• Polygenic risk scores for schizophrenia and bipolar disorder predict creativity.

      Power, Robert A; Steinberg, Stacy; Bjornsdottir, Gyda; Rietveld, Cornelius A; Abdellaoui, Abdel; Nivard, Michel M; Johannesson, Magnus; Galesloot, Tessel E; Hottenga, Jouke J; Willemsen, Gonneke; et al. (Nature Publishing Group, 2015-07)
      We tested whether polygenic risk scores for schizophrenia and bipolar disorder would predict creativity. Higher scores were associated with artistic society membership or creative profession in both Icelandic (P = 5.2 × 10(-6) and 3.8 × 10(-6) for schizophrenia and bipolar disorder scores, respectively) and replication cohorts (P = 0.0021 and 0.00086). This could not be accounted for by increased relatedness between creative individuals and those with psychoses, indicating that creativity and psychosis share genetic roots.
    • Prediction of intracellular metabolic states from extracellular metabolomic data.

      Aurich, Maike K; Paglia, Giuseppe; Rolfsson, Óttar; Hrafnsdóttir, Sigrún; Magnúsdóttir, Manuela; Stefaniak, Magdalena M; Palsson, Bernhard Ø; Fleming, Ronan M T; Thiele, Ines; Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland, Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Sur Alzette, Luxembourg, Univ Iceland, Sch Hlth Sci, Fac Food Sci & Nutr, Reykjavik, Iceland, Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA (Springer, 2015-06)
      Metabolic models can provide a mechanistic framework to analyze information-rich omics data sets, and are increasingly being used to investigate metabolic alternations in human diseases. An expression of the altered metabolic pathway utilization is the selection of metabolites consumed and released by cells. However, methods for the inference of intracellular metabolic states from extracellular measurements in the context of metabolic models remain underdeveloped compared to methods for other omics data. Herein, we describe a workflow for such an integrative analysis emphasizing on extracellular metabolomics data. We demonstrate, using the lymphoblastic leukemia cell lines Molt-4 and CCRF-CEM, how our methods can reveal differences in cell metabolism. Our models explain metabolite uptake and secretion by predicting a more glycolytic phenotype for the CCRF-CEM model and a more oxidative phenotype for the Molt-4 model, which was supported by our experimental data. Gene expression analysis revealed altered expression of gene products at key regulatory steps in those central metabolic pathways, and literature query emphasized the role of these genes in cancer metabolism. Moreover, in silico gene knock-outs identified unique control points for each cell line model, e.g., phosphoglycerate dehydrogenase for the Molt-4 model. Thus, our workflow is well-suited to the characterization of cellular metabolic traits based on extracellular metabolomic data, and it allows the integration of multiple omics data sets into a cohesive picture based on a defined model context.
    • Decoding the jargon of bottom-up metabolic systems biology.

      Rolfsson, Óttar; Palsson, Bernhard O; Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland, Univ Iceland, Biomed Ctr, Reykjavik, Iceland (Wiley-Blackwell, 2015-06)
    • The Y-chromosome point mutation rate in humans.

      Helgason, Agnar; Einarsson, Axel W; Guðmundsdóttir, Valdís B; Sigurðsson, Ásgeir; Gunnarsdóttir, Ellen D; Jagadeesan, Anuradha; Ebenesersdóttir, S Sunna; Kong, Augustine; Stefánsson, Kári; Amgen Inc, DeCODE Genet, Reykjavik, Iceland, Univ Iceland, Dept Anthropol, Reykjavik, Iceland, Univ Iceland, Fac Med, Reykjavik, Iceland (Nature Publishing Group, 2015-05)
      Mutations are the fundamental source of biological variation, and their rate is a crucial parameter for evolutionary and medical studies. Here we used whole-genome sequence data from 753 Icelandic males, grouped into 274 patrilines, to estimate the point mutation rate for 21.3 Mb of male-specific Y chromosome (MSY) sequence, on the basis of 1,365 meioses (47,123 years). The combined mutation rate for 15.2 Mb of X-degenerate (XDG), X-transposed (XTR) and ampliconic excluding palindromes (rAMP) sequence was 8.71 × 10(-10) mutations per position per year (PPPY). We observed a lower rate (P = 0.04) of 7.37 × 10(-10) PPPY for 6.1 Mb of sequence from palindromes (PAL), which was not statistically different from the rate of 7.2 × 10(-10) PPPY for paternally transmitted autosomes. We postulate that the difference between PAL and the other MSY regions may provide an indication of the rate at which nascent autosomal and PAL de novo mutations are repaired as a result of gene conversion.
    • Hazelnut allergy across Europe dissected molecularly: A EuroPrevall outpatient clinic survey.

