Replication Study of Candidate Genes Associated With Type 2 Diabetes Based On Genome-Wide Screening

OBJECTIVE—The present study was conducted to confirm possible associations between candidate genes from genome-wide association studies and type 2 diabetes in Japanese diabetic patients and a community-based general population. A total of 11 previously reported single-nucleotide polymorphisms (SNPs) from the TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2A/B, SLC30A8, and KCNJ11 genes were analyzed

A fitness assay for comparing RNAi effects across multiple C. elegans genotypes

<p>Abstract</p> <p>Background</p> <p>RNAi technology by feeding of <it>E. coli </it>containing dsRNA in <it>C. elegans </it>has significantly contributed to further our understanding of many different fields, including genetics, molecular biology, developmental biology and functional genomics. Most of this research has been carried out in a single genotype or genetic background. However, RNAi effects in one genotype do not reveal the allelic effects that segregate in natural populations and contribute to phenotypic variation.</p> <p>Results</p> <p>Here we present a method that allows for rapidly comparing RNAi effects among diverse genotypes at an improved high throughput rate. It is based on assessing the fitness of a population of worms by measuring the rate at which <it>E. coli </it>is consumed. Critically, we demonstrate the analytical power of this method by QTL mapping the loss of RNAi sensitivity (in the germline) in a recombinant inbred population derived from a cross between Bristol and a natural isolate from Hawaii. Hawaii has lost RNAi sensitivity in the germline. We found that polymorphisms in <it>ppw-1 </it>contribute to this loss of RNAi sensitivity, but that other loci are also likely to be important.</p> <p>Conclusions</p> <p>In summary, we have established a fast method that improves the throughput of RNAi in liquid, that generates quantitative data, that is easy to implement in most laboratories, and importantly that enables QTL mapping using RNAi.</p

In C. elegans, High Levels of dsRNA Allow RNAi in the Absence of RDE-4

C. elegans Dicer requires an accessory double-stranded RNA binding protein, RDE-4, to enact the first step of RNA interference, the cleavage of dsRNA to produce siRNA. While RDE-4 is typically essential for RNAi, we report that in the presence of high concentrations of trigger dsRNA, rde-4 deficient animals are capable of silencing a transgene. By multiple criteria the silencing occurs by the canonical RNAi pathway. For example, silencing is RDE-1 dependent and exhibits a decrease in the targeted mRNA in response to an increase in siRNA. We also find that high concentrations of dsRNA trigger lead to increased accumulation of primary siRNAs, consistent with the existence of a rate-limiting step during the conversion of primary to secondary siRNAs. Our studies also revealed that transgene silencing occurs at low levels in the soma, even in the presence of ADARs, and that at least some siRNAs accumulate in a temperature-dependent manner. We conclude that an RNAi response varies with different conditions, and this may allow an organism to tailor a response to specific environmental signals

Serum uric acid distribution according to SLC22A12 W258X genotype in a cross-sectional study of a general Japanese population

