An evaluation of the performance of HapMap SNP data in a Shanghai Chinese population: Analyses of allele frequency, linkage disequilibrium pattern and tagging SNPs transferability on chromosome 1q21-q25

<p>Abstract</p> <p>Background</p> <p>The HapMap project aimed to catalog millions of common single nucleotide polymorphisms (SNPs) in the human genome in four major populations, in order to facilitate association studies of complex diseases. To examine the transferability of Han Chinese in Beijing HapMap data to the Southern Han Chinese in Shanghai, we performed comparative analyses between genotypes from over 4,500 SNPs in a 21 Mb region on chromosome 1q21-q25 in 80 unrelated Shanghai Chinese and 45 HapMap Chinese data.</p> <p>Results</p> <p>Three thousand and forty-two SNPs were analyzed after removal of SNPs that failed quality control and those not in the HapMap panel. We compared the allele frequency distributions, linkage disequilibrium patterns, haplotype frequency distributions and tagging SNP sets transferability between the HapMap population and Shanghai Chinese population. Among the four HapMap populations, Beijing Chinese showed the best correlation with Shanghai population on allele frequencies, linkage disequilibrium and haplotype frequencies. Tagging SNP sets selected from four HapMap populations at different thresholds were evaluated in the Shanghai sample. Under the threshold of r²equal to 0.8 or 0.5, both HapMap Chinese and Japanese data showed better coverage and tagging efficiency than Caucasian and African data.</p> <p>Conclusion</p> <p>Our study supported the applicability of HapMap Beijing Chinese SNP data to the study of complex diseases among southern Chinese population.</p

Discovery and Validation of a New Class of Small Molecule Toll-Like Receptor 4 (TLR4) Inhibitors

Many inflammatory diseases may be linked to pathologically elevated signaling via the receptor for lipopolysaccharide (LPS), toll-like receptor 4 (TLR4). There has thus been great interest in the discovery of TLR4 inhibitors as potential anti-inflammatory agents. Recently, the structure of TLR4 bound to the inhibitor E5564 was solved, raising the possibility that novel TLR4 inhibitors that target the E5564-binding domain could be designed. We utilized a similarity search algorithm in conjunction with a limited screening approach of small molecule libraries to identify compounds that bind to the E5564 site and inhibit TLR4. Our lead compound, C34, is a 2-acetamidopyranoside (MW 389) with the formula C17H27NO9, which inhibited TLR4 in enterocytes and macrophages in vitro, and reduced systemic inflammation in mouse models of endotoxemia and necrotizing enterocolitis. Molecular docking of C34 to the hydrophobic internal pocket of the TLR4 co-receptor MD-2 demonstrated a tight fit, embedding the pyran ring deep inside the pocket. Strikingly, C34 inhibited LPS signaling ex-vivo in human ileum that was resected from infants with necrotizing enterocolitis. These findings identify C34 and the β-anomeric cyclohexyl analog C35 as novel leads for small molecule TLR4 inhibitors that have potential therapeutic benefit for TLR4-mediated inflammatory diseases. © 2013 Neal et al

Lack of association between genetic polymorphisms within DUSP12 - ATF6 locus and glucose metabolism related traits in a Chinese population

<p>Abstract</p> <p>Background</p> <p>Genome-wide linkage studies in multiple ethnic populations found chromosome 1q21-q25 was the strongest and most replicable linkage signal in the human chromosome. Studies in Pima Indian, Caucasians and African Americans identified several SNPs in <it>DUSP12 </it>and <it>ATF6</it>, located in chromosome 1q21-q23, were associated with type 2 diabetes.</p> <p>Methods</p> <p>We selected 19 single nucleotide polymorphisms (SNPs) that could tag 98% of the SNPs with minor allele frequencies over 0.1 within <it>DUSP12-ATF6 </it>region. These SNPs were genotyped in a total of 3,700 Chinese Han subjects comprising 1,892 type 2 diabetes patients and 1,808 controls with normal glucose regulation.</p> <p>Results</p> <p>None of the SNPs and haplotypes showed significant association to type 2 diabetes in our samples. No association between the SNPs and quantitative traits was observed either.</p> <p>Conclusions</p> <p>Our data suggests common SNPs within <it>DUSP12</it>-<it>ATF6 </it>locus may not play a major role in glucose metabolism in the Chinese.</p

PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 Are Associated with Type 2 Diabetes in a Chinese Population

