Influence of blood pressure polygenic risk scores and environmental factors on coronary artery disease in the Korean Genome and Epidemiology Study.

The present study aimed to investigate the association of blood pressure polygenic risk scores (BP PRSs) with coronary artery disease (CAD) in a Korean population and the interaction effects between PRSs and environmental factors on CAD. Data were derived from the Cardiovascular Disease Association Study (CAVAS; N = 5100) and the Health Examinee Study (HEXA; N = 58,623) within the Korean Genome and Epidemiology Study. PRSs for systolic and diastolic BP were calculated with the weighted allele sum of >200 single-nucleotide polymorphisms. Multivariable logistic regression models were used. BP PRSs were strongly associated with systolic BP (SBP), diastolic BP (DBP), and hypertension in both CAVAS and HEXA (p < 0.0001). PRSSBP was significantly associated with CAD in CAVAS, while PRSSBP and PRSDBP were significantly associated with CAD in HEXA. There was an interaction effect between the BP PRSs and environmental factors on CAD. The odds ratios (ORs) for CAD were 1.036 (95% confidence interval [CI], 1.016-1.055) for obesity, 1.028 (95% CI, 1.011-1.045) for abdominal obesity, 1.030 (95% CI, 1.009-1.050) for triglyceride, 1.024 (95% CI, 1.008-1.041) for high-density lipoprotein cholesterol, and 1.039 for smoking (95% CI, 1.003-1.077) in CAVAS. There was no significant interaction in HEXA, except between PRSDBP and triglyceride (OR, 1.012; 95% CI, 1.001-1.024). BP PRS was associated with an increased risk of hypertension and CAD. The interactions among PRSs and environmental risk factors increased the risk of CAD. Multi-component interventions to lower BP in the population via healthy behaviors are needed to prevent CAD regardless of genetic predisposition.

Ramlibacter paludis sp. nov., isolated from wetland.

A Gram-stain-negative, non-motile, rod-shaped, aerobic and white-coloured bacterium (designated XY19T) was isolated from a soil sample of wetland from Godeok Ecological Park, Gangdong-gu, Seoul, Republic of Korea. On the basis of 16S rRNA gene sequencing, strain XY19T clustered with species of the genus Ramlibacter and appeared closely related to R. ginsenosidimutans DSM 23480T (98.42 %), R. alkalitolerans JCM 32081T (97.68 %) and R. monticola JCM 31918T (97.66 %). The average nucleotide identity between strain XY19T and three strains (R. ginsenosidimutans DSM 23480T, R. alkalitolerans JCM 32081T and R. monticola JCM 31918T) were 80.7, 81.1 and 81.4 %. And the digital DNA-DNA hybridization (dDDH) calculated between strain XY19T and each of the three strains (R. ginsenosidimutans DSM 23480T, R. alkalitolerans JCM 32081T and R. monticola JCM 31918T) were 24.1, 24.4 and 24.5 %. ANI value and dDDH results were a novel species of the genus Ramlibacter. Growth occurs at 10-37 °C on R2A medium in the pressence of 0-1 % NaCl (w/v) and at pH 6.0-8.5. The DNA G+C content of the genomic DNA was 68.7 mol%, and ubiquinone-8 (Q-8) was the major respiratory quinone. The major cellular fatty acids (>5 %) were C16:1 ω7c and/or C16:1 ω6c (summed feature 3), C16 : 0, C17 : 0 cyclo and C18:1 ω7c and/or C18:1 ω6c (summed feature 8). The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, three unidentified lipids and unidentified aminophospholipid. Physiological and biochemical characteristics indicated that strain XY19T represents a novel species of the genus Ramlibacter, for which the name Ramlibacter paludis sp. nov. is proposed. The type strain is XY19T (= KACC 22220T = LMG 32190T).

Gene-environment interaction explains a part of missing heritability in human body mass index.