      Datema, Mareen R; Zuidmeer-Jongejan, Laurian; Asero, Riccardo; Barreales, Laura; Belohlavkova, Simona; de Blay, Frédéric; Bures, Peter; Clausen, Michael; Dubakiene, Ruta; Gislason, David; et al. (Elsevier, 2015-03-13)
      Hazelnut allergy is birch pollen-driven in Northern/Western Europe and lipid transfer protein-driven in Spain and Italy. Little is known about other regions and other allergens.
    • Inpatient drug utilization in Europe: nationwide data sources and a review of publications on a selected group of medicines (PROTECT project).

      Sabaté, Mònica; Ferrer, Pili; Ballarín, Elena; Rottenkolber, Marietta; Amelio, Justyne; Schmiedl, Sven; Reynolds, Robert; Klungel, Olaf; Ibáñez, Luisa; Addresses: [ 1 ] Fundacio Inst Catala Farmacol, Barcelona, Spain [ 2 ] Univ Hosp Vall dHebron, Dept Clin Pharmacol, Barcelona, Spain [Show the Organization-Enhanced name(s)] [ 3 ] Autonomous Univ Barcelona, Hosp Univ Vall dHebron, Dept Pharmacol Toxicol & Clin Therapeut, Barcelona 08029, Spain [Show the Organization-Enhanced name(s)] [ 4 ] Univ Munich, Inst Med Informat Sci Biometry & Epidemiol, Munich, Germany [ 5 ] Amgen Inc, Uxbridge, Middx, England [ 6 ] Helios Klin Wuppertal, Philipp Klee Inst Clin Pharmacol, Wuppertal, Germany [Show the Organization-Enhanced name(s)] [ 7 ] Univ Witten Herdecke, Fac Hlth, Sch Med, Dept Clin Pharmacol, Witten, Germany [Show the Organization-Enhanced name(s)] [ 8 ] Pfizer Res & Dev, Epidemiol, New York, NY USA [Show the Organization-Enhanced name(s)] [ 9 ] Univ Utrecht, Div Pharmacoepidemiol & Clin Pharmacol, Utrecht, Netherlands (Wiley-Blackwell, 2015-03)
      Drug utilization (DU) studies in inpatient settings at a national level are rarely conducted. The main objective of this study was to review the general information on hospital medicine management in Europe and to report on the availability and characteristics of nationwide administrative drug consumption databases. A secondary objective was to perform a review of published studies on hospital DU of a group of selected drugs, focusing on methodological characteristics (ATC/DDD). General information on hospital drug management was retrieved from several websites, nationwide administrative drug consumption databases and reports published by governmental organizations. A PubMed search was conducted using keywords related to the selected group of drugs AND 'hospital drug utilization'. The data sources for hospital DU information varied widely and included 14 databases from 25 reviewed countries. Bulgaria, Croatia, Denmark, Estonia, Finland, France, Hungary, Iceland, Latvia, Norway and Sweden obtain information on inpatient DU at a national level from wholesalers/manufacturers. In Belgium, Italy and Portugal, drugs dispensed to patients in hospitals are registered at a national level. Data are freely available online only for Denmark and Iceland. From the PubMed search, of a total of 868 retrieved studies, only 13 studies used the ATC/DDD methodology. Although the number of DDD/100 bed-days was used in four studies, other units of measure were also used. The type of information provided for the inpatient sector allowed primarily for conducting DU research at an aggregated data level. The existence of national administrative structures to monitor hospital DU would contribute to promoting the rational use of medicines and improving the safety and quality of prescribing.
    • Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

      Kuchenbaecker, Karoline B; Ramus, Susan J; Tyrer, Jonathan; Lee, Andrew; Shen, Howard C; Beesley, Jonathan; Lawrenson, Kate; McGuffog, Lesley; Healey, Sue; Lee, Janet M; et al. (Nature Publishing Group, 2015-02)
      Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
    • Metabolomic analysis of platelets during storage: a comparison between apheresis- and buffy coat-derived platelet concentrates.

