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l e t t e r sTo identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery metaanalysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall metaanalysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.

The effects of transcriptional activation on the chromatin structure of the Saccharomyces cerevisiae HIS3 gene were addressed by mapping the precise positions of nucleosomes in uninduced and induced chromatin. In the absence of the Gcn4p activator, the HIS3 gene is organized into a predominant nucleosomal array. In wild-type chromatin, this array is disrupted, and several alternative overlapping nucleosomal arrays are formed. The disruption of the predominant array also requires the SWI/SNF remodeling machine, indicating that the SWI/SNF complex plays an important role in nucleosome mobilization over the entire HIS3 gene. The Isw1 remodeling complex plays a more subtle role in determining nucleosome positions on HIS3, favoring positions different from those preferred by the SWI/SNF complex. Both the SWI/SNF and Isw1 complexes are constitutively present in HIS3 chromatin, although Isw1 tends to be excluded from the HIS3 promoter. Despite the apparent disorder of HIS3 chromatin generated by the formation of multiple nucleosomal arrays, nucleosome density profiles indicate that some long-range order is always present. We propose that Gcn4p stimulates nucleosome mobilization over the entire HIS3 gene by the SWI/SNF complex. We suggest that the net effect of interplay among remodeling machines at HIS3 is to create a highly dynamic chromatin structure.The central role of chromatin structure in gene regulation is currently the subject of intense interest. Much has been learned about the ATP-dependent chromatin remodeling machines, which use the free energy of ATP hydrolysis to move nucleosomes along DNA and alter nucleosome conformation (31), and the histone-modifying enzymes and their complexes. There is also a great deal of information available concerning changes in chromatin structure occurring at various gene promoters (3,20). Because most of the obvious changes in chromatin structure occur at gene promoters, emphasis has been placed on these events, which are clearly of major importance. However, in our high-resolution studies of the chromatin structure of the CUP1 and HIS3 genes of Saccharomyces cerevisiae, we have obtained evidence pointing to more widespread changes in chromatin structure resulting from induction; these changes involve the entire gene and flanking sequences (9, 29). Our observations indicate that, at least for these genes, chromatin remodeling is not confined to the promoter but occurs on the scale of a chromatin domain.It is now apparent that ATP-dependent chromatin remodeling machines can be grouped into several functional classes (2). One class includes the SWI/SNF and RSC complexes, which are capable of mobilizing nucleosomes and driving a conformational change in the nucleosome to create the remodeled state (24,31). A second class is defined by the ISWI group of complexes, exemplified in budding yeast by the Isw1 and Isw2 complexes, which are capable of mobilizing nucleosomes to create arrays with characteristic spacing but cannot remodel nucleosome structure (19,39). A third class of com...

ObjectivesThe prevalence of osteoporosis and related fractures has increased rapidly in Korean women. Proper nutrition intake is associated with the prevention of osteoporosis. We analyzed the association between dietary patterns and the risk of osteoporosis during a 4-year follow-up in postmenopausal Korean women.MethodsPostmenopausal women (n = 1,725) who participated in the Korean Genome and Epidemiology Study were enrolled. Food intake was assessed using a validated semiquantitative food frequency questionnaire, and a quantitative ultrasound device was used to measure the speed of sound at the radius and tibia.ResultsThree major dietary patterns were identified using factor analysis based on baseline intake data: traditional (high intake of rice, kimchi, and vegetables), dairy (high intake of milk, dairy products, and green tea), and western (high intake of sugar, fat, and bread). Multivariate Cox proportional hazards models were used to estimate relative risk for osteoporosis. An inverse association was detected between the dairy dietary pattern and the osteoporosis incidence [relative risk (RR): 0.63, 95% confidence interval (CI): 0.42–0.93, p-trend=0.055 in radius; RR: 0.56, 95% CI: 0.35–0.90, p-trend=0.048 in tibia]. Individuals in the highest quintile for the traditional dietary pattern (p-trend = 0.009 in tibia) and western dietary pattern (p-trend = 0.043 in radius) demonstrated a higher risk of osteoporosis incidence than those in the lowest quintile.ConclusionThese results suggested that high consumption of milk, dairy products, and green tea may reduce the risk of osteoporosis in postmenopausal Korean women.

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Previous reports have described several associations of PR, QRS, QT and heart rate with genomic variations by genome-wide association studies (GWASs). In the present study, we examined the association of ∼2.5 million SNPs from 2994 Japanese healthy volunteers obtained from the JPDSC database with electrocardiographic parameters. We confirmed associations of PR interval, QRS duration and QT interval in individuals of Japanese ancestry with 11 of the 45 SNPs (6 of 20 for QT, 5 of 19 for PR and 0 of 6 for QRS) observed among individuals of European, African and Asian (Indian and Korean) ancestries. Those results indicate that many of the electrocardiographic associations with genes are shared by different ethnic groups including Japanese. Possible novel associations found in this study were validated by Korean data. As a result, we identified a novel association of SNP rs4952632[G] (maps near SLC8A1, sodium-calcium exchanger) (P = 7.595 × 10(-6)) with PR interval in Japanese individuals, and replication testing among Koreans confirmed the association of the same SNP with prolonged PR interval. Meta-analysis of the Japanese and Korean datasets demonstrated highly significant associations of SNP rs4952632[G] with a 2.325-ms (95% CI, 1.693-2.957 ms) longer PR interval per minor allele copy (P = 5.598 × 10(-13)). Cell-type-specific SLC8A1 knockout mice have demonstrated a regulatory role of sodium-calcium exchanger in automaticity and conduction in sinoatrial node, atrium and atrioventricular node. Our findings support a functional role of sodium-calcium exchanger in human atrial and atrioventricular nodal conduction as suggested by genetically modified mouse models.

Diabetic nephropathy (DN) is a long-term complication of diabetes mellitus that leads to end-stage renal disease. Microalbuminuria is used for the early detection of diabetic renal damage, but such levels do not reflect the state of incipient DN precisely in type 2 diabetic patients because microalbuminuria develops in other diseases, necessitating more accurate biomarkers that detect incipient DN. Isobaric tags for relative and absolute quantification (iTRAQ) were used to identify urinary proteins that were differentially excreted in normoalbuminuric and microalbuminuric patients with type 2 diabetes where 710 and 196 proteins were identified and quantified, respectively. Some candidates were confirmed by 2-DE analysis, or validated by Western blot and multiple reaction monitoring (MRM). Specifically, some differentially expressed proteins were verified by MRM in urine from normoalbuminuric and microalbuminuric patients with type 2 diabetes, wherein alpha-1-antitrypsin, alpha-1-acid glycoprotein 1, and prostate stem cell antigen had excellent AUC values (0.849, 0.873, and 0.825, resp.). Moreover, we performed a multiplex assay using these biomarker candidates, resulting in a merged AUC value of 0.921. Although the differentially expressed proteins in this iTRAQ study require further validation in larger and categorized sample groups, they constitute baseline data on preliminary biomarker candidates that can be used to discover novel biomarkers for incipient DN.