MI-GWAS: a SAS platform for the analysis of inherited and maternal genetic effects in genome-wide association studies using log-linear models

<p>Abstract</p> <p>Background</p> <p>Several platforms for the analysis of genome-wide association data are available. However, these platforms focus on the evaluation of the genotype inherited by affected (i.e. case) individuals, whereas for some conditions (e.g. birth defects) the genotype of the mothers of affected individuals may also contribute to risk. For such conditions, it is critical to evaluate associations with both the maternal and the inherited (i.e. case) genotype. When genotype data are available for case-parent triads, a likelihood-based approach using log-linear modeling can be used to assess both the maternal and inherited genotypes. However, available software packages for log-linear analyses are not well suited to the analysis of typical genome-wide association data (e.g. including missing data).</p> <p>Results</p> <p>An integrated platform, Maternal and Inherited Analyses for Genome-wide Association Studies <b>(</b>MI-GWAS) for log-linear analyses of maternal and inherited genetic effects in large, genome-wide datasets, is described. MI-GWAS uses SAS and LEM software in combination to appropriately format data, perform the log-linear analyses and summarize the results. This platform was evaluated using existing genome-wide data and was shown to perform accurately and relatively efficiently.</p> <p>Conclusions</p> <p>The MI-GWAS platform provides a valuable tool for the analysis of association of a phenotype or condition with maternal and inherited genotypes using genome-wide data from case-parent triads. The source code for this platform is freely available at <url>http://www.sph.uth.tmc.edu/sbrr/mi-gwas.htm</url>.</p

Risk factors for sickness absence due to low back pain and prognostic factors for return to work in a cohort of shipyard workers

The purpose of this study was to determine risk factors for the occurrence of sickness absence due to low back pain (LBP) and to evaluate prognostic factors for return to work. A longitudinal study with 1-year follow-up was conducted among 853 shipyard workers. The cohort was drawn around January 2004 among employees in the shipyard industry. Baseline information was obtained by questionnaire on physical and psychosocial work load, need for recovery, perceived general health, musculoskeletal complaints, sickness absence, and health care use during the past year. During the 1-year follow-up for each subject medical certifications were retrieved for information on the frequency and duration of spells of sickness absence and associated diagnoses. Cox regression analyses were conducted on occurrence and on duration of sickness absence with hazard ratios (HR) with 95% confidence interval (95% CI) as measure of association. During the 1-year follow-up period, 14% of the population was on sick leave at least once with LBP while recurrence reached 41%. The main risk factors for sickness absence were previous absence due to a health problem other than LBP (HR 3.07; 95%CI 1.66–5.68) or previous sickness absence due to LBP (HR 6.52; 95%CI 3.16–13.46). Care seeking for LBP and lower educational level also hold significant influences (HR 2.41; 95%CI 1.45–4.01 and HR 2.46; 95%CI 1.19–5.07, respectively). Living with others, night shift and supervising duties were associated with less absenteeism due to LBP. Workers with a history of herniated disc had a significantly decreased rate of returning to work, whereas those who suffered from hand-wrist complaints and LBP returned to work faster. Prior sick leave due to LBP partly captured the effects of work-related physical and psychosocial factors on occurrence of sick leave. Our study showed that individual and job characteristics (living alone, night shift, lower education, sick leave, or care seeking during the last 12 months) influenced the decision to take sick leave due to LBP. An increased awareness of those frequently on sick leave and additional management after return to work may have a beneficial effect on the sickness absence pattern

BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes

BACKGROUND: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic. METHODS: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome. RESULTS: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients. CONCLUSIONS: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Day-care, early common infections and childhood acute leukaemia: a multicentre French case–control study

We conducted a case–control study to investigate the role of early infections in the aetiology of childhood acute leukaemias. The study included 280 incident cases (240 acute lymphoblastic leukaemia and 40 acute non-lymphoblastic leukaemia) and 288 hospital controls, frequency matched by age, gender, hospital, catchment area of the hospital and ethnic origin. Data were obtained from standardised face-to-face interviews of the mothers. The interviews included questions on early common infections, day-care attendance, breast-feeding, birth order and infantile diseases. Odds ratios were estimated using an unconditional regression model including the stratification variables, parental socio-economic status and perinatal characteristics. Birth order was not associated with childhood leukaemia (acute lymphoblastic or acute non-lymphoblastic). A statistically-significant inverse association was observed between childhood leukaemia and day-care attendance (odds ratio=0.6, 95% Confidence Interval=(0.4–1.0)), repeated early common infections (⩾4 per year before age two, odds ratio=0.6 (0.4–1.0)), surgical procedures for ear–nose–throat infections before age two (odds ratio=0.5 (0.2–1.0)) and prolonged breast-feeding (⩾6 months, odds ratio=0.5 (0.2–1.0)). In the multivariate model including day-care attendance, early common infections and breast-feeding, results concerning breast-feeding remained unchanged. A statistically significant interaction between day-care attendance and repeated early common infections was observed. When the interaction was taken into account, the simple effects of day-care and early common infections disappeared (odds ratio=1.1 (0.5–2.3) and odds ratio=0.8 (0.5–1.3), respectively) while the joint effect of day-care attendance and early common infections was negatively associated with childhood leukaemia (odds ratio=0.3 (0.1–0.8)). All the above associations were observed both for acute lymphoblastic leukaemia and acute non-lymphoblastic leukaemia. Our results support Greaves' hypothesis, even though they are not specific of common leukaemia

