Browsing by Subject "COPY-NUMBER"

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  • Kuras, Anita; Antonius, Kristina; Kalendar, Ruslan; Kruczynska, Dorota; Korbin, Malgorzata (2013)
  • Schizophrenia Working Grp Psychiat; Kamitaki, Nolan; Sekar, Aswin; Handsaker, Robert E.; McCarroll, Steven A.; Eriksson, Johan; Palotie, Aarno; Daly, Mark; Paunio, Tiina; Pietiläinen, Olli (2020)
    Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjogren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women(2). All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjogren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus(3-6). Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia(7), generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjogren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjogren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjogren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma(8,9) in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjogren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
  • Louhimo, Riku i; Laakso, Marko; Belitskin, Denis; Klefstrom, Juha; Lehtonen, Rainer; Hautaniemi, Sampsa (2016)
    Background: Genomic alterations affecting drug target proteins occur in several tumor types and are prime candidates for patient-specific tailored treatments. Increasingly, patients likely to benefit from targeted cancer therapy are selected based on molecular alterations. The selection of a precision therapy benefiting most patients is challenging but can be enhanced with integration of multiple types of molecular data. Data integration approaches for drug prioritization have successfully integrated diverse molecular data but do not take full advantage of existing data and literature. Results: We have built a knowledge-base which connects data from public databases with molecular results from over 2200 tumors, signaling pathways and drug-target databases. Moreover, we have developed a data mining algorithm to effectively utilize this heterogeneous knowledge-base. Our algorithm is designed to facilitate retargeting of existing drugs by stratifying samples and prioritizing drug targets. We analyzed 797 primary tumors from The Cancer Genome Atlas breast and ovarian cancer cohorts using our framework. FGFR, CDK and HER2 inhibitors were prioritized in breast and ovarian data sets. Estrogen receptor positive breast tumors showed potential sensitivity to targeted inhibitors of FGFR due to activation of FGFR3. Conclusions: Our results suggest that computational sample stratification selects potentially sensitive samples for targeted therapies and can aid in precision medicine drug repositioning. Source code is available from http://csblcanges.fimm.fi/GOPredict/.
  • Mahlamaki, E H; Kauraniemi, P; Monni, O; Wolf, Maija; Hautaniemi, S; Kallioniemi, Anne (2004)
  • Huusko, P; Ponciano-Jackson, D; Wolf, Maija; Kiefer, J A; Azorsa, D O; Tuzmen, S; Weaver, D; Robbins, C; Moses, T; Allinen, M; Hautaniemi, S; Chen, Y D; Elkahloun, A; Basik, M; Bova, G S; Bubendorf, L; Lugli, A; Sauter, G; Schleutker, J; Ozcelik, H; Elowe, S; Pawson, T; Trent, J M; Carpten, J D; Kallioniemi, O P; Mousses, S (2004)