      Paglia, Giuseppe; Sigurjónsson, Ólafur E; Rolfsson, Óttar; Hansen, Morten Bagge; Brynjólfsson, Sigurður; Gudmundsson, Sveinn; Palsson, Bernhard O; [ 1 ] Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland [ 2 ] Landspitali Univ Hosp, Blood Bank, IS-105 Reykjavik, Iceland [ 3 ] Reykjavik Univ, Sch Sci & Engn, Reykjavik, Iceland [ 4 ] Copenhagen Univ Hosp, Rigshosp, Dept Clin Immunol, Copenhagen, Denmark (Wiley-Blackwell, 2015-02)
      Platelet concentrates (PCs) can be prepared using three methods: platelet (PLT)-rich plasma, apheresis, and buffy coat. The aim of this study was to obtain a comprehensive data set that describes metabolism of buffy coat-derived PLTs during storage and to compare it with a previously published parallel data set obtained for apheresis-derived PLTs.
    • Ion mobility-derived collision cross section as an additional measure for lipid fingerprinting and identification.

      Paglia, Giuseppe; Angel, Peggi; Williams, Jonathan P; Richardson, Keith; Olivos, Hernando J; Thompson, J Will; Menikarachchi, Lochana; Lai, Steven; Walsh, Callee; Moseley, Arthur; et al. (Amer Chemical Soc, 2015-01-20)
      Despite recent advances in analytical and computational chemistry, lipid identification remains a significant challenge in lipidomics. Ion-mobility spectrometry provides an accurate measure of the molecules' rotationally averaged collision cross-section (CCS) in the gas phase and is thus related to ionic shape. Here, we investigate the use of CCS as a highly specific molecular descriptor for identifying lipids in biological samples. Using traveling wave ion mobility mass spectrometry (MS), we measured the CCS values of over 200 lipids within multiple chemical classes. CCS values derived from ion mobility were not affected by instrument settings or chromatographic conditions, and they were highly reproducible on instruments located in independent laboratories (interlaboratory RSD < 3% for 98% of molecules). CCS values were used as additional molecular descriptors to identify brain lipids using a variety of traditional lipidomic approaches. The addition of CCS improved the reproducibility of analysis in a liquid chromatography-MS workflow and maximized the separation of isobaric species and the signal-to-noise ratio in direct-MS analyses (e.g., "shotgun" lipidomics and MS imaging). These results indicate that adding CCS to databases and lipidomics workflows increases the specificity and selectivity of analysis, thus improving the confidence in lipid identification compared to traditional analytical approaches. The CCS/accurate-mass database described here is made publicly available.
    • Development of a hypoallergenic recombinant parvalbumin for first-in-man subcutaneous immunotherapy of fish allergy.

      Zuidmeer-Jongejan, Laurian; Huber, Hans; Swoboda, Ines; Rigby, Neil; Versteeg, Serge A; Jensen, Bettina M; Quaak, Suzanne; Akkerdaas, Jaap H; Blom, Lars; Asturias, Juan; et al. (Karger, 2015)
      The FAST (food allergy-specific immunotherapy) project aims at developing safe and effective subcutaneous immunotherapy for fish allergy, using recombinant hypoallergenic carp parvalbumin, Cyp c 1.
    • An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

      Blein, Sophie; Bardel, Claire; Danjean, Vincent; McGuffog, Lesley; Healey, Sue; Barrowdale, Daniel; Lee, Andrew; Dennis, Joe; Kuchenbaecker, Karoline B; Soucy, Penny; et al. (BioMed Central, 2015)
      Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.
    • Quality of care in European home care programs using the second generation interRAI Home Care Quality Indicators (HCQIs).

      Foebel, Andrea D; van Hout, Hein P; van der Roest, Henriëtte G; Topinkova, Eva; Garms-Homolova, Vjenka; Frijters, Dinnus; Finne-Soveri, Harriet; Jónsson, Pálmi V; Hirdes, John P; Bernabei, Roberto; et al. (BioMed Central, 2015)
      Evaluating the quality of care provided to older individuals is a key step to ensure that needs are being met and to target interventions to improve care. To this aim, interRAI's second-generation home care quality indicators (HCQIs) were developed in 2013. This study assesses the quality of home care services in six European countries using these HCQIs as well as the two derived summary scales.
    • A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.

      Evangelou, Evangelos; Kerkhof, Hanneke J; Styrkarsdottir, Unnur; Ntzani, Evangelia E; Bos, Steffan D; Esko, Tonu; Evans, Daniel S; Metrustry, Sarah; Panoutsopoulou, Kalliope; Ramos, Yolande F M; et al. (BMJ Publishing Group, 2014-12)
      Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects.
    • Functional metabolic map of Faecalibacterium prausnitzii, a beneficial human gut microbe.