Gene-environment (G×E) interaction could partially explain missing heritability in traits; however, the magnitudes of G×E interaction effects remain unclear. Here, we estimate the heritability of G×E interaction for body mass index (BMI) by subjecting genome-wide interaction study data of 331,282 participants in the UK Biobank to linkage disequilibrium score regression (LDSC) and linkage disequilibrium adjusted kinships-software for estimating SNP heritability from summary statistics (LDAK-SumHer) analyses. Among 14 obesity-related lifestyle factors, MET score, pack years of smoking, and alcohol intake frequency significantly interact with genetic factors in both analyses, accounting for the partial variance of BMI. The G×E interaction heritability (%) and standard error of these factors by LDSC and LDAK-SumHer are as follows: MET score, 0.45% (0.12) and 0.65% (0.24); pack years of smoking, 0.52% (0.13) and 0.93% (0.26); and alcohol intake frequency, 0.32% (0.10) and 0.80% (0.17), respectively. Moreover, these three factors are partially validated for their interactions with genetic factors in other obesity-related traits, including waist circumference, hip circumference, waist-to-hip ratio adjusted with BMI, and body fat percentage. Our results suggest that G×E interaction may partly explain the missing heritability in BMI, and two G×E interaction loci identified could help in understanding the genetic architecture of obesity.

Total marrow irradiation reduces organ damage and enhances tissue repair with the potential to increase the targeted dose of bone marrow in both young and old mice.

Total body irradiation (TBI) is a commonly used conditioning regimen for hematopoietic stem cell transplant (HCT), but dose heterogeneity and long-term organ toxicity pose significant challenges. Total marrow irradiation (TMI), an evolving radiation conditioning regimen for HCT can overcome the limitations of TBI by delivering the prescribed dose targeted to the bone marrow (BM) while sparing organs at risk. Recently, our group demonstrated that TMI up to 20 Gy in relapsed/refractory AML patients was feasible and efficacious, significantly improving 2-year overall survival compared to the standard treatment. Whether such dose escalation is feasible in elderly patients, and how the organ toxicity profile changes when switching to TMI in patients of all ages are critical questions that need to be addressed. We used our recently developed 3D image-guided preclinical TMI model and evaluated the radiation damage and its repair in key dose-limiting organs in young (~8 weeks) and old (~90 weeks) mice undergoing congenic bone marrow transplant (BMT). Engraftment was similar in both TMI and TBI-treated young and old mice. Dose escalation using TMI (12 to 16 Gy in two fractions) was well tolerated in mice of both age groups (90% survival ~12 Weeks post-BMT). In contrast, TBI at the higher dose of 16 Gy was particularly lethal in younger mice (0% survival ~2 weeks post-BMT) while old mice showed much more tolerance (75% survival ~13 weeks post-BMT) suggesting higher radio-resistance in aged organs. Histopathology confirmed worse acute and chronic organ damage in mice treated with TBI than TMI. As the damage was alleviated, the repair processes were augmented in the TMI-treated mice over TBI as measured by average villus height and a reduced ratio of relative mRNA levels of amphiregulin/epidermal growth factor (areg/egf). These findings suggest that organ sparing using TMI does not limit donor engraftment but significantly reduces normal tissue damage and preserves repair capacity with the potential for dose escalation in elderly patients.

Development and characterization of a preclinical total marrow irradiation conditioning-based bone marrow transplant model for sickle cell disease.

Sickle cell disease (SCD) is a serious global health problem, and currently, the only curative option is hematopoietic stem cell transplant (HCT). However, myeloablative total body irradiation (TBI)-based HCT is associated with high mortality/morbidity in SCD patients. Therefore, reduced-intensity (2-4 Gy) total body radiation (TBI) is currently used as a conditioning regimen resulting in mixed chimerism with the rescue of the SCD disease characteristic features. However, donor chimerism gradually reduces in a few years, resulting in a relapse of the SCD features, and organ toxicities remained the primary concern for long-term survivors. Targeted marrow irradiation (TMI) is a novel technique developed to deliver radiation to the desired target while sparing vital organs and is successfully used for HCT in refractory/relapsed patients with leukemia. However, it is unknown if TMI will be an effective treatment for a hematological disorder like SCD without adverse effects seen on TBI. Therefore, we examined preclinical feasibility to determine the tolerated dose escalation, its impact on donor engraftment, and reduction in organ damage using our recently developed TMI in the humanized homozygous Berkley SCD mouse model (SS). We show that dose-escalated TMI (8:2) (8 Gy to the bone marrow and 2 Gy to the rest of the body) is tolerated with reduced organ pathology compared with TBI (4:4)-treated mice. Furthermore, with increased SCD control (AA) mice (25 million) donor BM cells, TMI (8:2)-treated mice show successful long-term engraftment while engraftment failed in TBI (2:2)-treated mice. We further evaluated the benefit of dose-escalated TMI and donor cell engraftment in alleviating SCD features. The donor engraftment in SCD mice completely rescues SCD disease features including recovery in RBCs, hematocrit, platelets, and reduced reticulocytes. Moreover, two-photon microscopy imaging of skull BM of transplanted SCD mice shows reduced vessel density and leakiness compared to untreated control SCD mice, indicating vascular recovery post-BMT.