Recent advance in genetic studies added the confirmed susceptible loci for type 2 diabetes to eighteen. In this study, we attempt to analyze the independent and joint effect of variants from these loci on type 2 diabetes and clinical phenotypes related to glucose metabolism.Twenty-one single nucleotide polymorphisms (SNPs) from fourteen loci were successfully genotyped in 1,849 subjects with type 2 diabetes and 1,785 subjects with normal glucose regulation. We analyzed the allele and genotype distribution between the cases and controls of these SNPs as well as the joint effects of the susceptible loci on type 2 diabetes risk. The associations between SNPs and type 2 diabetes were examined by logistic regression. The associations between SNPs and quantitative traits were examined by linear regression. The discriminative accuracy of the prediction models was assessed by area under the receiver operating characteristic curves. We confirmed the effects of SNPs from PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 on risk for type 2 diabetes, with odds ratios ranging from 1.114 to 1.406 (P value range from 0.0335 to 1.37E-12). But no significant association was detected between SNPs from WFS1, FTO, JAZF1, TSPAN8-LGR5, THADA, ADAMTS9, NOTCH2-ADAM30 and type 2 diabetes. Analyses on the quantitative traits in the control subjects showed that THADA SNP rs7578597 was association with 2-h insulin during oral glucose tolerance tests (P = 0.0005, empirical P = 0.0090). The joint effect analysis of SNPs from eleven loci showed the individual carrying more risk alleles had a significantly higher risk for type 2 diabetes. And the type 2 diabetes patients with more risk allele tended to have earlier diagnostic ages (P = 0.0006).The current study confirmed the association between PPARG, KCNJ11, CDKAL1, CDKN2A-CDKN2B, IDE-KIF11-HHEX, IGF2BP2 and SLC30A8 and type 2 diabetes. These type 2 diabetes risk loci contributed to the disease additively

Effects of GCK, GCKR, G6PC2 and MTNR1B Variants on Glucose Metabolism and Insulin Secretion

were found to modulate the fasting glucose levels. The current study aimed to replicate this association in the Chinese population and further analyze their effects on biphasic insulin secretion.). genetic variant was associated with first-phase insulin secretion, but not second-phase insulin secretion

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of an association with T2D for PEPD5 and HNF4A6,7 has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D

Dissolved organic carbon in permafrost regions : A review

A large quantity of organic carbon (C) is stored in northern and elevational permafrost regions. A portion of this large terrestrial organic C pool will be transferred by water into soil solution (~0.4 Pg C yr−1) (1 Pg=1015 g), rivers (~0.06 Pg C yr−1), wetlands, lakes, and oceans. The lateral transport of dissolved organic carbon (DOC) is the primary pathway, impacting river biogeochemistry and ecosystems. However, climate warming will substantially alter the lateral C shifts in permafrost regions. Vegetation, permafrost, precipitation, soil humidity and temperature, and microbial activities, among many other environmental factors, will shift substantially under a warming climate. It remains uncertain as to what extent the lateral C cycle is responding, and will respond, to climate change. This paper reviews recent studies on terrestrial origins of DOC, biodegradability, transfer pathways, and modelling, and on how to forecast of DOC fluxes in permafrost regions under a warming climate, as well as the potential anthropogenic impacts on DOC in permafrost regions. It is concluded that: (1) surface organic layer, permafrost soils, and vegetation leachates are the main DOC sources, with about 4.72 Pg C DOC stored in the topsoil at depths of 0–1 m in permafrost regions; (2) in-stream DOC concentrations vary spatially and temporally to a relatively small extent (1–60 mg C L−1) and annual export varies from 0.1–10 g C m–2 yr–1; (3) biodegradability of DOC from the thawing permafrost can be as high as 71%, with a median at 52%; (4) DOC flux is controlled by multiple factors, mainly including vegetation, soil properties, permafrost occurrence, river discharge and other related environmental factors, and (5) many statistical and process-based models have been developed, but model predictions are inconsistent with observational results largely dependent on the individual watershed characteristics and future discharge trends. Thus, it is still difficult to predict how future lateral C flux will respond to climate change, but changes in the DOC regimes in individual catchments can be predicted with a reasonable reliability. It is advised that sampling protocols and preservation and analysis methods should be standardized, and analytical techniques at molecular scales and numerical modeling on thermokarsting processes should be prioritized.</p

Erratum to: dissolved organic carbon in permafrost regions: a review

The article Dissolved organic carbon in permafrost regions: A review, written by Qiang MA, Huijun JIN, Congrong YU, and Victor F. BENSE, was erroneously originally published online without open access. After publication in Vol 62 Issue 2 this was corrected and the article is now an open access publication. Therefore, the copyright of the article has been changed to</p