Sex-specific gene and pathway modeling of inherited glioma risk

Ostrom, Quinn T.; Coleman, Warren; Huang, William; Rubin, Joshua B.; Lathia, Justin D.; Berens, Michael E.; Speyer, Gil; Liao, Peter; Wrensch, Margaret; Eckel‐Passow, Jeanette E.; Armstrong, Georgina; Rice, Terri; Wiencke, John K.; McCoy, Lucie; Hansen, Helen M.; Amos, Christopher I.; Bernstein, Jonine L.; Claus, Elizabeth B.; Houlston, Richard S.; Il’yasova, Dora; Jenkins, Robert B.; Johansen, Christoffer; Lachance, Daniel H.; Lai, Rose; Merrell, Ryan; Olson, Sara H.; Sadetzki, Siegal; Schildkraut, Joellen M.; Shete, Sanjay; Andersson, Ulrika; Rajaraman, Preetha; Chanock, Stephen J.; Linet, Martha S.; Wang, Zhaoming; Yeager, Meredith; Melin, Beatrice; Bondy, Melissa L.; Barnholtz‐Sloan, Jill S.

doi:10.1093/neuonc/noy135

Cited by 30 publications

(21 citation statements)

References 52 publications

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“…The criteria for selecting variables conformed to clinical relevance and multivariate Cox analysis [37]. It has been reported that age, IDH status and sex are associated with the incidence rate or prognosis of glioma [1, 38–40]. Considering the clinical factors of glioma, these parameters (ARL3 expression level, age, sex, WHO grade and IDH status) were included in the predictive model.…”

Section: Resultsmentioning

confidence: 99%

ARL3 is downregulated and acts as a prognostic biomarker in glioma

et al. 2019

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Background Glioma is the most common primary malignant brain tumor in adults with a poor prognosis. ARL3 is a member of the ARF family, and plays a key role in ciliary function and lipid-modified protein trafficking. ARL3 has been reported to be involved in ciliary diseases, in which it affects kidney and photoreceptor development. However, the functional role of ARL3 in cancer remains unknown. In this study, we aimed to explore ARL3 expression and its roles in glioma prognosis. Methods RT-PCR and immunohistochemistry were performed to examine the expression level of ARL3 in glioma samples. Data from The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA) and Repository for Molecular Brain Neoplasia Data (REMBRANDT) databases were employed to investigate ARL3 expression and its roles in glioma prognosis. A nomogram for predicting 3- or 5-year survival was established using Cox proportional hazards regression. Finally, gene ontology (GO) analysis, gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were performed to explore the biological function. Results ARL3 expression was downregulated in glioma, and associated with poor prognosis in glioma patients. The C-indexes, areas under the ROC curve and calibration plots of the nomogram indicated an effective predictive performance for glioma patients. In addition, GO and pathway analyses suggested the involvement of ARL3 in angiogenesis and immune cell infiltration in the microenvironment. Conclusions Low ARL3 expression predicted poor prognosis and contributed to antiangiogenesis and the proportion of infiltrating immune cells in the GBM microenvironment. Thus, ARL3 may be a prognostic marker and therapeutic target for glioma. Electronic supplementary material The online version of this article (10.1186/s12967-019-1914-3) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

ARL3 is downregulated and acts as a prognostic biomarker in glioma

et al. 2019

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“…We used PASCAL to compute pathway-scored ( 36 – 38 ). In this approach, genetic markers SNPs were first mapped to genes, and the association scores of all genes in the pathway were computed.…”

Section: Methodsmentioning

confidence: 99%

Heritability and Genome-Wide Association Study of Plasma Cholesterol in Chinese Adult Twins

