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author:("behling, Jill")
1.  Genetic Variation in the Lipoxygenase Pathway and Risk of Colorectal Neoplasia 
Genes, chromosomes & cancer  2013;52(5):437-449.
Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation-associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with non-steroidal anti-inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wildtype=5, OR>5/≥5=0.42, 95% CI 0.20-0.92; p=0.01). Four SNPs in FLAP (rs17239025), ALOX 12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at p≤0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in arachidonate lipoxygenases may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia.
doi:10.1002/gcc.22042
PMCID: PMC3698944  PMID: 23404351
2.  Characterization of 9p24 risk locus and colorectal adenoma and cancer: gene-environment interaction and meta-analysis 
Background
A potential susceptibility locus for colorectal cancer on chromosome 9p24 (rs719725) was initially identified through a genome-wide association study, though replication attempts have been inconclusive.
Methods
We genotyped this locus and explored interactions with known risk factors as potential sources of heterogeneity, which may explain the previously inconsistent replication. We included Caucasians with colorectal adenoma or colorectal cancer and controls from four studies (total 3891 cases, 4490 controls): the Women’s Health Initiative (WHI); the Diet, Activity and Lifestyle Study (DALS); a Minnesota population-based case-control study (MinnCCS); and the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). We used logistic regression to evaluate the association and test for gene-environment interactions.
Results
SNP rs719725 was statistically significantly associated with risk of colorectal cancer in WHI (OR per A allele 1.19; 95% CI 1.01–1.40; p-trend 0.04), marginally associated with adenoma risk in PLCO (OR per A allele 1.11; 95% CI 0.99–1.25; p-trend 0.07), and not associated in DALS and MinnCCS. Evaluating for gene-environment interactions yielded no consistent results across the studies. A meta-analysis of seventeen studies (including these four) gave an OR per A allele of 1.07 (95% CI 1.03–1.12; p-trend 0.001).
Conclusions
Our results suggest the A allele for SNP rs719725 at locus 9p24 is positively associated with a small increase in risk for colorectal tumors. Environmental risk factors for colorectal cancer do not appear to explain heterogeneity across studies.
Impact
If this finding is supported by further replication and functional studies, it may highlight new pathways underlying colorectal neoplasia.
doi:10.1158/1055-9965.EPI-10-0878
PMCID: PMC3005543  PMID: 20978172
colorectal; adenoma; cancer; 9p24; rs719725
3.  Characterization of the association between 8q24 and colon cancer: gene-environment exploration and meta-analysis 
BMC Cancer  2010;10:670.
Background
Genome-wide association studies and subsequent replication studies have shown that single nucleotide polymorphisms (SNPs) in the chromosomal region 8q24 are associated with colorectal cancer susceptibility.
Methods
We examined 11 SNP markers in the 8q24 region between 128.47 and 128.54 Mb, using a total of 1,987 colon cases and 2,339 controls who self-reported as white from two independent, well-characterized study populations. Analysis was performed separately within each study, and combined using random effects meta-analysis. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) and to test for effect modification by known colon cancer risk factors. We also performed a meta-analysis combining our results with previous studies.
Results
We observed evidence of association for four SNPs in low to high linkage disequilibrium (r2 ranging from 0.18 to 0.93) localized in a 16.2 kb region defined by rs10505477 and rs1056368. The combined results for our two studies of colon cancer showed an OR of 1.10 (95% CI: 1.01-1.20, Ptrend = 0.023), and a meta-analysis of our results with previously reported studies of colon and colorectal cancer strongly support the association for this SNP (combined OR for rs6983267 = 1.21, 95% CI: 1.18-1.24, p = 5.5 × 10-44). We did not observe any notable evidence of effect modification by known colon cancer risk factors, and risk did not differ significantly by tumor site or stage.
Conclusions
Our study confirms the association between polymorphisms on chromosome 8q24 and colon cancer risk and suggests that the susceptibility locus in region 8q24 is not strongly modified by various lifestyle, environmental, and demographic risk factors for colon cancer.
doi:10.1186/1471-2407-10-670
PMCID: PMC3017062  PMID: 21129217
4.  Resolving Individuals Contributing Trace Amounts of DNA to Highly Complex Mixtures Using High-Density SNP Genotyping Microarrays 
PLoS Genetics  2008;4(8):e1000167.
We use high-density single nucleotide polymorphism (SNP) genotyping microarrays to demonstrate the ability to accurately and robustly determine whether individuals are in a complex genomic DNA mixture. We first develop a theoretical framework for detecting an individual's presence within a mixture, then show, through simulations, the limits associated with our method, and finally demonstrate experimentally the identification of the presence of genomic DNA of specific individuals within a series of highly complex genomic mixtures, including mixtures where an individual contributes less than 0.1% of the total genomic DNA. These findings shift the perceived utility of SNPs for identifying individual trace contributors within a forensics mixture, and suggest future research efforts into assessing the viability of previously sub-optimal DNA sources due to sample contamination. These findings also suggest that composite statistics across cohorts, such as allele frequency or genotype counts, do not mask identity within genome-wide association studies. The implications of these findings are discussed.
Author Summary
In this report we describe a framework for accurately and robustly resolving whether individuals are in a complex genomic DNA mixture using high-density single nucleotide polymorphism (SNP) genotyping microarrays. We develop a theoretical framework for detecting an individual's presence within a mixture, show its limits through simulation, and finally demonstrate experimentally the identification of the presence of genomic DNA of individuals within a series of highly complex genomic mixtures. Our approaches demonstrate straightforward identification of trace amounts (<1%) of DNA from an individual contributor within a complex mixture. We show how probe-intensity analysis of high-density SNP data can be used, even given the experimental noise of a microarray. We discuss the implications of these findings in two fields: forensics and genome-wide association (GWA) genetic studies. Within forensics, resolving whether an individual is contributing trace amounts of genomic DNA to a complex mixture is a tremendous challenge. Within GWA studies, there is a considerable push to make experimental data publicly available so that the data can be combined with other studies. Our findings show that such an approach does not completely conceal identity, since it is straightforward to assess the probability that a person or relative participated in a GWA study.
doi:10.1371/journal.pgen.1000167
PMCID: PMC2516199  PMID: 18769715

Results 1-4 (4)