Severity of Nonalcoholic Fatty Liver Disease is Associated with Development of Metabolic Syndrome: Results of a 5-Year Cohort Study

Aims: Nonalcoholic fatty liver disease (NAFLD) is considered to be a hepatic manifestation of metabolic syndrome (MS). However, a few studies have examined the effect of NAFLD on the development of MS. We evaluated the relationship between the development of MS and clinical severity of NAFLD according to alanine aminotransferase (ALT) levels. Methods: A retrospective cohort study was conducted. Participants who underwent abdominal ultrasonography and blood samplings for health check-ups both in 2005 and 2010 were recruited. NAFLD was diagnosed if a person showed fatty liver on ultrasonography without significant alcohol consumption. Subjects with MS at baseline were excluded. Results: A total of 2,728 subjects met the inclusion criteria. Fatty liver (FL) with normal ALT was found in 369 (13.5%) subjects and FL with elevated ALT in 328 (12.0%). During 5 years of follow up, 582 (21.3%) incident cases of MS developed between 2005 and 2010. The incidence of MS was higher in patients with NAFLD compared to control group (41.2% in FL with elevated ALT, 34.7% in FL with normal ALT and 15.7% in control, p<0.001). Multivariate analysis showed that odds ratio (OR) and 95% confidence interval (CI) for MS increased according to the severity of NAFLD [OR (95% CI), 1.29 (0.97−1.71) in FL with normal ALT and 1.54 (1.18−1.33) in FL with elevated ALT, p=0.01]. Conclusions: We have demonstrated that development of MS is significantly increased according to the clinical severity of NAFLD. These findings have implications in the clinical availability of NAFLD as a predictor of MS

A BAC pooling strategy combined with PCR-based screenings in a large, highly repetitive genome enables integration of the maize genetic and physical maps

BACKGROUND: Molecular markers serve three important functions in physical map assembly. First, they provide anchor points to genetic maps facilitating functional genomic studies. Second, they reduce the overlap required for BAC contig assembly from 80 to 50 percent. Finally, they validate assemblies based solely on BAC fingerprints. We employed a six-dimensional BAC pooling strategy in combination with a high-throughput PCR-based screening method to anchor the maize genetic and physical maps. RESULTS: A total of 110,592 maize BAC clones (~ 6x haploid genome equivalents) were pooled into six different matrices, each containing 48 pools of BAC DNA. The quality of the BAC DNA pools and their utility for identifying BACs containing target genomic sequences was tested using 254 PCR-based STS markers. Five types of PCR-based STS markers were screened to assess potential uses for the BAC pools. An average of 4.68 BAC clones were identified per marker analyzed. These results were integrated with BAC fingerprint data generated by the Arizona Genomics Institute (AGI) and the Arizona Genomics Computational Laboratory (AGCoL) to assemble the BAC contigs using the FingerPrinted Contigs (FPC) software and contribute to the construction and anchoring of the physical map. A total of 234 markers (92.5%) anchored BAC contigs to their genetic map positions. The results can be viewed on the integrated map of maize [1,2]. CONCLUSION: This BAC pooling strategy is a rapid, cost effective method for genome assembly and anchoring. The requirement for six replicate positive amplifications makes this a robust method for use in large genomes with high amounts of repetitive DNA such as maize. This strategy can be used to physically map duplicate loci, provide order information for loci in a small genetic interval or with no genetic recombination, and loci with conflicting hybridization-based information

SLC11A1 (NRAMP1) Polymorphisms and Tuberculosis Susceptibility: Updated Systematic Review and Meta-Analysis

Background: Natural resistance associated macrophage protein 1 (NRAMP1), encoded by the SLC11A1 gene, has been described to regulate macrophage activation and be associated with infectious and autoimmune diseases. The relation between SLC11A1 polymorphisms and tuberculosis susceptibility has been studied in different populations. Methods: We systematically reviewed published studies on SLC11A1 polymorphisms and tuberculosis susceptibility until September 15, 2010 and quantitatively summarized associations of the most widely studied polymorphisms using metaanalysis. Results: In total, 36 eligible articles were included in this review. In Meta-analysis, significant associations were observed between tuberculosis risk and widely studied SLC11A1 polymorphisms with summarized odds ratio of 1.35 (95%CI, 1.17– 1.54), 1.25 (95 % CI, 1.04–1.50), 1.23 (95 % CI, 1.04–1.44), 1.31 (95%CI, 1.08–1.59) for 39 UTR, D543N, INT4, and 59 (GT)n, respectively. Heterogeneity between studies was not pronounced, and the associations did not remarkably vary in the stratified analysis with respect to study population and study base. Conclusions: The association between SLC11A1 polymorphisms and tuberculosis susceptibility observed in our analyses supports the hypothesis that NRAMP1 might play an important role in the host defense to the development of tuberculosis