Smoking-Interaction Loci Affect Obesity Traits: A Gene-Smoking Stratified Meta-Analysis of 545,131 Europeans.

INTRODUCTION: Although many studies have investigated the association between smoking and obesity, very few have analyzed how obesity traits are affected by interactions between genetic factors and smoking. Here, we aimed to identify the loci that affect obesity traits via smoking status-related interactions in European samples. METHODS: We performed stratified analysis based on the smoking status using both the UK Biobank (UKB) data (N = 334,808) and the Genetic Investigation of ANthropometric Traits (GIANT) data (N = 210,323) to identify gene-smoking interaction for obesity traits. We divided the UKB subjects into two groups, current smokers and nonsmokers, based on the smoking status, and performed genome-wide association study (GWAS) for body mass index (BMI), waist circumference adjusted for BMI (WCadjBMI), and waist-hip ratio adjusted for BMI (WHRadjBMI) in each group. And then we carried out the meta-analysis using both GWAS summary statistics of UKB and GIANT for BMI, WCadjBMI, and WHRadjBMI and computed the stratified p values (pstratified) based on the differences between meta-analyzed estimated beta coefficients with standard errors in each group. RESULTS: We identified four genome-wide significant loci in interactions with the smoking status (pstratified < 5 × 10-8): rs336396 (INPP4B) and rs12899135 (near CHRNB4) for BMI, and rs998584 (near VEGFA) and rs6916318 (near RSPO3) for WHRadjBMI. Moreover, we annotated the biological functions of the SNPs using expression quantitative trait loci (eQTL) and GWAS databases, along with publications, which revealed possible mechanisms underlying the association between the smoking status-related genetic variants and obesity. CONCLUSIONS: Our findings suggest that obesity traits can be modified by the smoking status via interactions with genetic variants through various biological pathways.

Association between high-sensitivity C-reactive protein levels and depression: Moderation by age, sex, obesity, and aerobic physical activity.

BACKGROUND: Low-grade systemic inflammation evidenced by elevated serum high-sensitivity C-reactive protein (hsCRP) levels can be a biomarker for depression. This study aimed to investigate the association between serum hsCRP levels and depressive symptoms and to explore the potential moderating effects of age, sex, body mass index (BMI), and aerobic physical activity on the association. METHODS: Data of 10,702 adults (≥ 19 years) were obtained from the nationwide cross-sectional Korea National Health and Nutrition Examination Surveys of 2016 and 2018. Significant depressive symptoms were defined as ≥ 10 on the Patient Health Questionnaire-9, and high hsCRP level was defined as > 3.0 mg/L. RESULTS: Adults with high hsCRP levels were more likely to have depressive symptoms (odds ratio [OR]: 1.41, 95% confidence interval [CI]: 1.07-1.84) and suicidal ideation (OR: 1.39, 95% CI: 1.07-1.80) than those with low hsCRP levels. In the age- and sex-stratified analysis, high hsCRP levels were associated with depressive symptoms in the non-geriatric population (age ≤ 64 years) alone, with a higher OR in males than females. In subgroup analyses, the association between them was observed only among obese adults and adults without aerobic physical activity. LIMITATIONS: Causal interpretation is limited due to the cross-sectional design. CONCLUSIONS: Our results replicate previous findings of an association between high hsCRP levels and depressive symptoms in adults using a large nationally representative sample. The association between them was more prominent in the non-geriatric population, males, obese adults, and those without aerobic physical activity.

Identification of genetic loci affecting body mass index through interaction with multiple environmental factors using structured linear mixed model.