<p>Abstract</p> <p>Background</p> <p>Although <it>SLC22A12 258X </it>allele was found among those with hypouricemia, it was unknown that serum uric acid distribution among those with <it>SLC22A12 258X </it>allele. This study examined serum uric acid (SUA) distribution according to <it>SLC22A12 </it>W258X genotype in a general Japanese population.</p> <p>Methods</p> <p>Subjects were 5,023 health checkup examinees (3,413 males and 1,610 females) aged 35 to 69 years with creatinine < 2.0 mg/dL, who were participants of a cohort study belonging to the Japan Multi-Institutional Collaborative Cohort Study (J-MICC Study). <it>SLC22A12 </it>W258X was genotyped with a polymerase chain reaction with confronting two-pair primers.</p> <p>Results</p> <p>The genotype frequency was 4,793 for <it>WW</it>, 225 for <it>WX</it>, and 5 for <it>XX</it>, which was in Hardy-Weinberg equilibrium (p = 0.164) with <it>X </it>allele 0.023 (95% confidence interval [0.021-0.027]). Mean (range) SUA was 6.2 (2.1-11.4) mg/dL for <it>WW</it>, 3.9 (0.8-7.8) mg/dL for <it>WX</it>, and 0.8 (0.7-0.9) mg/dL for <it>XX </it>among males, and 4.5 (1.9-8.9) mg/dL, 3.3 (2.0-6.5) mg/dL, and 0.60 (0.5-0.7) mg/dL among females, respectively. Six individuals with SUA less than 1.0 mg/dL included two males with <it>XX </it>genotype, one male with <it>WX </it>genotype, and three females with <it>XX </it>genotype. Subjects with <it>WX </it>genotype were 14 (77.8%) of 18 males with a SUA of 1.0-2.9 mg/dL, and 28 (34.6%) of 81 females with the same range of SUA. The corresponding values were 131 (25.1%) of 522 males and 37 (3.5%) of 1,073 females for SUA 3.0-4.9 mg/dL, and 8 (0.4%) of 2,069 males and 5 (1.1%) of 429 females for SUA 5.0-6.9 mg/dL. The <it>X </it>allele effect for SUA less than 3 mg/dL was significantly (p < 0.001) higher in males (OR = 102.5, [33.9-309.8]) than in females (OR = 25.6 [14.4-45.3]).</p> <p>Conclusions</p> <p>Although <it>SLC22A12 </it>W258X was a determining genetic factor on SUA, SUA of those with <it>WX </it>genotype distributed widely from 0.8 mg/dL to 7.8 mg/dL. It indicated that other genetic traits and/or lifestyle affected SUA of those with <it>WX </it>genotype, as well as those with <it>WW </it>genotype.</p

A Conserved PHD Finger Protein and Endogenous RNAi Modulate Insulin Signaling in Caenorhabditis elegans

Insulin signaling has a profound effect on longevity and the oxidative stress resistance of animals. Inhibition of insulin signaling results in the activation of DAF-16/FOXO and SKN-1/Nrf transcription factors and increased animal fitness. By studying the biological functions of the endogenous RNA interference factor RDE-4 and conserved PHD zinc finger protein ZFP-1 (AF10), which regulate overlapping sets of genes in Caenorhabditis elegans, we identified an important role for these factors in the negative modulation of transcription of the insulin/PI3 signaling-dependent kinase PDK-1. Consistently, increased expression of pdk-1 in zfp-1 and rde-4 mutants contributed to their reduced lifespan and sensitivity to oxidative stress and pathogens due to the reduction in the expression of DAF-16 and SKN-1 targets. We found that the function of ZFP-1 in modulating pdk-1 transcription was important for the extended lifespan of the age-1(hx546) reduction-of-function PI3 kinase mutant, since the lifespan of the age-1; zfp-1 double mutant strain was significantly shorter compared to age-1(hx546). We further demonstrate that overexpression of ZFP-1 caused an increased resistance to oxidative stress in a DAF-16–dependent manner. Our findings suggest that epigenetic regulation of key upstream signaling components in signal transduction pathways through chromatin and RNAi may have a large impact on the outcome of signaling and expression of numerous downstream genes.Leukemia & Lymphoma Society of America (3260-07 Special Fellow Award)Arnold and Mabel Beckman Foundation (Young Investigator Award)United States. National Institutes of Health (Director's New Innovator Award (1 DP2 OD006412-01))United States. National Institutes of Health (grant GM66269)modENCODE (grant U01 HG004270)United States. National Institutes of Health (training grant 5T32 GM07088-34

Evaluation of the combined use of adiponectin and C-reactive protein levels as biomarkers for predicting the deterioration in glycaemia after a median of 5.4 years

