11 research outputs found

    Novel Common Genetic Susceptibility Loci for Colorectal Cancer

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    BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screenin

    Data from: Natural variation in GL1 and its effects on trichome density in Arabidopsis thaliana

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    The ultimate understanding of how biological diversity arises, is maintained, and lost depends on identifying the genes responsible. Although a good deal has been discovered about gene function over the past few decades, far less is understood about gene effects; i.e., how natural variation in a gene contributes to natural variation in phenotypes. Trichome density in Arabidopsis thaliana is an ideal trait for studies of natural molecular and phenotypic variation, as trichome initiation is genetically well-characterised and trichome density is highly variable in and among natural populations. Here, we show that variation at GLABRA1 (GL1), an R2R3 MYB transcription factor gene, which has a role in trichome initiation, has qualitative and likely quantitative effects on trichome density in natural accessions of A. thaliana. Specifically, we characterize four independent loss-of-function alleles for GL1, each of which yields a glabrous phenotype. Further, we find that a pattern of common polymorphisms confined to the GL1 locus is associated with quantitative variation for trichome density. While mutations resulting in a glabrous phenotype are primarily coding changes, the pattern resulting in quantitative variation spans both coding and regulatory regions. These data show that GL1 is an important source of trichome density variation within A. thaliana and, along with recent reports, suggest that the TTG1 epidermal cell fate pathway generally may be the key molecular genetic source of natural trichome density variation and an important model for the study of molecular evolution

    The Genetic Architecture of Constitutive and Induced Trichome Density in Two New Recombinant Inbred Line Populations of Arabidopsis Thaliana: Phenotypic Plasticity, Epistasis, and Bidirectional Leaf Damage Response

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    Herbivory imposes an important selective pressure on plants. In Arabidopsis thaliana leaf trichomes provide a key defense against insect herbivory; however, trichome production incurs a fitness cost in the absence of herbivory. Previous work on A. thaliana has shown an increase in trichome density in response to leaf damage, suggesting a mechanism by which the cost associated with constitutively high trichome density might be mitigated; however, the genetic basis of trichome density induction has not been studied. Results: Here, we describe the mapping of quantitative trait loci (QTL) for constitutive and damage induced trichome density in two new recombinant inbred line populations of A. thaliana; mapping for constitutive and induced trichome density also allowed for the investigation of damage response (plasticity) QTL. Both novel and previously identified QTL for constitutive trichome density and the first QTL for induced trichome density and response are identified. Interestingly, two of the four parental accessions and multiple RILs in each population exhibited lower trichome density following leaf damage, a response not previously described in A. thaliana. Importantly, a single QTL was mapped for the response phenotype and allelic variation at this locus appears to determine response trajectory in RILs. The data also show that epistatic interactions are a significant component of the genetic architecture of trichome density. Conclusions: Together, our results provide further insights into the genetic architecture of constitutive trichome density and new insights into induced trichome density in A. thaliana specifically and to our understanding of the genetic underpinnings of natural variation generally.National Science Foundation IBN-0344200Marsden Foundation 09-MAU-114Integrative Biolog

    Data from: The genetic architecture of constitutive and induced trichome density in two new RIL populations of Arabidopsis thaliana: phenotypic plasticity, epistasis, and bidirectional leaf damage response

