Immuno-virological and toxicity outcomes of HIV-infected patients after 48 months of ART in Phnom Penh, Cambodia

Mexico AIDS Conference 200

A method for gene-based pathway analysis using genomewide association study summary statistics reveals nine new type 1 diabetes associations.

Pathway analysis can complement point-wise single nucleotide polymorphism (SNP) analysis in exploring genomewide association study (GWAS) data to identify specific disease-associated genes that can be candidate causal genes. We propose a straightforward methodology that can be used for conducting a gene-based pathway analysis using summary GWAS statistics in combination with widely available reference genotype data. We used this method to perform a gene-based pathway analysis of a type 1 diabetes (T1D) meta-analysis GWAS (of 7,514 cases and 9,045 controls). An important feature of the conducted analysis is the removal of the major histocompatibility complex gene region, the major genetic risk factor for T1D. Thirty-one of the 1,583 (2%) tested pathways were identified to be enriched for association with T1D at a 5% false discovery rate. We analyzed these 31 pathways and their genes to identify SNPs in or near these pathway genes that showed potentially novel association with T1D and attempted to replicate the association of 22 SNPs in additional samples. Replication P-values were skewed (P=9.85×10-11) with 12 of the 22 SNPs showing P<0.05. Support, including replication evidence, was obtained for nine T1D associated variants in genes ITGB7 (rs11170466, P=7.86×10-9), NRP1 (rs722988, 4.88×10-8), BAD (rs694739, 2.37×10-7), CTSB (rs1296023, 2.79×10-7), FYN (rs11964650, P=5.60×10-7), UBE2G1 (rs9906760, 5.08×10-7), MAP3K14 (rs17759555, 9.67×10-7), ITGB1 (rs1557150, 1.93×10-6), and IL7R (rs1445898, 2.76×10-6). The proposed methodology can be applied to other GWAS datasets for which only summary level data are available.This is the final version. It was first published by Wiley at http://onlinelibrary.wiley.com/doi/10.1002/gepi.21853/abstract

Timeliness of Clinic Attendance is a good predictor of Virological Response and Resistance to Antiretroviral drugs in HIV-infected patients

Ensuring long-term adherence to therapy is essential for the success of HIV treatment. As access to viral load monitoring and genotyping is poor in resource-limited settings, a simple tool to monitor adherence is needed. We assessed the relationship between an indicator based on timeliness of clinic attendance and virological response and HIV drug resistance

Is early center-based child care associated with tantrums and unmanageable behavior over time up to school entry?

Background. Existing research suggests that there is a relationship between greater exposure to center-based child care and child behavioral problems though the mechanism for the impact is unclear. However the measure used to document child care has usually been average hours, which may be particularly unreliable in the early months when fewer children are in center care. In addition individual trajectories for behavior difficulties have not been studied. Objective. The purpose of the current study was to examine whether the extent of exposure to center-based child care before two years predicted the trajectory of children’s difficult behavior (i.e., tantrums and unmanageable behavior) from 30 to 51 months controlling for child and maternal characteristics. Method. Data were drawn from UK-based Families, Children and Child Care (FCCC) study (n=1201). Individual growth models were fitted to test the relation between early center-based child care experiences and subsequent difficult behavior. Results. Children with more exposure to center-based care before two had less difficult behavior at 30 months, but more increase over time. Initial levels were predicted by higher difficult temperament and lower verbal ability. Higher difficult temperament and lower family socio-economic status predicted its change over time. Conclusion. Findings suggest that early exposure to center-based care before two years old is a risk factor for subsequent behavior problems especially when children have a longer period of exposure. A possible explanatory process is that child coping strategies to manage frustration are less well developed in a group context, especially when they lag behind in expressive language

Dissection of a Complex Disease Susceptibility Region Using a Bayesian Stochastic Search Approach to Fine Mapping.

Identification of candidate causal variants in regions associated with risk of common diseases is complicated by linkage disequilibrium (LD) and multiple association signals. Nonetheless, accurate maps of these variants are needed, both to fully exploit detailed cell specific chromatin annotation data to highlight disease causal mechanisms and cells, and for design of the functional studies that will ultimately be required to confirm causal mechanisms. We adapted a Bayesian evolutionary stochastic search algorithm to the fine mapping problem, and demonstrated its improved performance over conventional stepwise and regularised regression through simulation studies. We then applied it to fine map the established multiple sclerosis (MS) and type 1 diabetes (T1D) associations in the IL-2RA (CD25) gene region. For T1D, both stepwise and stochastic search approaches identified four T1D association signals, with the major effect tagged by the single nucleotide polymorphism, rs12722496. In contrast, for MS, the stochastic search found two distinct competing models: a single candidate causal variant, tagged by rs2104286 and reported previously using stepwise analysis; and a more complex model with two association signals, one of which was tagged by the major T1D associated rs12722496 and the other by rs56382813. There is low to moderate LD between rs2104286 and both rs12722496 and rs56382813 (r2 ≃ 0:3) and our two SNP model could not be recovered through a forward stepwise search after conditioning on rs2104286. Both signals in the two variant model for MS affect CD25 expression on distinct subpopulations of CD4+ T cells, which are key cells in the autoimmune process. The results support a shared causal variant for T1D and MS. Our study illustrates the benefit of using a purposely designed model search strategy for fine mapping and the advantage of combining disease and protein expression data.We acknowledge use of DNA from The UK Blood Services collection of Common Controls (UKBS-CC collection), which is funded by the Wellcome Trust grant 076113/C/04/Z and by the USA National Institute for Health Research program grant to the National Health Service Blood and Transplant (RP-PG-0310-1002). We acknowledge the use of DNA from the British 1958 Birth Cohort collection, which is funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. This research utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the National Institute of Child Health and Human Development and the JDRF and is supported by the USA National Institutes of Health grant U01-DK062418. The JDRF/Wellcome Trust Diabetes and Inflammation Laboratory is funded by the JDRF (9-2011-253), the Wellcome Trust (091157) and the National Institute for Health Research Cambridge Biomedical Centre. The research leading to these results has received funding from the European Union's 7th Framework Programme (FP7/2007-2013) under grant agreement no.241447 (NAIMIT). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). CW is supported by the Wellcome Trust (089989). We acknowledge the National Institute for Health Research Cambridge Biomedical Research Centre for funding.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pgen.100527