Multiple environmental factors could interact with a single genetic factor to affect disease phenotypes. We used Struct-LMM to identify genetic variants that interacted with environmental factors related to body mass index (BMI) using data from the Korea Association Resource. The following factors were investigated: alcohol consumption, education, physical activity metabolic equivalent of task (PAMET), income, total calorie intake, protein intake, carbohydrate intake, and smoking status. Initial analysis identified 7 potential single nucleotide polymorphisms (SNPs) that interacted with the environmental factors (P value < 5.00 × 10-6). Of the 8 environmental factors, PAMET score was excluded for further analysis since it had an average Bayes Factor (BF) value < 1 (BF = 0.88). Interaction analysis using 7 environmental factors identified 11 SNPs (P value < 5.00 × 10-6). Of these, rs2391331 had the most significant interaction (P value = 7.27 × 10-9) and was located within the intron of EFNB2 (Chr 13). In addition, the gene-based genome-wide association study verified EFNB2 gene significantly interacting with 7 environmental factors (P value = 5.03 × 10-10). BF analysis indicated that most environmental factors, except carbohydrate intake, contributed to the interaction of rs2391331 on BMI. Although the replication of the results in other cohorts is warranted, these findings proved the usefulness of Struct-LMM to identify the gene-environment interaction affecting disease.

Cytokine profiling in serum-derived exosomes isolated by different methods.

Exosomes in blood play an important role in cell-to-cell signaling and are a novel source of biomarkers for the diagnosis and prognosis of diseases. Recently, evidence has accumulated that cytokines are released from encapsulated exosomes and are capable of eliciting biological effects upon contact with sensitive cells. However, there is currently limited information on exosome isolation methods for cytokine research. In this study, we evaluated three exosome isolation methods for their usability, yield, purity, and effectiveness in subsequent cytokine profiling. We found that ultracentrifugation (UC) and Exoquick (EQ), but not exoEasy, yielded appropriate exosome sizes, and EQ had higher exosome extraction efficiency than the other two methods. Although UC generated markedly fewer particles than EQ, it yielded a relatively high purity. Next, we performed a multiplex assay with the ProcartaPlex Immune Monitoring 65-Plex Panel to determine the feasibility of these methods for cytokine profiling. The results indicated significant differences among isolation methods when analyzing exosomal cytokine profiles. We further investigated the changes of exosomal cytokines according to breast cancer progression in triple-negative breast cancer. We found significantly decreased concentrations of MIP-3 alpha, IL-23, M-CSF, Eotaxin-3, BLC, SDF-1 alpha, IL-2R, MDC, FGF-2, IL-22, and IL-31 in exosomes from metastatic breast cancer (MBC) patients.

An Electrospun Core-Shell Nanofiber Web as a High-Performance Cathode for Iron Disulfide-Based Rechargeable Lithium Batteries.

FeS2 /C core-shell nanofiber webs were synthesized for the first time by a unique synthesis strategy that couples electrospinning and carbon coating of the nanofibers with sucrose. The design of the one-dimensional core-shell morphology was found to be greatly beneficial for accommodating the volume changes encountered during cycling, to induce shorter lithium ion diffusion pathways in the electrode, and to prevent sulfur dissolution during cycling. A high discharge capacity of 545 mAh g-1 was retained after 500 cycles at 1 C, exhibiting excellent stable cycling performance with 98.8 % capacity retention at the last cycle. High specific capacities of 854 mAh g-1 , 518 mAh g-1 , and 208 mAh g-1 were obtained at 0.1 C, 1 C, and 10 C rates, respectively, demonstrating the exceptional rate capability of this nanofiber web cathode.

Identification of five novel genetic loci related to facial morphology by genome-wide association studies.

BACKGROUND: Face morphology is strongly determined by genetic factors. However, only a small number of genes related to face morphology have been identified to date. Here, we performed a two-stage genome-wide association study (GWAS) of 85 face morphological traits in 7569 Koreans (5643 in the discovery set and 1926 in the replication set). RESULTS: In this study, we analyzed 85 facial traits, including facial angles. After discovery GWAS, 128 single nucleotide polymorphisms (SNPs) showing an association of P < 5 × 10- 6 were selected to determine the replication of the associations, and meta-analysis of discovery GWAS and the replication analysis resulted in five genome-wide significant loci. The OSR1-WDR35 [rs7567283, G allele, beta (se) = -0.536 (0.096), P = 2.75 × 10- 8] locus was associated with the facial frontal contour; the HOXD1-MTX2 [rs970797, A allele, beta (se) = 0.015 (0.003), P = 3.97 × 10- 9] and WDR27 [rs3736712, C allele, beta (se) = 0.293 (0.048), P = 8.44 × 10- 10] loci were associated with eye shape; and the SOX9 [rs2193054, C allele, beta (se) (ln-transformed) = -0.007 (0.001), P = 6.17 × 10- 17] and DHX35 [rs2206437, A allele, beta (se) = -0.283 (0.047), P = 1.61 × 10- 9] loci were associated with nose shape. WDR35 and SOX9 were related to known craniofacial malformations, i.e., cranioectodermal dysplasia 2 and campomelic dysplasia, respectively. In addition, we found three independent association signals in the SOX9 locus, and six known loci for nose size and shape were replicated in this study population. Interestingly, four SNPs within these five face morphology-related loci showed discrepancies in allele frequencies among ethnic groups. CONCLUSIONS: We identified five novel face morphology loci that were associated with facial frontal contour, nose shape, and eye shape. Our findings provide useful genetic information for the determination of face morphology.

