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  • Sajantila, Antti (BioMed Central Ltd, 2014)
    Abstract No abstract
  • Sajantila, Antti (BioMed Central Ltd, 2014)
  • Kurra, Venla; Vehmas, Tuija; Eräranta, Arttu; Jokihaara, Jarkko; Pirttiniemi, Päivi; Ruskoaho, Heikki; Tokola, Heikki; Niemelä, Onni; Mustonen, Jukka; Pörsti, Ilkka (BioMed Central, 2015)
    Abstract Background Recent studies suggest a causal role for increased plasma uric acid in the progression of chronic renal insufficiency (CRI). However, uric acid also functions as an antioxidant with possible beneficial effects. Methods We investigated the influence of hyperuricemia on mesenteric arterial tone (main and second order branch) and morphology in experimental CRI. Forty-four Sprague–Dawley rats were 5/6 nephrectomized (NX) or Sham-operated and fed 2.0% oxonic acid or control diet for 9 weeks. Results Oxonic acid feeding elevated plasma uric acid levels 2.4 and 3.6-fold in the NX and Sham groups, respectively. Plasma creatinine and urea were elevated 2-fold and blood pressure increased by 10 mmHg in NX rats, while hyperuricemia did not significantly influence these variables. Right and left ventricular weight, and atrial and B-type natriuretic peptide mRNA content were increased in NX rats, but were not affected by hyperuricemia. In the mesenteric artery, hyperuricemia did not influence vasoconstrictor responses in vitro to norepinephrine or potassium chloride. The small arteries of NX rats featured hypertrophic remodeling independent of uric acid levels: wall to lumen ratio, wall thickness and cross-sectional area were increased without changes in lumen diameter. In the main branch, vasorelaxations to acetylcholine were impaired in NX rats, but were not affected by hyperuricemia. In contrast, relaxations to the large-conductance Ca2+-activated K+-channel (BKCa) opener NS-1619 were reduced by oxonic acid feeding, whereas responses to nitroprusside were not affected. Conclusions Experimental hyperuricemia did not influence cardiac load or vascular remodeling, but impaired BKCa -mediated vasorelaxation in experimental CRI.
  • Grönthal, Thomas; Ollilainen, Matti; Eklund, Marjut; Piiparinen, Heli; Gindonis, Veera; Junnila, Jouni; Saijonmaa-Koulumies, Leena; Liimatainen, Riitta; Rantala, Merja (BioMed Central, 2015)
    Abstract Background Methicillin resistant Staphylococcus pseudintermedius (MRSP) and Staphylococcus aureus (MRSA) are common multi-drug resistant (MDR) bacteria in dogs. In 2012–2013 three dogs of the Guide Dog School of the Finnish Federation of the Visually Impaired were found to be MRSP positive. Guide dogs have regular contact with each other during their first year of life and prolonged contact when in training. Since dogs are placed in different parts of Finland after training, there is a risk for national spread of MDR bacteria. In this study the prevalence of MRSP and MRSA, as well as the risk factors for MRSP were determined in the Finnish guide dog population. MRSP isolates were investigated using molecular methods and compared to the earlier isolates. Results Out of 132 tested dogs 4 were MRSP positive thus giving the prevalence estimate of 3% (95% CI: 1–8%) for MRSP in the target population. MRSA was not detected (prevalence estimate 0%, 95% CI: 0–3%). Risk factors associated with MRSP were being a breeding bitch (OR = 8.4; 95% CI: 1.1–64.1, P = 0.012), the number of veterinary visits (OR = 1.23; 95% CI: 1.0–1.5, P = 0.025) and number of antimicrobial courses (OR = 1.63; 95% CI: 1.0–2.55; P = 0.035). Identified MRSP isolates belonged to five different sequence types (ST45, 71, 402, 403 and 404). All ST71 isolates carried SCCmec II-III, while the SCCmec type of the ST45 and ST402 (a single locus variant of ST45) isolates were non-typeable with the method used. Conclusions MRSP and MRSA had low prevalence in the studied dog population despite the close contact between dogs, and the MRSP population was heterogenic. Antimicrobial therapy and veterinary visits are risk factors for MRSP even among a small case group.