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 × 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.This research uses resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), the National Human Genome Research Institute (NHGRI), the National Institute of Child Health and Human Development (NICHD) and JDRF and supported by grant U01 DK062418 from the US National Institutes of Health. Further support was provided by grants from the NIDDK (DK046635 and DK085678) to P.C. and by a joint JDRF and Wellcome Trust grant (WT061858/09115) to the Diabetes and Inflammation Laboratory at Cambridge University, which also received support from the NIHR Cambridge Biomedical Research Centre. ImmunoBase receives support from Eli Lilly and Company. C.W. and H.G. are funded by the Wellcome Trust (089989). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140). We gratefully acknowledge the following groups and individuals who provided biological samples or data for this study. We obtained DNA samples from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council and the Wellcome Trust. We acknowledge use of DNA samples from the NIHR Cambridge BioResource. We thank volunteers for their support and participation in the Cambridge BioResource and members of the Cambridge BioResource Scientific Advisory Board (SAB) and Management Committee for their support of our study. We acknowledge the NIHR Cambridge Biomedical Research Centre for funding. Access to Cambridge BioResource volunteers and to their data and samples are governed by the Cambridge BioResource SAB. Documents describing access arrangements and contact details are available at http://www.cambridgebioresource.org.uk/. We thank the Avon Longitudinal Study of Parents and Children laboratory in Bristol, UK, and the British 1958 Birth Cohort team, including S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton, for preparing and providing the control DNA samples. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113; a full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/.This is the author accepted manuscript. The final version is available via NPG at http://www.nature.com/ng/journal/v47/n4/full/ng.3245.html

Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk.

Variation in the human leukocyte antigen (HLA) genes accounts for one-half of the genetic risk in type 1 diabetes (T1D). Amino acid changes in the HLA-DR and HLA-DQ molecules mediate most of the risk, but extensive linkage disequilibrium complicates the localization of independent effects. Using 18,832 case-control samples, we localized the signal to 3 amino acid positions in HLA-DQ and HLA-DR. HLA-DQβ1 position 57 (previously known; P = 1 × 10(-1,355)) by itself explained 15.2% of the total phenotypic variance. Independent effects at HLA-DRβ1 positions 13 (P = 1 × 10(-721)) and 71 (P = 1 × 10(-95)) increased the proportion of variance explained to 26.9%. The three positions together explained 90% of the phenotypic variance in the HLA-DRB1-HLA-DQA1-HLA-DQB1 locus. Additionally, we observed significant interactions for 11 of 21 pairs of common HLA-DRB1-HLA-DQA1-HLA-DQB1 haplotypes (P = 1.6 × 10(-64)). HLA-DRβ1 positions 13 and 71 implicate the P4 pocket in the antigen-binding groove, thus pointing to another critical protein structure for T1D risk, in addition to the HLA-DQ P9 pocket.This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD), and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. This work is supported in part by funding from the National Institutes of Health (5R01AR062886-02 (PIdB), 1R01AR063759 (SR), 5U01GM092691-05 (SR), 1UH2AR067677-01 (SR), R01AR065183 (PIWdB)), a Doris Duke Clinical Scientist Development Award (SR), the Wellcome Trust (JAT) and the National Institute for Health Research (JAT and JMMH), and a Vernieuwingsimpuls VIDI Award (016.126.354) from the Netherlands Organization for Scientific Research (PIWdB). TLL was supported by the German Research Foundation (LE 2593/1-1 and LE 2593/2-1).This is the accepted manuscript. The final version is available at http://www.nature.com/ng/journal/v47/n8/full/ng.3353.html

Persistent C-peptide secretion in Type 1 diabetes and its relationship to the genetic architecture of diabetes

Background: The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. Methods: C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. Results: Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. Conclusions: Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

Magnetic properties, anisotropy, and microstructure of sputtered rare-earth iron multilayers

A study of compositionally modulated magnetic films of the form Fe/RE, particularly for RE=Nd and Dy, has been performed by vibrating sample magnetometry, ac susceptibility and x-ray diffraction. The relationship between the magnetic properties and the layer thickness was studied systematically for X-Å Fe/Y-Å Dy, as the layer thicknesses X and Y were varied from 1.8 to 20 Å. The ranges of layer thicknesses required for perpendicular anisotropy were determined. The interface and volume anisotropy energies were estimated for X-Å Fe/Y-Å Nd and the differences in the magnetic properties between X-Å Fe/7-Å Dy and X-Å Fe/7-Å Nd are discussed. Journal of Applied Physics is copyrighted by The American Institute of Physics