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    Background: Herbivory imposes an important selective pressure on plants. In Arabidopsis thaliana leaf trichomes provide a key defense against insect herbivory; however, trichome production incurs a fitness cost in the absence of herbivory. Previous work on A. thaliana has shown an increase in trichome density in response to leaf damage, suggesting a mechanism by which the cost associated with constitutively high trichome density might be mitigated; however, the genetic basis of trichome density induction has not been studied. Results: Here, we describe the mapping of quantitative trait loci (QTL) for constitutive and damage induced trichome density in two new recombinant inbred line populations of A. thaliana; mapping for constitutive and induced trichome density also allowed for the investigation of damage response (plasticity) QTL. Both novel and previously identified QTL for constitutive trichome density and the first QTL for induced trichome density and response are identified. Interestingly, two of the four parental accessions and multiple RILs in each population exhibited lower trichome density following leaf damage, a response not previously described in A. thaliana. Importantly, a single QTL was mapped for the response phenotype and allelic variation at this locus appears to determine response trajectory in RILs. The data also show that epistatic interactions are a significant component of the genetic architecture of trichome density. Conclusions: Together, our results provide further insights into the genetic architecture of constitutive trichome density and new insights into induced trichome density in A. thaliana specifically and to our understanding of the genetic underpinnings of natural variation generally

    HixOb RIL genotypes for dryad - VV Symonds

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    Genotype file for the HixOb RIL mapping population.The first row is marker names, second row is chromosome number, and third row is position in cM based on linkage maps used in the publication

    Implications of a pre-exercise alkalosis-mediated attenuation of HSP72 on its response to a subsequent bout of exercise

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    The aim of this study was to investigate if a pre-exercise alkalosis-mediated attenuation of HSP72 had any effect on the response of the same stress protein after a subsequent exercise. Seven physically active males [25.0 ± 6.5 years, 182.1 ± 6.0 cm, 74.0 ± 8.3 kg, peak aerobic power (PPO) 316 ± 46 W] performed a repeated sprint exercise (EXB1) following a dose of 0.3 g kg⁻Âč body mass of sodium bicarbonate (BICARB), or a placebo of 0.045 g kg⁻Âč body mass of sodium chloride (PLAC). Participants then completed a 90-min intermittent cycling protocol (EXB2). Monocyte expressed HSP72 was significantly attenuated after EXB1 in BICARB compared to PLAC, however, there was no difference in the HSP72 response to the subsequent EXB2 between conditions. Furthermore there was no difference between conditions for measures of oxidative stress (protein carbonyl and HSP32). These findings confirm the sensitivity of the HSP72 response to exercise-induced changes in acid–base status in vivo, but suggest that the attenuated response has little effect upon subsequent stress in the same day

    Study protocol: phase II study to evaluate the effect of cetuximab monotherapy after immunotherapy with PD-1 inhibitors in patients with head and neck squamous cell cancer

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    Background: Immunotherapy with programmed death receptor-1 (PD-1) inhibitors, as a single agent or in combination with chemotherapy, is the standard first-line treatment for recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC). Unfortunately, there is no established second-line treatment for the many patients who fail immunotherapy. Cetuximab is the only targeted therapy approved in HNSCC but historically has a low response rate of 13%. Objectives: We hypothesize that cetuximab monotherapy following an immune checkpoint inhibitor (ICI) will lead to increased efficacy due to a potential synergistic effect on the antitumor immune response, as a result of activation effects of both treatments on innate and adaptative immune responses. To the authors’ knowledge, this is the only ongoing prospective clinical study that evaluates the combination of cetuximab and ICIs administered sequentially. Methods and analysis: In this non-randomized, open-label, phase II trial, 30 patients with R/M HNSCC who have previously failed or could not tolerate a PD-1 inhibitor as a single agent or in combination with chemotherapy will subsequently be treated with cetuximab monotherapy. Outcomes of interest include overall response rate, duration of response, progression-free survival, overall survival, and treatment toxicity, as well as treatment outcome measured by a patient-reported outcome questionnaire. Saliva and blood will be collected for correlative studies to investigate the immune response status at the end of therapy with an ICI and the effect of cetuximab on the antitumor immune response. The results will be correlated with the response to cetuximab and the time window between the last administration of an ICI and the loading dose of cetuximab. The clinical study is actively recruiting. Ethics: This study was approved by the Wake Forest Comprehensive Cancer Center Institutional Review Board: IRB00065239. Clinical trial registration: This study is registered on ClinicalTrials.gov: NCT04375384
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