Aims/hypothesis: Hypoadiponectinaemia and raised C-reactive protein (CRP) level are obesity-related biomarkers associated with glucose dysregulation. We evaluated the combined use of these two biomarkers in predicting the deterioration of glycaemia in a prospective study after a median of 5.4 years. Methods: In total 1,288 non-diabetic participants from the Hong Kong Cardiovascular Risk Factor Prevalence Study-2, with high-sensitivity CRP (hsCRP) and total adiponectin levels measured were included. OGTT was performed in all participants. Two hundred and six participants had deterioration of glycaemia at follow-up, whereas 1,082 participants did not. Results: Baseline age, hsCRP and adiponectin levels were significant independent predictors of the deterioration of glycaemia in a Cox regression analysis after adjusting for baseline age, sex, BMI, hypertension, triacylglycerols, 2 h post-OGTT glucose and homeostasis model assessment of insulin resistance index (all p < 0.01). The introduction of hsCRP or adiponectin level to a regression model including the other biomarker improved the prediction of glycaemic progression significantly in all participants, especially in women (all p < 0.01). The combined inclusion of the two biomarkers resulted in a modest improvement in model discrimination, compared with the inclusion of either one alone. Among participants with impaired fasting glucose/impaired glucose tolerance (IFG/IGT) at baseline, hsCRP and adiponectin levels were not predictive of progression or improvement of glycaemic status. Conclusions/interpretation: Adiponectin and hsCRP levels are independent factors in predicting the deterioration of glycaemia, supporting the role of adiposity-related inflammation in the development of type 2 diabetes. Their combined use as predictive biomarkers is especially useful in women, but not in participants with IFG/IGT. © 2011 The Author(s).published_or_final_versionSpringer Open Choice, 21 Feb 201

Milestones in the Observations of Cosmic Magnetic Fields

Magnetic fields are observed everywhere in the universe. In this review, we concentrate on the observational aspects of the magnetic fields of Galactic and extragalactic objects. Readers can follow the milestones in the observations of cosmic magnetic fields obtained from the most important tracers of magnetic fields, namely, the star-light polarization, the Zeeman effect, the rotation measures (RMs, hereafter) of extragalactic radio sources, the pulsar RMs, radio polarization observations, as well as the newly implemented sub-mm and mm polarization capabilities. (Another long paragraph is omitted due to the limited space here)Comment: Invited Review (ChJA&A); 32 pages. Sorry if your significant contributions in this area were not mentioned. Published pdf & ps files (with high quality figures) now availble at http://www.chjaa.org/2002_2_4.ht

A tagging SNP in INSIG2 is associated with obesity-related phenotypes among Samoans

<p>Abstract</p> <p>Background</p> <p>A genome wide association study found significant association of a sequence variant, rs7566605, in the insulin-induced gene 2 (<it>INSIG2</it>) with obesity. However, the association remained inconclusive in follow-up studies. We tested for association of four tagging SNPs (tagSNPs) including this variant with body mass index (BMI) and abdominal circumference (ABDCIR) in the Samoans of the Western Pacific, a population with high levels of obesity.</p> <p>Methods</p> <p>We studied 907 adult Samoan participants from a longitudinal study of adiposity and cardiovascular disease risk in two polities, American Samoa and Samoa. Four tagSNPs were identified from the Chinese HapMap database based on pairwise <it>r</it>^{<it>2 </it>}of ≥0.8 and minor allele frequency of ≥0.05. Genotyping was performed using the TaqMan assay. Tests of association with BMI and ABDCIR were performed under the additive model.</p> <p>Results</p> <p>We did not find association of rs7566605 with either BMI or ABDCIR in any group of the Samoans. However, the most distally located tagSNPs in Intron 3 of the gene, rs9308762, showed significant association with both BMI (p-value 0.024) and ABDCIR (p-value 0.009) in the combined sample and with BMI (p-value 0.038) in the sample from Samoa.</p> <p>Conclusion</p> <p>Although rs7566605 was not significantly associated with obesity in our study population, we can not rule out the involvement of <it>INSIG2 </it>in obesity related traits as we found significant association of another tagSNP in <it>INSIG2 </it>with both BMI and ABDCIR. This study suggests the importance of comprehensive assessment of sequence variants within a gene in association studies.</p