating stem/progenitor cells (CSPCs) system comprises a variety of rare cells with mixed primitive and differentiation characteristics. So far, this system has eluded traditional methods of characterization. We recently showed that quantitative real-time PCR, the most sensitive and reliable gene expression analysis tool available, consistently detects a comprehensive battery of gene markers in all tested peripheral blood mononuclear cell samples from adult human subjects. Moreover, network representation of these genes’ co-variation across samples organizes them into two modules of the hierarchical transcriptional network. One module, termed the ‘cardiovascular module’ (CVM), was inversely related with the age, vascular stiffness and blood pressure of healthy blood donors, and highly depressed (but paradoxically more compact) in hypertensive patients. However, the targeted definition of CVM composition required an expansion to include more potential members. These could be extracted from high-throughput, unbiased methods such as gene microarrays. Approach and Results: We verified the ability of Affymetrix gene chips, available on public databases, to sense the CVM-associated rare transcripts, and found that only two (out of 15) were detectable. This oriented us towards gene chips hybridized with samples from children, where the frequency of CSPCs is known to be higher, and found that 5 CVM members were detectable. Implementing the ‘guilt-by-association’ (GBA) principle, we used these markers as ‘seed genes’ to generate co-variation lists. These were organized as network ‘neighborhoods’ which were then fused in increasingly higher gene communities that maintained their modular organization around their hub (i.e., ‘seed’) gene. This ‘bottom-up’ approach to reconstitute a network is both original and promising, as it reveals a large crop of candidate genes with meaningful known roles in the cardiovascular field (currently being validated by qRT-PCR). We also compared our method with the traditional “top-down” Weighted Gene Correlation Network Analysis (WGCNA) method, as well as a direct ‘Clique Mining’ protocol applied to an expanded list of stemness genes. Neither method produced modules enriched in CVM genes, even when the source data were blood samples from patients recovering from burn injury, a condition expected to stimulate CSPC release from bone marrow. However, the latter method did suggest the existence of a module containing the CVM gene Notch4 as being mobilized in burn patients, and one organized around OLR1/oxidized LDL receptor with a more widespread occurrence. Conclusions: Here, we demonstrate a new method to expand a transcriptional network by detection of candidate members with particular relevance for the analysis of rare transcripts, such as CSPC markers. This method has the potential to be applied for cell isolation, diagnostic, prognostic, and treatment purposes in a variety of CSPC and other cell-dependent medical conditions.No embargoAcademic Major: Biolog