et al. 2018

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Dyslipidemia represents a strong and independent risk factor for cardiovascular disease. Plasma cholesterol, such as total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), and high density lipoprotein cholesterol (HDL-C), is the common indicator of diagnosing dyslipidemia. Here based on 382 Chinese twin pairs, we explored the magnitude of genetic impact on TC, HDL-C, LDL-C variation and further searched for genetic susceptibility loci for them using genome-wide association study (GWAS). The ACE model was the best fit model with additive genetic parameter (A) accounting for 26.6%, common or shared environmental parameter (C) accounting for 47.8%, unique/non-shared environmental parameter (E) accounting for 25.6% for the variance in HDL-C. The AE model was the best fit model for TC (A: 61.4%; E: 38.6%) and LDL-C (A: 65.5%; E: 34.5%). While no SNPs reached the genome-wide significance level (P < 5 × 10−8), 8, 14, 9 SNPs exceeded the suggestive significance level (P < 1 × 10−5) for TC, HDL-C, LDL-C, respectively. The promising genetic regions for TC, HDL-C, LDL-C were on chromosome 11 around rs7107698, chromosome 5 around rs12518218, chromosome 2 around rs10490120, respectively. Gene-based analysis found 1038, 1033 and 1090 genes nominally associated with TC, HDL-C, LDL-C (P < 0.05), especially FAF1, KLKB1 for TC, KLKB1 for HDL-C, and NTRK1, FAF1, SNTB2 for LDL-C, respectively. The number of common related genes among TC, HDL-C and LDL-C was 71, including FAF1, KLKB1, etc. Pathway enrichment analysis discovered known related pathways-zinc transporters, metal ion SLC transporters for TC, cell adhesion molecules CAMs, IL-6 signaling for HDL, FC epsilon RI signaling pathway, NFAT pathway for LDL, respectively. In conclusion, the TC and LDL-C level is moderately heritable and the HDL-C level is lowly heritable in Chinese population. The genomic loci, functional genes and pathways are identified to account for the heritability of plasma cholesterol level. Our findings provide important insights into plasma cholesterol molecular physiology and expect future research to replicate and validate our results.

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“…However, pinpointing the causative variation is more di cult. To reveal the mechanism through which a mutation site affects a phenotype and to perform subsequent functional research, GWAS joint analysis on multiple genomic levels can be used and biological pathway analysis can be applied to detect the superposition of multiple minor genes by examining genes involved in the same biological pathway, thus enabling deeper mining of GWAS data [10][11][12][13]. With the development of genome sequencing technology and the continuous improvement of statistical methods, GWAS is expected to be more e ciently applied to gene identi cation for important traits in livestock and poultry and to play an increasingly important role in animal breeding.…”

Section: Introductionmentioning

confidence: 99%

Pathway-based analysis enables deeper mining of GWAS data on H/L in chickens

Wang¹,

Zhu²,

Wen³

et al. 2020

Preprint

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Background Heterophils are refers to white blood cells with phagocytosis and killing functions in the avian immune system, These cells identify and kill pathogenic microorganisms through precise regulatory mechanisms. As a simple index, the heterophil/lymphocyte ratio (H/L) in the blood reflects the immune system status of chickens. H/L is a complex trait affected by multiple genetic loci, but single nucleotide polymorphisms (SNPs) significantly associated with traits can usually explain only part of the phenotypic variation. Combining a genome-wide association study (GWAS) with pathway analysis can improve understanding of the biological pathways affecting traits. Our objective was to conduct a SNP- and pathway-based analysis to identify possible biological mechanisms involved in H/L traits. Methods GWAS for H/L was performed in 1,317 Cobb broilers to identify significant single nucleotide polymorphisms (SNPs) associated with H/L. Eight SNPs (P< 1/8,068) reached a significant level of association. The following results were obtained through a series of analyses, including pathway-based association analysis and analysis of the proportion of phenotypic variance explained by SNPs. Results On the basis of GWAS analysis results, one associated SNP (5% genome-wide significance (6.80E-6,0.05/8,068)) on GGA 1(chicken chromosome 1) and seven suggestively associated SNPs with a trend toward significance(1.24E-4, 1/8,068) on GGAs 1, 7, 13 and 19 were detected. The significant SNP on GGA 19 was in Complement C1q Binding Protein (C1QBP). The wild-type and mutant individuals showed significant differences in H/L at five loci (P< 0.05). According to the results of pathway-based analysis, nine associated pathways (P < 0.05) were identified, including small cell lung cancer, proteoglycans in cancer, sulfur relay system, pathways in cancer, gastric acid secretion and purine metabolism. By combining GWAS with pathway analysis, we found that all SNPs after QC explained 12.4% of the phenotypic variation in H/L and 53 SNPs associated with H/L explained as much as 9.7% of the phenotypic variation in H/L. Conclusions Our findings contribute to understanding of the genetic regulation of H/L and provide theoretical support.

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Sex-specific gene and pathway modeling of inherited glioma risk

Abstract: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

Cited by 30 publications

References 52 publications

ARL3 is downregulated and acts as a prognostic biomarker in glioma

ARL3 is downregulated and acts as a prognostic biomarker in glioma

Heritability and Genome-Wide Association Study of Plasma Cholesterol in Chinese Adult Twins

Pathway-based analysis enables deeper mining of GWAS data on H/L in chickens

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