  • Siggberg, Linda; Ala-Mello, Sirpa; Linnankivi, Tarja; Avela, Kristiina; Scheinin, Ilari; Kristiansson, Kati; Lahermo, Päivi; Hietala, Marja; Metsähonkala, Liisa; Kuusinen, Esa; Laaksonen, Maarit; Saarela, Janna; Knuutila, Sakari (BioMed Central Ltd, 2014)
    Abstract No abstract
  • Walker, Logan C; Fredericksen, Zachary S; Wang, Xianshu; Tarrell, Robert; Pankratz, Vernon S; Lindor, Noralane M; Beesley, Jonathan; Healey, Sue; Chen, Xiaoqing; kConFab; Stoppa-Lyonnet, Dominique; Tirapo, Carole; Giraud, Sophie; Mazoyer, Sylvie; Muller, Danièle; Fricker, Jean-Pierre; Delnatte, Capucine; GEMO Study Collaborators; Schmutzler, Rita K; Wappenschmidt, Barbara; Engel, Christoph; Schönbuchner, Ines; Deissler, Helmut; Meindl, Alfons; Hogervorst, Frans B; Verheus, Martijn; Hooning, Maartje J; van den Ouweland, Ans MW; Nelen, Marcel R; Ausems, Margreet GEM; Aalfs, Cora M; van Asperen, Christi J; Devilee, Peter; Gerrits, Monique M; Waisfisz, Quinten; HEBON; Szabo, Csilla I; ModSQuaD; Easton, Douglas F; Peock, Susan; Cook, Margaret; Oliver, Clare T; Frost, Debra; Harrington, Patricia; Evans, D Gareth; Lalloo, Fiona; Eeles, Ros; Izatt, Louise; Chu, Carol; Davidson, Rosemarie; Eccles, Diana; Ong, Kai-Ren; Cook, Jackie; EMBRACE; Rebbeck, Tim; Nathanson, Katherine L; Domchek, Susan M; Singer, Christian F; Gschwantler-Kaulich, Daphne; Dressler, Anne-Catharina; Pfeiler, Georg; Godwin, Andrew K; Heikkinen, Tuomas; Nevanlinna, Heli; Agnarsson, Bjarni A; Caligo, Maria A; Olsson, Håkan; Kristoffersson, Ulf; Liljegren, Annelie; Arver, Brita; Karlsson, Per; Melin, Beatrice; SWE-BRCA; Sinilnikova, Olga M; McGuffog, Lesley; Antoniou, Antonis C; Chenevix-Trench, Georgia; Spurdle, Amanda B; Couch, Fergus J (BioMed Central Ltd, 2010)
    Abstract Introduction Current attempts to identify genetic modifiers of BRCA1 and BRCA2 associated risk have focused on a candidate gene approach, based on knowledge of gene functions, or the development of large genome-wide association studies. In this study, we evaluated 24 SNPs tagged to 14 candidate genes derived through a novel approach that analysed gene expression differences to prioritise candidate modifier genes for association studies. Methods We successfully genotyped 24 SNPs in a cohort of up to 4,724 BRCA1 and 2,693 BRCA2 female mutation carriers from 15 study groups and assessed whether these variants were associated with risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Results SNPs in five of the 14 candidate genes showed evidence of association with breast cancer risk for BRCA1 or BRCA2 carriers (P < 0.05). Notably, the minor alleles of two SNPs (rs7166081 and rs3825977) in high linkage disequilibrium (r 2 = 0.77), located at the SMAD3 locus (15q22), were each associated with increased breast cancer risk for BRCA2 mutation carriers (relative risk = 1.25, 95% confidence interval = 1.07 to 1.45, P trend = 0.004; and relative risk = 1.20, 95% confidence interval = 1.03 to 1.40, P trend = 0.018). Conclusions This study provides evidence that the SMAD3 gene, which encodes a key regulatory protein in the transforming growth factor beta signalling pathway and is known to interact directly with BRCA2, may contribute to increased risk of breast cancer in BRCA2 mutation carriers. This finding suggests that genes with expression associated with BRCA1 and BRCA2 mutation status are enriched for the presence of common genetic modifiers of breast cancer risk in these populations.
