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Sarah E Kleinstein,
Laura Heath,
Karen W Makar,
Elizabeth M Poole,
Brenna L Seufert,
Martha L Slattery,
Liren Xiao,
David J Duggan,
Li Hsu,
Karen Curtin,
Lisel Koepl,
Jill Muehling, Darin Taverna,
Bette J Caan,
Christopher S Carlson,
John D Potter,
Cornelia M Ulrich
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ABSTRACT: 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 nonsteroidal 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 (1,424 cases/1,780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had a decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wild type = 5, OR>5/≥5 = 0.42, 95% CI 0.20-0.92; P = 0.01). Four SNPs in FLAP (rs17239025), ALOX12 (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 ALOXs 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. © 2013 Wiley Periodicals, Inc.
Genes Chromosomes and Cancer 02/2013; · 3.31 Impact Factor
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Ulrike Peters,
Shuo Jiao,
Fredrick R Schumacher,
Carolyn M Hutter,
Aaron K Aragaki,
John A Baron,
Sonja I Berndt,
Stéphane Bézieau,
Hermann Brenner,
Katja Butterbach, [......], Darin Taverna,
Stephen N Thibodeau,
Cornelia M Ulrich,
Emily White,
Yongbing Xiang,
Brent W Zanke,
Yi-Xin Zeng,
Ben Zhang,
Wei Zheng,
Li Hsu
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ABSTRACT: BACKGROUND & AIMS: Heritable factors contribute to development of colorectal cancer (CRC). Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis. METHODS: We conducted a genome-wide association study (GWAS) that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent. RESULTS: Based on the combined analysis we identified a locus that reached the conventional genome-wide significance level at <5.0 x 10-8: an intergenic region on chromosome 2q32.3, close toNABP1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR]=1.15 per risk allele;P =3.7 x 10-8). We also found evidence for 3 additional loci with P values <5.0 x 10-7: a locus within theLAMC1gene on chromosome 1q25.3 (rs10911251; OR=1.10 per risk allele;P =9.5 x 10-8), a locus within theCCND2gene on chromosome 12p13.32 (rs3217810 per risk allele; OR=0.84;P =5.9 x 10-8), and a locus in theTBX3gene on chromosome 12q24.21 (rs59336, OR=0.91 per risk allele;P =3.7 x 10-7). CONCLUSIONS: In a large GWAS, we associated polymorphisms close toNABP (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms inLAMC1 (this is the second gene in the laminin family to be associated with CRCs),CCND2 (which encodes for cyclin D2), andTBX3 (which encodes a T-box transcription factor and is a target of Wnt signaling to -catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.
Gastroenterology 12/2012; · 11.68 Impact Factor
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Nora Franceschini,
Cara Carty,
Petra Bůzková,
Alex P Reiner,
Tiana Garrett,
Yi Lin,
Jens-S Vöckler,
Lucia A Hindorff,
Shelley A Cole,
Eric Boerwinkle, [......],
Charles Eaton,
Philip Greenland,
Nancy Jenny,
Kari E North, Darin Taverna,
Alicia M Young,
Ewa Deelman,
Charles Kooperberg,
Bruce Psaty,
Gerardo Heiss
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ABSTRACT: Genome-wide association studies identified several single nucleotide polymorphisms (SNP) associated with prevalent coronary heart disease (CHD), but less is known of associations with incident CHD. The association of 13 published CHD SNPs was examined in 5 ancestry groups of 4 large US prospective cohorts.
The analyses included incident coronary events over an average 9.1 to 15.7 follow-up person-years in up to 26 617 white individuals (6626 events), 8018 black individuals (914 events), 1903 Hispanic individuals (113 events), 3669 American Indian individuals (595 events), and 885 Asian/Pacific Islander individuals (66 events). We used Cox proportional hazards models (with additive mode of inheritance) adjusted for age, sex, and ancestry (as needed). Nine loci were statistically associated with incident CHD events in white participants: 9p21 (rs10757278; P=4.7 × 10(-41)), 16q23.1 (rs2549513; P=0.0004), 6p24.1 (rs499818; P=0.0002), 2q36.3 (rs2943634; P=6.7 × 10(-6)), MTHFD1L (rs6922269, P=5.1 × 10(-10)), APOE (rs429358; P=2.7×10(-18)), ZNF627 (rs4804611; P=5.0 × 10(-8)), CXCL12 (rs501120; P=1.4 × 10(-6)) and LPL (rs268; P=2.7 × 10(-17)). The 9p21 region showed significant between-study heterogeneity, with larger effects in individuals age 55 years or younger and in women. Inclusion of coronary revascularization procedures among the incident CHD events introduced heterogeneity. The SNPs were not associated with CHD in black participants, and associations varied in other US minorities.
Prospective analyses of white participants replicated several reported cross-sectional CHD-SNP associations.
Circulation Cardiovascular Genetics 12/2011; 4(6):661-72. · 6.11 Impact Factor
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Ulrike Peters,
Carolyn M Hutter,
Li Hsu,
Fredrick R Schumacher,
David V Conti,
Christopher S Carlson,
Christopher K Edlund,
Robert W Haile,
Steven Gallinger,
Brent W Zanke, [......],
John L Hopper,
Mark A Jenkins,
Loic Le Marchand,
Noralane M Lindor,
Polly A Newcomb,
Daniela Seminara,
Thomas J Hudson,
David J Duggan,
John D Potter,
Graham Casey
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ABSTRACT: Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.
Human Genetics 07/2011; 131(2):217-34. · 5.07 Impact Factor
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Aedan Roberts,
Derek Nancarrow,
Mark Clendenning,
Daniel D Buchanan,
Mark A Jenkins,
David Duggan, Darin Taverna,
Diane McKeone,
Rhiannon Walters,
Michael D Walsh, [......],
Julie Arnold,
Kathy Tucker,
Amanda Muir,
Musa Drini,
Finlay Macrae,
Polly Newcomb,
John D Potter,
Erika Pavluk,
Annika Lindblom,
Joanne P Young
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ABSTRACT: Causative genetic variants have to date been identified for only a small proportion of familial colorectal cancer (CRC). While conditions such as Familial Adenomatous Polyposis and Lynch syndrome have well defined genetic causes, the search for variants underlying the remainder of familial CRC is plagued by genetic heterogeneity. The recent identification of families with a heritable predisposition to malignancies arising through the serrated pathway (familial serrated neoplasia or Jass syndrome) provides an opportunity to study a subset of familial CRC in which heterogeneity may be greatly reduced. A genome-wide linkage screen was performed on a large family displaying a dominantly-inherited predisposition to serrated neoplasia genotyped using the Affymetrix GeneChip Human Mapping 10 K SNP Array. Parametric and nonparametric analyses were performed and resulting regions of interest, as well as previously reported CRC susceptibility loci at 3q22, 7q31 and 9q22, were followed up by finemapping in 10 serrated neoplasia families. Genome-wide linkage analysis revealed regions of interest at 2p25.2-p25.1, 2q24.3-q37.1 and 8p21.2-q12.1. Finemapping linkage and haplotype analyses identified 2q32.2-q33.3 as the region most likely to harbour linkage, with heterogeneity logarithm of the odds (HLOD) 2.09 and nonparametric linkage (NPL) score 2.36 (P = 0.004). Five primary candidate genes (CFLAR, CASP10, CASP8, FZD7 and BMPR2) were sequenced and no segregating variants identified. There was no evidence of linkage to previously reported loci on chromosomes 3, 7 and 9.
Familial Cancer 12/2010; 10(2):245-54. · 1.30 Impact Factor