      Heinken, Almut; Khan, M Tanweer; Paglia, Giuseppe; Rodionov, Dmitry A; Harmsen, Hermie J M; Thiele, Ines; Univ Luxembourg, Luxembourg Ctr Syst Biomed, Belval, Luxembourg [ 2 ] Univ Iceland, Ctr Syst Biol, Reykjavik, Iceland [ 3 ] Univ Groningen, Univ Med Ctr Groningen, Dept Med Microbiol, Groningen, Netherlands [ 4 ] Sanford Burnham Med Res Inst, La Jolla, CA USA [ 5 ] Russian Acad Sci, AA Kharkevich Inst Informat Transmiss Problems, Moscow, Russia (Amer Soc Microbiology, 2014-09)
      The human gut microbiota plays a central role in human well-being and disease. In this study, we present an integrated, iterative approach of computational modeling, in vitro experiments, metabolomics, and genomic analysis to accelerate the identification of metabolic capabilities for poorly characterized (anaerobic) microorganisms. We demonstrate this approach for the beneficial human gut microbe Faecalibacterium prausnitzii strain A2-165. We generated an automated draft reconstruction, which we curated against the limited biochemical data. This reconstruction modeling was used to develop in silico and in vitro a chemically defined medium (CDM), which was validated experimentally. Subsequent metabolomic analysis of the spent medium for growth on CDM was performed. We refined our metabolic reconstruction according to in vitro observed metabolite consumption and secretion and propose improvements to the current genome annotation of F. prausnitzii A2-165. We then used the reconstruction to systematically characterize its metabolic properties. Novel carbon source utilization capabilities and inabilities were predicted based on metabolic modeling and validated experimentally. This study resulted in a functional metabolic map of F. prausnitzii, which is available for further applications. The presented workflow can be readily extended to other poorly characterized and uncharacterized organisms to yield novel biochemical insights about the target organism.
    • Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age.

      Deelen, Joris; Beekman, Marian; Uh, Hae-Won; Broer, Linda; Ayers, Kristin L; Tan, Qihua; Kamatani, Yoichiro; Bennet, Anna M; Tamm, Riin; Trompet, Stella; et al. (Oxford Univ Press, 2014-08-15)
      The genetic contribution to the variation in human lifespan is ∼ 25%. Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality. We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16 121 younger controls (<65 years) followed by replication in an additional set of 13 060 long-lived individuals and 61 156 controls. In addition, we performed a subset analysis in cases aged ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P = 1.74 × 10(-8)). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 × 10(-36)), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34 103), the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.
    • Health-related quality of life in food-allergic adults from eight European countries.

      Goossens, Nicole J; Flokstra-de Blok, Bertine M J; van der Meulen, Gerbrich N; Arnlind, Marianne H; Asero, Ricardo; Barreales, Laura; Burney, Peter; Cerecedo, Imnaculada; Clausen, Michael; Fernandéz-Rivas, Monteserrat; et al. (Elsevier Science Inc, 2014-07)
      Food allergy can impair health-related quality of life (HRQL). Food Allergy Quality of Life Questionnaires (FAQLQs) have been developed and validated, including an adult form (FAQLQ-AF). HRQL has not, to date, been measured across different European countries using a uniform methodology.
    • Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene.

      Luo, X-J; Li, M; Huang, L; Steinberg, S; Mattheisen, M; Liang, G; Donohoe, G; Shi, Y; Chen, C; Yue, W; et al. (Nature Publishing Group, 2014-07)
      Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10(-6)) and lymphoblastoid cell lines (the lowest P=8.4 × 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.
    • Severe osteoarthritis of the hand associates with common variants within the ALDH1A2 gene and with rare variants at 1p31.