  • Grote, Anne; Abbas, Mahmoud; Linder, Nina; Kreipe, Hans H; Lundin, Johan; Feuerhake, Friedrich (BioMed Central Ltd, 2014)
    Abstract Background Comprehensive spatial assessment of hormone receptor immunohistochemistry staining in digital whole slide images of breast cancer requires accurate detection of positive nuclei within biologically relevant regions of interest. Herein, we propose a combination of automated region labeling at low resolution and subsequent detailed tissue evaluation of subcellular structures in lobular structures adjacent to breast cancer, as a proof of concept for the approach to analyze estrogen and progesterone receptor expression in the spatial context of surrounding tissue. Methods Routinely processed paraffin sections of hormone receptor-negative ductal invasive breast cancer were stained for estrogen and progesterone receptor by immunohistochemistry. Digital whole slides were analyzed using commercially available image analysis software for advanced object-based analysis, applying textural, relational, and geometrical features. Mammary gland lobules were targeted as regions of interest for analysis at subcellular level in relation to their distance from coherent tumor as neighboring relevant tissue compartment. Lobule detection quality was evaluated visually by a pathologist. Results After rule set optimization in an estrogen receptor-stained training set, independent test sets (progesterone and estrogen receptor) showed acceptable detection quality in 33% of cases. Presence of disrupted lobular structures, either by brisk inflammatory infiltrate, or diffuse tumor infiltration, was common in cases with lower detection accuracy. Hormone receptor detection tended towards higher percentage of positively stained nuclei in lobules distant from the tumor border as compared to areas adjacent to the tumor. After adaptations of image analysis, corresponding evaluations were also feasible in hormone receptor positive breast cancer, with some limitations of automated separation of mammary epithelial cells from hormone receptor-positive tumor cells. Conclusions As a proof of concept for object-oriented detection of steroid hormone receptors in their spatial context, we show that lobular structures can be classified based on texture-based image features, unless brisk inflammatory infiltration disrupts the normal morphological structure of the tubular gland epithelium. We consider this approach as prototypic for detection and spatial analysis of nuclear markers in defined regions of interest. We conclude that advanced image analysis at this level of complexity requires adaptation to the individual tumor phenotypes and morphological characteristics of the tumor environment.
  • Almeda-Valdes, Paloma; Cuevas-Ramos, Daniel; Mehta, Roopa; Muñoz-Hernandez, Liliana; Cruz-Bautista, Ivette; Perez-Mendez, Oscar; Tusie-Luna, Maria T; Gomez-Perez, Francisco J; Pajukanta, Päivi; Matikainen, Niina; Taskinen, Marja-Riitta; Aguilar-Salinas, Carlos A (BioMed Central Ltd, 2014)
    Abstract Background Alterations in postprandial metabolism have been described in familial combined hyperlipidemia (FCH); however, their underlying mechanisms are not well characterized. We aimed to identify factors related to the magnitude of postprandial lipemia and apolipoprotein (apo) A-V levels in subjects with FCH. Methods FCH cases (n = 99) were studied using a standardized meal test. Abdominal obesity was assessed using the waist to hip ratio (WHR). A linear regression model was performed to investigate the variables associated with the triglycerides incremental area under the curve (iAUC). Independent associations between metabolic variables and apo A-V iAUC were also investigated in a randomly selected subgroup (n = 44). The study sample was classified according to the presence of fasting hypertriglyceridemia (≥150 mg/dL) and abdominal obesity (WHR ≥0.92 in men and ≥0.85 in women) to explore differences in parameters. Results The fasting apo B-48 levels (r = 0.404), and the WHR (r = 0.359) were independent factors contributing to the triglycerides iAUC (r2 = 0.29, P < 0.001). The triglycerides iAUC was independently associated with the apo A-V iAUC (r2 = 0.54, P < 0.01). Patients with both hypertriglyceridemia and abdominal obesity showed the most robust triglycerides and apo A-V postprandial responses. Conclusions In patients with FCH the fasting apo B-48 level is the main factor associated with postprandial lipemia. Abdominal obesity also contributes to the magnitude of the postprandial response.The triglycerides postprandial increment is the principal factor associated with the apo A-V postprandial response.