Validation of the new AJCC eighth edition of the TNM classification for breast cancer with a single-center breast cancer cohort.

PURPOSE: The new eighth edition TNM classification by the AJCC for breast cancer (BC) incorporates biologic factors and gene expression prognostic panels, in addition to traditional anatomic factors. In this study, we evaluated the prognostic value of this new staging system compared to the previous AJCC 7th edition staging system. METHODS: We conducted a retrospective analysis of women with stage I, II, or III BC who underwent curative surgery with/without adjuvant systemic therapy at Samsung Medical Center between July 2004 and December 2008. RESULTS: Of 3,208 BCs, this study was analyzed using the information of 2,790 BC patients. Hormone receptor-positive (HR+) and human epidermal growth factor 2 (HER2)- BCs were observed in 62.9% of BCs, HR+/ HER2+ in 9.3%, HR-/HER2- in 17.0%, and HR-/HER2+ in 10.8%. In survival analysis, we observed 245 distant recurrences and 198 deaths caused by BC progression. The median follow-up duration was 116.2 months. 10-year disease-specific survival (DSS) rates according to the AJCC 7th edition criteria were 97.2% of stage IA, 100% of IB, 94.9% of IIA, 87.9% of IIB, 86.4% of IIIA, 95.7% of IIIB, and 65.7% of IIIC (p < 0.001). After applying 8th edition criteria, the 10-year DSS rates were 98.1% of stage IA, 97.7% of IB, 93.8% of IIA, 92.7% of IIB, 88.2% of IIIA, 80.8% of IIIB, and 70.3% of IIIC (p < 0.001). CONCLUSIONS: The AJCC 8th edition clinical staging system provides a good prognostic value and addresses the weakness of the AJCC 7th edition, which uses only anatomical pathologic staging.

A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNγ.

Macrophage polarization plays an important role in tissue damage and repair. In this study, we show that Substance-P (SP) can directly induce M2 polarization of inflammatory macrophages. SP induced the differentiation of GM-CSF-differentiated pro-inflammatory macrophages into alternatively activated phagocytic M2 like macrophages (M2SP) through direct activation of the PI3K/Akt/mTOR/S6kinase pathway and induction of Arginase-1, CD163, and CD206, all of which were nullified by pretreatment with the neurokinin-1 receptor (NK-1R) antagonist RP67580 and specific signaling pathway inhibitors. M2SP were distinct from IL-4/IL-13-induced M2a and IL-10-induced M2c subtypes; they did not show STAT activation and exhibited high phagocytic and endothelial adhesive activity. Furthermore, SP had a dominant effect on M2 polarization over Interferon gamma (IFNγ), a potent M1-skewing cytokine, and effectively induced the M2 phenotype in monocytes and the human THP-1 cell line. Finally, adoptively transferred M2SP migrated to a spinal cord injury (SCI) lesion site and improved functional recovery. Collectively, our findings show that SP, a neuropeptide, plays a role as a novel cytokine by inducing tissue-repairing M2SP macrophages and thus may be developed for pharmacological intervention in diseases involving chronic inflammation and acute injury.

Interaction of iron status with single nucleotide polymorphisms on incidence of type 2 diabetes.