Myotis rufoniger genome sequence and analyses: M-rufoniger&apos;s genomic feature and the decreasing effective population size of Myotis bats

Myotis rufoniger is a vesper bat in the genus Myotis. Here we report the whole genome sequence and analyses of the M. rufoniger. We generated 124 Gb of short-read DNA sequences with an estimated genome size of 1.88 Gb at a sequencing depth of 66x fold. The sequences were aligned to M. brandtii bat reference genome at a mapping rate of 96.50% covering 95.71% coding sequence region at 10x coverage. The divergence time of Myotis bat family is estimated to be 11.5 million years, and the divergence time between M. rufoniger and its closest species M. davidii is estimated to be 10.4 million years. We found 1,239 function-altering M. rufoniger specific amino acid sequences from 929 genes compared to other Myotis bat and mammalian genomes. The functional enrichment test of the 929 genes detected amino acid changes in melanin associated DCT, SLC45A2, TYRP1, and OCA2 genes possibly responsible for the M. rufoniger&apos;s red fur color and a general coloration in Myotis. N6AMT1 gene, associated with arsenic resistance, showed a high degree of function alteration in M. rufoniger. We further confirmed that the M. rufoniger also has batspecific sequences within FSHB, GHR, IGF1R, TP53, MDM2, SLC45A2, RGS7BP, RHO, OPN1SW, and CNGB3 genes that have already been published to be related to bat&apos;s reproduction, lifespan, flight, low vision, and echolocation. Additionally, our demographic history analysis found that the effective population size of Myotis clade has been consistently decreasing since similar to 30k years ago. M. rufoniger&apos;s effective population size was the lowest in Myotis bats, confirming its relatively low genetic diversity

BAC library resources for map-based cloning and physical map construction in barley (Hordeum vulgare L.)

Background: Although second generation sequencing (2GS) technologies allow re-sequencing of previously gold-standard-sequenced genomes, whole genome shotgun sequencing and de novo assembly of large and complex eukaryotic genomes is still difficult. Availability of a genome-wide physical map is therefore still a prerequisite for whole genome sequencing for genomes like barley. To start such an endeavor, large insert genomic libraries, i.e. Bacterial Artificial Chromosome (BAC) libraries, which are unbiased and representing deep haploid genome coverage, need to be ready in place. Result: Five new BAC libraries were constructed for barley (Hordeum vulgare L.) cultivar Morex. These libraries were constructed in different cloning sites (HindIII, EcoRI, MboI and BstXI) of the respective vectors. In order to enhance unbiased genome representation and to minimize the number of gaps between BAC contigs, which are often due to uneven distribution of restriction sites, a mechanically sheared library was also generated. The new BAC libraries were fully characterized in depth by scrutinizing the major quality parameters such as average insert size, degree of contamination (plate wide, neighboring, and chloroplast), empty wells and off-scale clones (clones with 250 fragments). Additionally a set of gene-based probes were hybridized to high density BAC filters and showed that genome coverage of each library is between 2.4 and 6.6 X. Conclusion: BAC libraries representing >20 haploid genomes are available as a new resource to the barley research community. Systematic utilization of these libraries in high-throughput BAC fingerprinting should allow developing a genome-wide physical map for the barley genome, which will be instrumental for map-based gene isolation and genome sequencing.Daniela Schulte, Ruvini Ariyadasa, Bujun Shi, Delphine Fleury, Chris Saski, Michael Atkins, Pieter deJong, Cheng-Cang Wu, Andreas Graner, Peter Langridge and Nils Stei

Change of Gene Structure and Function by Non-Homologous End-Joining, Homologous Recombination, and Transposition of DNA

An important objective in genome research is to relate genome structure to gene function. Sequence comparisons among orthologous and paralogous genes and their allelic variants can reveal sequences of functional significance. Here, we describe a 379-kb region on chromosome 1 of maize that enables us to reconstruct chromosome breakage, transposition, non-homologous end-joining, and homologous recombination events. Such a high-density composition of various mechanisms in a small chromosomal interval exemplifies the evolution of gene regulation and allelic diversity in general. It also illustrates the evolutionary pace of changes in plants, where many of the above mechanisms are of somatic origin. In contrast to animals, somatic alterations can easily be transmitted through meiosis because the germline in plants is contiguous to somatic tissue, permitting the recovery of such chromosomal rearrangements. The analyzed region contains the P1-wr allele, a variant of the genetically well-defined p1 gene, which encodes a Myb-like transcriptional activator in maize. The P1-wr allele consists of eleven nearly perfect P1-wr 12-kb repeats that are arranged in a tandem head-to-tail array. Although a technical challenge to sequence such a structure by shotgun sequencing, we overcame this problem by subcloning each repeat and ordering them based on nucleotide variations. These polymorphisms were also critical for recombination and expression analysis in presence and absence of the trans-acting epigenetic factor Ufo1. Interestingly, chimeras of the p1 and p2 genes, p2/p1 and p1/p2, are framing the P1-wr cluster. Reconstruction of sequence amplification steps at the p locus showed the evolution from a single Myb-homolog to the multi-gene P1-wr cluster. It also demonstrates how non-homologous end-joining can create novel gene fusions. Comparisons to orthologous regions in sorghum and rice also indicate a greater instability of the maize genome, probably due to diploidization following allotetraploidization