  • Savanheimo, Nora; Vehkalahti, Miira M (BioMed Central Ltd, 2014)
    Abstract Background Dental general anesthesia (DGA) is part of public dental care in Finland, but the intention is to return the patient to routine dental care. The aims of this study were to describe the details of treatments under DGA given to generally healthy children and to explore the outcome of their dental care during a 5-year follow-up, with special focus on preventive care. In particular, we examined the return of the patients to routine dental care, of which, to our knowledge, little is known. Methods Our prospective 5-year follow-up of generally healthy children (aged 0–13 years) treated under DGA by the Helsinki Public Dental Service in 2004 was based on official dental and general anesthesia documents. The statistical analyses employed chi-square tests, t-tests, Pearson’s correlation coefficient (r), Fisher’s transformation to test r ≠ 0, and logistic regression modeling. Results The most common reason for DGA was uncooperation (82%), followed by dental fear (56%). Filling therapy predominated in the treatments given under anesthesia, and the mean number of treatments per patients was 9.5 (SD = 4.2). Throughout the follow-up, 54% of the patients continued to have co-operation problems and 53% expressed dental fear; 11% of the patients received repeat DGA. The mean follow-up time was 48 (median 52) months. The postoperative review visit was actualized within 1.5 (SD = 0.8) months and the first visit to the home dental clinic of the patients in 12.0 (SD = 11.8) months for the 0–5-year-olds and in 7.2 (SD = 5.9) months for the 6–13-year-olds (p < 0.001). The mean time elapsed to the first need for treatment was 18.5 (SD = 14.1) months. During the follow-up, the mean number of treatments per patient was 5.3 (SD = 4.9); almost all patients (97%) received preventive treatment at one of two visits, but the control of dental fear remained rare. Conclusions To return to routine dental care after DGA, most of the generally healthy children in our study still needed special attention due to their uncooperation and dental fear, thus calling for a renewal of practices to treat these patients.
  • Paassilta, Marita; Kuusela, Elina; Korppi, Matti; Lemponen, Riina; Kaila, Minna; Nikkari, Seppo T (BioMed Central Ltd, 2014)
    Abstract Background Elevated serum Mead acid as a proportion of total fatty acids is an indirect marker of a deficiency of essential fatty acids (EFA). The aim of the study was to evaluate the symptoms and nutrition of food-allergic children with elevated or normal serum Mead acid. Methods Serum fatty acid compositions from 400 children were studied by clinical indications, mostly by suspicion of deficiency of EFA due to inadequate nutrition. A Mead acid level exceeding 0.21% (percentage of total fatty acids) was considered to be a specific sign of an insufficient EFA supply. From a total of 31 children with elevated Mead acid (MEADplus group), 23 (74%) had food allergy. The symptoms and dietary restrictions of this MEADplus group of food allergic children were compared to 54 age-and sex-matched controls with food allergy but normal Mead acid proportions (MEADminus group) before and 6 months after the serum fatty acid determination. Results At the beginning of the 6-month follow-up, 44% of the food allergic children in both MEADplus and MEADminus groups were on an elimination diet. These diets did not differ between the two groups and we were not able to document an association between the severity of elimination diet and elevated Mead acid proportion. However, the MEADplus children were on average more symptomatic than MEADminus children. In the MEADplus group, food allergy presented with skin symptoms in 100% (vs. 70% in the MEADminus group, p < 0.001) and with vomiting or diarrhea in 70% (vs. 44% in the MEADminus group, p < 0.05). Clinical suspicion of malnutrition resulted in increase in the use of vegetable oil and milk-free margarine in both groups from <50% to 65-74% during the follow-up. After 6 months, 64% of the MEADplus children with food allergy had been sent to a control serum fatty acid analysis. Of these children, Mead acid had declined to normal level in 69%, and remained elevated in 31%. Conclusions Severe symptoms of food allergy combined with elimination diets in children may lead to insufficient nutrition presenting with elevated serum Mead acid. Adding of supplementary polyunsaturated fat to the diet should be considered in these children.