The objective of this study is to find single nucleotide polymorphisms (SNPs) associated with a risk of Type 2 diabetes (T2D) in Korean adults and to investigate the longitudinal association between these SNPs and T2D and the interaction effects of iron intake and average hemoglobin level. Data from the KoGES_Ansan and Ansung Study were used. Gene-iron interaction analysis was conducted using a two-step approach. To select candidate SNPs associated with T2D, a total of 7,935 adults at baseline were included in genome-wide association analysis (step one). After excluding T2D prevalent cases, prospective analyses were conducted with 7,024 adults aged 40-69 (step two). The association of selected SNPs and iron status with T2D and their interaction were determined using a Cox proportional hazard model. A total of 3 SNPs [rs9465871 (CDKAL1), rs10761745 (JMJD1C), and rs163177 (KCNQ1)] were selected as candidate SNPs related to T2D. Among them, rs10761745 (JMJD1C) and rs163177 (KCNQ1) were prospectively associated with T2D. High iron intake was also prospectively associated with the risk of T2D after adjusting for covariates. Average hemoglobin level was positively associated with T2D after adjusting for covariates in women. We also found significant interaction effects between rs10761745 (JMJD1C) and average hemoglobin levels on the risk of T2D among women with normal inflammation and without anemia at baseline. In conclusion, KCNQ1 and JMJD1C may prospectively contribute to the risk of T2D incidence among adults over the age of 40 and JMJD1C, but CDKAL1 may not, and iron status may interactively contribute to T2D incidence in women.

Endogenous Stem Cells in Homeostasis and Aging.

In almost all human tissues and organs, adult stem cells or tissue stem cells are present in a unique location, the so-called stem cell niche or its equivalent, continuously replenishing functional differentiated cells. Those endogenous stem cells can be expanded for cell therapeutics using ex vivo cell culture or recalled for tissue repair in situ through cell trafficking and homing. In the aging process, inefficiency in the endogenous stem cell-mediated healing mechanism can emerge from a variety of impairments that accumulate in the processes of stem cell self-renewal, function, differentiation capacity, and trafficking through cell autonomous intrinsic pathways (such as epigenetic alterations) or systemic extrinsic pathways. This review examines the homeostasis of endogenous stem cells, particularly bone marrow stem cells, and their dysregulation in disease and aging and discusses possible intervention strategies. Several systemic pro-aging and rejuvenating factors, recognized in heterochronic parabiosis or premature aging progeroid animal models, are reviewed as possible anti-aging pharmaceutical targets from the perspective of a healthy environment for endogenous stem cells. A variety of epigenetic modifications and chromosome architectures are reviewed as an intrinsic cellular pathway for aging and senescence. A gradual increase in inflammatory burden during aging is also reviewed. Finally, the tissue repair and anti-aging effects of Substance-P, a peptide stimulating stem cell trafficking from the bone marrow and modifying the inflammatory response, are discussed as a future anti-aging target.

The Mechanism of p53 Rescue by SUSP4.

p53 is an important tumor-suppressor protein deactivation of which by mdm2 results in cancers. A SUMO-specific protease 4 (SUSP4) was shown to rescue p53 from mdm2-mediated deactivation, but the mechanism is unknown. The discovery by NMR spectroscopy of a "p53 rescue motif" in SUSP4 that disrupts p53-mdm2 binding is presented. This 29-residue motif is pre-populated with two transient helices connected by a hydrophobic linker. The helix at the C-terminus binds to the well-known p53-binding pocket in mdm2 whereas the N-terminal helix serves as an affinity enhancer. The hydrophobic linker binds to a previously unidentified hydrophobic crevice in mdm2. Overall, SUSP4 appears to use two synergizing modules, the p53 rescue motif described here and a globular-structured SUMO-binding catalytic domain, to stabilize p53. A p53 rescue motif peptide exhibits an anti-tumor activity in cancer cell lines expressing wild-type p53. A pre-structures motif in the intrinsically disordered proteins is thus important for target recognition.

Silencing of Atp2b1 increases blood pressure through vasoconstriction.

BACKGROUND: Recent genome-wide association studies (GWASs) have identified 30 genetic loci that regulate blood pressure, increasing our understanding of the cause of hypertension. However, it has been difficult to define the causative genes at these loci due to a lack of functional analyses. METHOD: In this study, we aimed to validate the candidate gene ATP2B1 in 12q21, variants near which have the strongest association with blood pressure in Asians and Europeans. ATP2B1 functions as a calcium pump to fine-tune calcium concentrations - necessary for repolarization following muscular contractions. We silenced Atp2b1 using an siRNA complex, injected into mouse tail veins. RESULTS: In treated mice, blood pressure rose and the mesenteric arteries increased in wall : lumen ratio. Moreover, the arteries showed enhanced myogenic responses to pressure, and contractile responses to phenylephrine increased compared with the control, suggesting that blood pressure is regulated by ATP2B1 through the contraction and dilation of the vessel, likely by controlling calcium concentrations in the resting state. CONCLUSION: These results support that ATP2B1 is the causative gene in the blood pressure-associated 12q21 locus and demonstrate that ATP2B1 expression in the vessel influences blood pressure.