      Styrkarsdottir, Unnur; Thorleifsson, Gudmar; Helgadottir, Hafdis T; Bomer, Nils; Metrustry, Sarah; Bierma-Zeinstra, S; Strijbosch, Annelieke M; Evangelou, Evangelos; Hart, Deborah; Beekman, Marian; et al. (Nature, 2014-05)
      Osteoarthritis is the most common form of arthritis and is a major cause of pain and disability in the elderly. To search for sequence variants that confer risk of osteoarthritis of the hand, we carried out a genome-wide association study (GWAS) in subjects with severe hand osteoarthritis, using variants identified through the whole-genome sequencing of 2,230 Icelanders. We found two significantly associated loci in the Icelandic discovery set: at 15q22 (frequency of 50.7%, odds ratio (OR) = 1.51, P = 3.99 × 10(-10)) in the ALDH1A2 gene and at 1p31 (frequency of 0.02%, OR = 50.6, P = 9.8 × 10(-10)). Among the carriers of the variant at 1p31 is a family with several members in whom the risk allele segregates with osteoarthritis. The variants within the ALDH1A2 gene were confirmed in replication sets from The Netherlands and the UK, yielding an overall association of OR = 1.46 and P = 1.1 × 10(-11) (rs3204689).
    • Ion mobility derived collision cross sections to support metabolomics applications.

      Paglia, Giuseppe; Williams, Jonathan P; Menikarachchi, Lochana; Thompson, J Will; Tyldesley-Worster, Richard; Halldórsson, Skarphédinn; Rolfsson, Ottar; Moseley, Arthur; Grant, David; Langridge, James; et al. (Amer Chemical Soc, 2014-04-15)
      Metabolomics is a rapidly evolving analytical approach in life and health sciences. The structural elucidation of the metabolites of interest remains a major analytical challenge in the metabolomics workflow. Here, we investigate the use of ion mobility as a tool to aid metabolite identification. Ion mobility allows for the measurement of the rotationally averaged collision cross-section (CCS), which gives information about the ionic shape of a molecule in the gas phase. We measured the CCSs of 125 common metabolites using traveling-wave ion mobility-mass spectrometry (TW-IM-MS). CCS measurements were highly reproducible on instruments located in three independent laboratories (RSD < 5% for 99%). We also determined the reproducibility of CCS measurements in various biological matrixes including urine, plasma, platelets, and red blood cells using ultra performance liquid chromatography (UPLC) coupled with TW-IM-MS. The mean RSD was < 2% for 97% of the CCS values, compared to 80% of retention times. Finally, as proof of concept, we used UPLC-TW-IM-MS to compare the cellular metabolome of epithelial and mesenchymal cells, an in vitro model used to study cancer development. Experimentally determined and computationally derived CCS values were used as orthogonal analytical parameters in combination with retention time and accurate mass information to confirm the identity of key metabolites potentially involved in cancer. Thus, our results indicate that adding CCS data to searchable databases and to routine metabolomics workflows will increase the identification confidence compared to traditional analytical approaches.
    • DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

      Osorio, Ana; Milne, Roger L; Kuchenbaecker, Karoline; Vaclová, Tereza; Pita, Guillermo; Alonso, Rosario; Peterlongo, Paolo; Blanco, Ignacio; de la Hoya, Miguel; Duran, Mercedes; et al. (Public Library Science, 2014-04)
      Single Nucleotide Polymorphisms (SNPs) in genes involved in the DNA Base Excision Repair (BER) pathway could be associated with cancer risk in carriers of mutations in the high-penetrance susceptibility genes BRCA1 and BRCA2, given the relation of synthetic lethality that exists between one of the components of the BER pathway, PARP1 (poly ADP ribose polymerase), and both BRCA1 and BRCA2. In the present study, we have performed a comprehensive analysis of 18 genes involved in BER using a tagging SNP approach in a large series of BRCA1 and BRCA2 mutation carriers. 144 SNPs were analyzed in a two stage study involving 23,463 carriers from the CIMBA consortium (the Consortium of Investigators of Modifiers of BRCA1 and BRCA2). Eleven SNPs showed evidence of association with breast and/or ovarian cancer at p<0.05 in the combined analysis. Four of the five genes for which strongest evidence of association was observed were DNA glycosylases. The strongest evidence was for rs1466785 in the NEIL2 (endonuclease VIII-like 2) gene (HR: 1.09, 95% CI (1.03-1.16), p = 2.7 × 10(-3)) for association with breast cancer risk in BRCA2 mutation carriers, and rs2304277 in the OGG1 (8-guanine DNA glycosylase) gene, with ovarian cancer risk in BRCA1 mutation carriers (HR: 1.12 95%CI: 1.03-1.21, p = 4.8 × 10(-3)). DNA glycosylases involved in the first steps of the BER pathway may be associated with cancer risk in BRCA1/2 mutation carriers and should be more comprehensively studied.