Browsing by Subject "single-nucleotide polymorphism"

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  • Mateos, Marion K.; Tulstrup, Morten; Quinn, Michael C. J.; Tuckuviene, Ruta; Marshall, Glenn M.; Gupta, Ramneek; Mayoh, Chelsea; Wolthers, Benjamin O.; Barbaro, Pasquale M.; Ruud, Ellen; Sutton, Rosemary; Huttunen, Pasi; Revesz, Tamas; Trakymiene, Sonata S.; Barbaric, Draga; Tedgard, Ulf; Giles, Jodie E.; Alvaro, Frank; Jonsson, Olafur G.; Mechinaud, Francoise; Saks, Kadri; Catchpoole, Daniel; Kotecha, Rishi S.; Dalla-Pozza, Luciano; Chenevix-Trench, Georgia; Trahair, Toby N.; MacGregor, Stuart; Schmiegelow, Kjeld (2020)
    Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p <5 x 10(-8)) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p <1 x 10(-6)), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 x 10(-7)) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 x 10(-7)) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.
  • Tanskanen, Tomas; van den Berg, Linda; Valimaki, Niko; Aavikko, Mervi; Ness-Jensen, Eivind; Hveem, Kristian; Wettergren, Yvonne; Lindskog, Elinor Bexe; Tonisson, Neeme; Metspalu, Andres; Silander, Kaisa; Orlando, Giulia; Law, Philip J.; Tuupanen, Sari; Gylfe, Alexandra E.; Hanninen, Ulrika A.; Cajuso, Tatiana; Kondelin, Johanna; Sarin, Antti-Pekka; Pukkala, Eero; Jousilahti, Pekka; Salomaa, Veikko; Ripatti, Samuli; Palotie, Aarno; Jarvinen, Heikki; Renkonen-Sinisalo, Laura; Lepisto, Anna; Bohm, Jan; Mecklin, Jukka-Pekka; Al-Tassan, Nada A.; Palles, Claire; Martin, Lynn; Barclay, Ella; Tenesa, Albert; Farrington, Susan M.; Timofeeva, Maria N.; Meyer, Brian F.; Wakil, Salma M.; Campbell, Harry; Smith, Christopher G.; Idziaszczyk, Shelley; Maughan, Tim S.; Kaplan, Richard; Kerr, Rachel; Kerr, David; Buchanan, Daniel D.; Win, Aung K.; Hopper, John; Jenkins, Mark A.; Newcomb, Polly A.; Gallinger, Steve; Conti, David; Schumacher, Fredrick R.; Casey, Graham; Cheadle, Jeremy P.; Dunlop, Malcolm G.; Tomlinson, Ian P.; Houlston, Richard S.; Palin, Kimmo; Aaltonen, Lauri A. (2018)
    Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p=2.08 x 10(-4); OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p=1.50 x 10(-9); OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate
  • Kelemen, Linda E.; Earp, Madalene; Fridley, Brooke L.; Chenevix-Trench, Georgia; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Lambrechts, Diether; Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Vergote, Ignace; Rossing, Mary Anne; Doherty, Jennifer A.; Chang-Claude, Jenny; Behrens, Sabine; Moysich, Kirsten B.; Cannioto, Rikki; Lele, Shashikant; Odunsi, Kunle; Goodman, Marc T.; Shvetsov, Yurii B.; Thompson, Pamela J.; Wilkens, Lynne R.; Doerk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Hillemanns, Peter; Runnebaum, Ingo B.; du Bois, Andreas; Harter, Philipp; Heitz, Florian; Schwaab, Ira; Butzow, Ralf; Pelttari, Liisa M.; Nevanlinna, Heli; Modugno, Francesmary; Edwards, Robert P.; Kelley, Joseph L.; Ness, Roberta B.; Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine; Kjaer, Susanne K.; Jensen, Allan; Cunningham, Julie M.; Vierkant, Robert A.; Giles, Graham G.; Bruinsma, Fiona (2018)
    Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97-1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03-1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 x 10(-28)), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.
  • Trontti, Kalevi; Väänänen, Juho; Sipilä, Tessa; Greco, Dario; Hovatta, Iiris (2018)
    Diversity in the structure and expression of microRNAs, important regulators of gene expression, arises from SNPs, duplications followed by divergence, production of isomiRs, and RNA editing. Inbred mouse strains and crosses using them are important reference populations for genetic mapping, and as models of human disease. We determined the nature and extent of interstrain miRNA variation by (i) identifying miRNA SNPs in whole-genome sequence data from 36 strains, and (ii) examining miRNA editing and expression in hippocampus (Hpc) and frontal cortex (FCx) of six strains, to facilitate the study of miRNAs in neurobehavioral phenotypes. miRNA loci were strongly conserved among the 36 strains, but even the highly conserved seed region contained 16 SNPs. In contrast, we identified RNA editing in 58.9% of miRNAs, including 11 consistent editing events in the seed region. We confirmed the functional significance of three conserved edits in the miR-379/410 cluster, demonstrating that edited miRNAs gained novel target mRNAs not recognized by the unedited miRNAs. We found significant interstrain differences in miRNA and isomiR expression: Of 779 miRNAs expressed in Hpc and 719 in FCx, 262 were differentially expressed (190 in Hpc, 126 in FCx, 54 in both). We also identified 32 novel miRNA candidates using miRNA prediction tools. Our studies provide the first comprehensive analysis of SNP, isomiR, and RNA editing variation in miRNA loci across inbred mouse strains, and a detailed catalog of expressed miRNAs in Hpc and FCx in six commonly used strains. These findings will facilitate the molecular analysis of neurological and behavioral phenotypes in this model organism.