Residential mobility and risk of childhood acute lymphoblastic leukaemia: an ecological study

We conducted an ecological analysis of childhood acute lymphoblastic leukaemia-incidence data from children ⩽5 years old during 1992–1998 from the Surveillance, Epidemiology, and End Results Program in 200 counties and Hawaii. The response variable was the count of cases in each county race–sex stratum, examined in relation to data from the United States Census and the United States Department of Agriculture. The final models for both sexes included race, proportion moved during 1985–1990, and proportion of households with income ⩾$5000 as potential predictors. Incidence was lower among black boys (rate ratio (RR)=0.5) and black girls (RR=0.4) than among other children of the same sex; no other significant racial differences were detected. Incidence was elevated among males (but not females) residing in counties where ⩾50$5000 (RR=1.5). These sex differences in risk factors were unexpected

Variations in Stress Sensitivity and Genomic Expression in Diverse S. cerevisiae Isolates

Interactions between an organism and its environment can significantly influence phenotypic evolution. A first step toward understanding this process is to characterize phenotypic diversity within and between populations. We explored the phenotypic variation in stress sensitivity and genomic expression in a large panel of Saccharomyces strains collected from diverse environments. We measured the sensitivity of 52 strains to 14 environmental conditions, compared genomic expression in 18 strains, and identified gene copy-number variations in six of these isolates. Our results demonstrate a large degree of phenotypic variation in stress sensitivity and gene expression. Analysis of these datasets reveals relationships between strains from similar niches, suggests common and unique features of yeast habitats, and implicates genes whose variable expression is linked to stress resistance. Using a simple metric to suggest cases of selection, we found that strains collected from oak exudates are phenotypically more similar than expected based on their genetic diversity, while sake and vineyard isolates display more diverse phenotypes than expected under a neutral model. We also show that the laboratory strain S288c is phenotypically distinct from all of the other strains studied here, in terms of stress sensitivity, gene expression, Ty copy number, mitochondrial content, and gene-dosage control. These results highlight the value of understanding the genetic basis of phenotypic variation and raise caution about using laboratory strains for comparative genomics

Effects of DHA- Rich n-3 Fatty Acid Supplementation on Gene Expression in Blood Mononuclear Leukocytes: The OmegAD Study

Background: Dietary fish oil, rich in n-3 fatty acids (n-3 FAs), e. g. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), regulate inflammatory reactions by various mechanisms, e. g. gene activation. However, the effects of long-term treatment with DHA and EPA in humans, using genome wide techniques, are poorly described. Hence, our aim was to determine the effects of 6 mo of dietary supplementation with an n-3 FA preparation rich in DHA on global gene expression in peripheral blood mononuclear cells. Methods and Findings: In the present study, blood samples were obtained from a subgroup of 16 patients originating from the randomized double-blind, placebo-controlled OmegAD study, where 174 Alzheimer disease (AD) patients received daily either 1.7 g of DHA and 0.6 g EPA or placebo for 6 months. In blood samples obtained from 11 patients receiving n-3 FA and five placebo, expressions of approximately 8000 genes were assessed by gene array. Significant changes were confirmed by real-time PCR. At 6 months, the n-3 FAs group displayed significant rises of DHA and EPA plasma concentrations, as well as up-and down-regulation of nine and ten genes, respectively, was noticed. Many of these genes are involved in inflammation regulation and neurodegeneration, e. g. CD63, MAN2A1, CASP4, LOC399491, NAIP, and SORL1 and in ubiqutination processes, e. g. ANAPC5 and UBE2V1. Down-regulations of ANAPC5 and RHOB correlated to increases of plasma DHA and EPA levels. Conclusions: We suggest that 6 months of dietary n-3 FA supplementatio

More stories on Th17 cells

For more than two decades, immunologists have been using the so-called Th1/Th2 paradigm to explain most of the phenomena related to adaptive immunity. the Th1/Th2 paradigm implied the existence of two different, mutually regulated, CD4(+) T helper subsets: Th1 cells, driving cell-mediated immune responses involved in tissue damage and fighting infection against intracellular parasites; and Th2 cells that mediate IgE production and are particularly involved in eosinophilic inflammation, allergy and clearance of helminthic infections. A third member of the T helper set, IL-17-producing CD4(+) T cells, now called Th17 cells, was recently described as a distinct lineage that does not share developmental pathways with either Th1 or Th2 cells. the Th17 subset has been linked to autoimmune disorders, being able to produce IL-17, IL-17F and IL-21 among other inflammatory cytokines. Interestingly, it has been reported that there is not only a cross-regulation among Th1, Th2 and Th17 effector cells but there is also a dichotomy in the generation of Th17 and T regulatory cells. Therefore, Treg and Th17 effector cells arise in a mutually exclusive fashion, depending on whether they are activated in the presence of TGF-beta or TGF-beta plus inflammatory cytokines such as IL-6. This review will address the discovery of the Th17 cells, and recent progress on their development and regulation.Crohn's and Colitis Foundation of AmericaNIHLa Jolla Inst Allergy & Immunol, La Jolla, CA 92037 USAUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Microbiol Immunol & Parasitol, São Paulo, BrazilNIH: RO1 AI050265-06Web of Scienc