A Genome Wide Association Scan of Bovine Tuberculosis Susceptibility in Holstein-Friesian Dairy Cattle

peer-reviewedBackground: Bovine tuberculosis is a significant veterinary and financial problem in many parts of the world. Although many factors influence infection and progression of the disease, there is a host genetic component and dissection of this may enlighten on the wider biology of host response to tuberculosis. However, a binary phenotype of presence/absence of infection presents a noisy signal for genomewide association study. Methodology/Principal Findings: We calculated a composite phenotype of genetic merit for TB susceptibility based on disease incidence in daughters of elite sires used for artificial insemination in the Irish dairy herd. This robust measure was compared with 44,426 SNP genotypes in the most informative 307 subjects in a genome wide association analysis. Three SNPs in a 65 kb genomic region on BTA 22 were associated (i.e. p,1025, peaking at position 59588069, p = 4.0261026) with tuberculosis susceptibility. Conclusions/Significance: A genomic region on BTA 22 was suggestively associated with tuberculosis susceptibility; it contains the taurine transporter gene SLC6A6, or TauT, which is known to function in the immune system but has not previously been investigated for its role in tuberculosis infection

Effects of Interleukin-10 Polymorphisms, Helicobacter pylori Infection, and Smoking on the Risk of Noncardia Gastric Cancer

OBJECTIVE: Both variations in the interleukin-10 (IL10) gene and environmental factors are thought to influence inflammation and gastric carcinogenesis. Therefore, we investigated the associations between IL10 polymorphisms, Helicobacter pylori (H. pylori) infection, and smoking in noncardia gastric carcinogenesis in Koreans. METHODS: We genotyped three promoter polymorphisms (-1082A>G, -819T>C, and -592 A>C) of IL10 in a case-control study of 495 noncardia gastric cancer patients and 495 sex- and age-matched healthy controls. Multiple logistic regression models were used to detect the effects of IL10 polymorphisms, H. pylori infection, and smoking on the risk of gastric cancer, which was stratified by the histological type of gastric cancer. RESULTS: The IL10-819C and -592C alleles were found to have complete linkage disequilibrium, and all three IL10 polymorphisms were associated with an increased risk of intestinal-type noncardia gastric cancer. These associations were observed only in H. pylori-positive subjects and current smokers. A statistically significant interaction between the IL10-592 genotype and H. pylori infection on the risk of intestinal-type gastric cancer was observed (P for interaction  = 0.047). In addition, H. pylori-positive smokers who were carriers of either the IL10-1082G (OR [95% CI]  = 17.76 [6.17-51.06]) or the -592C (OR [95% CI]  = 8.37 [2.79-25.16]) allele had an increased risk of intestinal-type gastric cancer compared to H. pylori-negative nonsmokers homozygous for IL10-1082A and -592A, respectively. The interaction between the IL10-1082 polymorphism and the combined effects of H. pylori infection and smoking tended towards significance (P for interaction  = 0.080). CONCLUSIONS: Inflammation-related genetic variants may interact with H. pylori infection and smoking to increase the risk of noncardia gastric cancer, particularly the intestinal-type. These findings may be helpful in identifying individuals at an increased risk for developing noncardia gastric cancer

Chronic hepatitis B: whom to treat and for how long? Propositions, challenges, and future directions

Recent guidelines of the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver 2008 update of the “Asian-Pacific consensus statement on the management of chronic hepatitis B” offer comprehensive recommendations for the general management of chronic hepatitis B (CHB). These recommendations highlight preferred approaches to the prevention, diagnosis, and treatment of CHB. Nonetheless, the results of recent studies have led to an improved understanding of the disease and a belief that current recommendations on specific therapeutic considerations, including CHB treatment initiation and cessation criteria, particularly in patient populations with special circumstances, can be improved. Twelve experts from the Asia-Pacific region formed the Asia-Pacific Panel Recommendations for the Optimal Management of Chronic Hepatitis B (APPROACH) Working Group to review, challenge, and assess relevant new data and inform future updates of CHB treatment guidelines. The significance of and controversy about reported findings were discussed and debated in an expert meeting of the Working Group in Beijing, China, in November 2008. This review paper attempts to identify areas requiring improved CHB management and provide suggestions for future guideline updates, with special emphasis on treatment initiation and duration