Recapitulation of the association of the Val66Met polymorphism of BDNF gene with BMI in Koreans.

Recent evidence suggests that brain-derived neurotrophic factor (BDNF) regulates food intake and the control of body weight. A common polymorphism in human BDNF, Val66Met (single-nucleotide polymorphism database (dbSNP) no. rs6265), impairs intracellular trafficking, resulting in the reduced secretion of BDNF. Several European studies have indicated that Val66Met is associated with BMI. In this study, we examined the association of the Val66Met polymorphism with BMI in Koreans (n = 20,270) from three independent epidemiological cohorts. All three studies observed a consistent association of this polymorphism with BMI, and their combined analysis demonstrated a robust correlation (ß = -0.17 ± 0.03 and P = 5.6 × 10(-8)). We also examined the effect of smoking on the link between Val66Met and BMI. The association of Val66Met with BMI was statistically significant only in the smoking group, reflecting a possible interaction between smoking and the BDNF polymorphism for BMI. Thus, we have confirmed BDNF as a genetic risk factor for BMI in an Asian population and hypothesize that the Val66Met mutation influences individual differences in BMI. In addition, smoking might interact with BDNF Val66Met to modulate BMI.

Association between renin-angiotensin-aldosterone system-related genes and blood pressure in a Korean population.

AIMS. Blood pressure control is influenced by various genetic and environmental factors, and genetic susceptibility is important in the development of essential hypertension. Because the renin-angiotensin-aldosterone system (RAAS) has a key role in vasoconstriction, vasodilation, and sodium and electrolyte balance, it is central in blood pressure control and so is an appropriate target in hypertension treatments. The present study assessed the association of RAAS-related genes with blood pressure and hypertension in a Korean population. Single nucleotide polymorphisms (SNPs, n = 114) in nine RAAS-related genes (AGT, REN, ACE, ACE2, AGTR1, CYP11B2, NR3C2, MAS1, and CMA1) were assessed for their correlation with blood pressure and hypertension using genotype data of 8842 individuals from the Korea Association Resource subject pool. MAJOR FINDINGS. Linear regression analysis revealed a statistically significant association with blood pressure of 10 SNPs in six genes (ACE, ACE2, CYP11B2, NR3C2, MAS1, and CMA1). An additional hypertension case-control study identified 10 SNPs in NR3C2 and ACE that were linked to hypertension. PRINCIPAL CONCLUSION. Three SNPs (rs11737660, rs6810951, and rs10519963) in NR3C2 correlate with both blood pressure and hypertension. Genetic polymorphisms in RAAS-related genes appear to be associated with hypertension in a Korean population.

A regulatory SNP in AKAP13 is associated with blood pressure in Koreans.

High blood pressure contributes to more than 10 million deaths per year worldwide through stroke and ischemic heart disease. Yet, genome-wide association studies (GWASs) have identified a small fraction of its underlying genetic factors. To identify biologically important single-nucleotide polymorphisms (SNPs) that regulate variations in blood pressure, we analyzed SNPs in a genome-wide association study. Genome-wide genotype data (original study n = 7551, SNP = 352,228; replication study n = 3703, SNP = 20) were obtained from the Korea National Institute of Health, wherein 29,921 of 352,228 SNPs lay within 5 kbp upstream of genes. Linear regression analysis was performed for systolic and diastolic blood pressure (DBP) by controlling for cohort, age, sex and body mass index. For the 20 SNPs that were associated with both blood pressure values, a replication study was performed in an independent population. A total of 20 SNPs were significantly associated with both blood pressure values in the original study, 13 of which lay in a conserved transcription factor-binding site. One SNP (rs11638762), in the GATA-3 binding site upstream of the AKAP13 gene, was significantly replicated in another cohort (P-value of the meta-analysis = 1.4 × 10(-5) for systolic blood pressure and 6.3 × 10(-4) for DBP). A functional GWAS was performed using upstream SNPs, and a novel genetic factor (AKAP13), which is essential for cardiac myocyte development in mice, was identified as a regulator of blood pressure.