scholarly journals Genetic variants and risk of prostate cancer using pathway analysis of a genome-wide association study

Neoplasma ◽  
2016 ◽  
Vol 63 (04) ◽  
pp. 629-634 ◽  
Author(s):  
Y. S. KIM ◽  
Y. KIM ◽  
J. W. CHOI ◽  
H. E. OH ◽  
J. H. LEE
Keyword(s):  
Prostate Cancer ◽  
Association Study ◽  
Pathway Analysis ◽  
Genetic Variants ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome

A genome-wide association study (GWAS) of docetaxel-induced peripheral neuropathy in CALGB 90401 (Alliance).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11053-11053
Author(s):  
Daniel Louis Hertz ◽  
Kouros Owzar ◽  
Susan Halabi ◽  
William Kevin Kelly ◽  
Hitoshi Zembutsu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Clinical Trial ◽  
Peripheral Neuropathy ◽  
Association Study ◽  
Genome Wide Association Study ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Grade 3

11053 Background: There are currently no effective methods for predicting, preventing, or treating chemotherapy-induced peripheral neuropathy. We performed a genome-wide association study in a clinical trial of castration-resistant prostate cancer (CRPC) to discover variants that may be useful for identifying patients at high risk of neuropathy during docetaxel treatment. Methods: Treatment and toxicity data were collected prospectively on the Cancer and Leukemia Group B (CALGB) 90401 trial of chemotherapy naïve CRPC patients treated with docetaxel and prednisone ± bevacizumab. Genotyping was performed by the RIKEN Institute using the Illumina HumanHap610-Quad platform. Genetically defined European subjects were included in the discovery analysis of all single nucleotide polymorphisms (SNPs) that passed quality control. The primary endpoint was the cumulative dose level triggering a grade 3+ sensory neuropathy. The inference was conducted within the framework of a competing risk model accounting for early treatment termination induced by death or progression, or other toxicities. SNPs that were highly associated with neuropathy were assessed for a broader taxane effect in a cohort of paclitaxel-treated patients from a breast cancer clinical trial, CALGB 40101. Results: 623 Caucasian patients and 498,022 SNPs were included in the discovery analysis. The incidence of grade 3 neuropathy was 8%. One intergenic SNP (rs11017056) was associated with increased risk of neuropathy (HR=2.83, p=4.7x10-7). This association surpassed the genome-wide significance threshold after covariate adjustment (p=7.2x10-8). However, none of the 7 SNPs selected for replication were associated with neuropathy in the paclitaxel-treated breast cancer cohort. Conclusions: Using a prospectively enrolled prostate cancer patient cohort we identified multiple SNPs that may identify risk of docetaxel-induced peripheral neuropathy, but not paclitaxel-induced neuropathy. However, since it is unknown whether the genetic factors that affect taxane neuropathy are drug-specific, further replication studies in docetaxel-treated cohorts are of great interest.

scholarly journals Integrative pathway analysis of a genome-wide association study of V̇o2max response to exercise training

2013 ◽  
Vol 115 (9) ◽  
pp. 1343-1359 ◽  
Author(s):  
Sujoy Ghosh ◽  
Juan C. Vivar ◽  
Mark A. Sarzynski ◽  
Yun Ju Sung ◽  
James A. Timmons ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Exercise Training ◽  
Association Study ◽  
Pathway Analysis ◽  
Genome Wide Association Study ◽  
Gene Set Enrichment Analysis ◽  
Genome Wide Association ◽  
Fatty Acid Transport ◽  
Genome Wide ◽  
A Genome

We previously reported the findings from a genome-wide association study of the response of maximal oxygen uptake (V̇o2max) to an exercise program. Here we follow up on these results to generate hypotheses on genes, pathways, and systems involved in the ability to respond to exercise training. A systems biology approach can help us better establish a comprehensive physiological description of what underlies V̇o2maxtrainability. The primary material for this exploration was the individual single-nucleotide polymorphism (SNP), SNP-gene mapping, and statistical significance levels. We aimed to generate novel hypotheses through analyses that go beyond statistical association of single-locus markers. This was accomplished through three complementary approaches: 1) building de novo evidence of gene candidacy through informatics-driven literature mining; 2) aggregating evidence from statistical associations to link variant enrichment in biological pathways to V̇o2max trainability; and 3) predicting possible consequences of variants residing in the pathways of interest. We started with candidate gene prioritization followed by pathway analysis focused on overrepresentation analysis and gene set enrichment analysis. Subsequently, leads were followed using in silico analysis of predicted SNP functions. Pathways related to cellular energetics (pantothenate and CoA biosynthesis; PPAR signaling) and immune functions (complement and coagulation cascades) had the highest levels of SNP burden. In particular, long-chain fatty acid transport and fatty acid oxidation genes and sequence variants were found to influence differences in V̇o2max trainability. Together, these methods allow for the hypothesis-driven ranking and prioritization of genes and pathways for future experimental testing and validation.

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