  • Tiainen, Marjaana; Poutiainen, Erja; Oksanen, Tuomas; Kaukonen, Kirsi-Maija; Pettilä, Ville; Skrifvars, Markus; Varpula, Tero; Castrén, Maaret (BioMed Central, 2015)
    Abstract Background To study functional neurologic and cognitive outcome and health-related quality of life (HRQoL) in a cohort of patients included in a randomised controlled trial on glucose control following out-of-hospital cardiac arrest (OHCA) from ventricular fibrillation (VF) treated with therapeutic hypothermia. Methods Patients alive at 6 months after being discharged from the hospital underwent clinical neurological and extensive neuropsychological examinations. Functional outcome was evaluated with the Cerebral Performance Category scale, the modified Rankin scale and the Barthel Index. Cognitive outcome was evaluated by neuropsychological test battery including two measures of each cognitive function: cognitive speed, execution, memory, verbal skills and visuospatial performance. We also assessed quality of life with a HRQoL 15D questionnaire. Results Of 90 OHCA-VF patients included in the original trial, 57 were alive at 6 months. Of these, 52 (91%) were functionally independent and 54 (95%) lived at their previous home. Focal neurological deficits were scarce. Intact cognitive performance was observed in 20 (49%), mild to moderate deficits in 14 (34%) and severe cognitive deficits in 7 (17%) of 41 patients assessed by a neuropsychologist. Cognitive impairments were most frequently detected in executive and memory functions. HRQoL of the CA survivors was comparable to that of age- and gender matched population. Conclusions Functional outcome six months after OHCA and therapeutic hypothermia was good in the great majority of the survivors, and half of them were cognitively intact. Of note, the HRQoL of CA survivors did not differ from that of age- and gender matched population.
  • Choi, Jaeyoung; Kim, Ki-Tae; Jeon, Jongbum; Wu, Jiayao; Song, Hyeunjeong; Asiegbu, Fred O; Lee, Yong-Hwan (BioMed Central Ltd, 2014)
    Abstract Background RNA interference (RNAi) is involved in genome defense as well as diverse cellular, developmental, and physiological processes. Key components of RNAi are Argonaute, Dicer, and RNA-dependent RNA polymerase (RdRP), which have been functionally characterized mainly in model organisms. The key components are believed to exist throughout eukaryotes; however, there is no systematic platform for archiving and dissecting these important gene families. In addition, few fungi have been studied to date, limiting our understanding of RNAi in fungi. Here we present funRNA http://funrna.riceblast.snu.ac.kr/, a fungal kingdom-wide comparative genomics platform for putative genes encoding Argonaute, Dicer, and RdRP. Description To identify and archive genes encoding the abovementioned key components, protein domain profiles were determined from reference sequences obtained from UniProtKB/SwissProt. The domain profiles were searched using fungal, metazoan, and plant genomes, as well as bacterial and archaeal genomes. 1,163, 442, and 678 genes encoding Argonaute, Dicer, and RdRP, respectively, were predicted. Based on the identification results, active site variation of Argonaute, diversification of Dicer, and sequence analysis of RdRP were discussed in a fungus-oriented manner. funRNA provides results from diverse bioinformatics programs and job submission forms for BLAST, BLASTMatrix, and ClustalW. Furthermore, sequence collections created in funRNA are synced with several gene family analysis portals and databases, offering further analysis opportunities. Conclusions funRNA provides identification results from a broad taxonomic range and diverse analysis functions, and could be used in diverse comparative and evolutionary studies. It could serve as a versatile genomics workbench for key components of RNAi.
  • Katayama, Shintaro; Skoog, Tiina; Jouhilahti, Eeva-Mari; Siitonen, H. A; Nuutila, Kristo; Tervaniemi, Mari H; Vuola, Jyrki; Johnsson, Anna; Lönnerberg, Peter; Linnarsson, Sten; Elomaa, Outi; Kankuri, Esko; Kere, Juha (BioMed Central, 2015)
    Abstract Background Keratinocytes (KCs) are the most frequent cells in the epidermis, and they are often isolated and cultured in vitro to study the molecular biology of the skin. Cultured primary cells and various immortalized cells have been frequently used as skin models but their comparability to intact skin has been questioned. Moreover, when analyzing KC transcriptomes, fluctuation of polyA+ RNA content during the KCs’ lifecycle has been omitted. Results We performed STRT RNA sequencing on 10 ng samples of total RNA from three different sample types: i) epidermal tissue (split-thickness skin grafts), ii) cultured primary KCs, and iii) HaCaT cell line. We observed significant variation in cellular polyA+ RNA content between tissue and cell culture samples of KCs. The use of synthetic RNAs and SAMstrt in normalization enabled comparison of gene expression levels in the highly heterogenous samples and facilitated discovery of differences between the tissue samples and cultured cells. The transcriptome analysis sensitively revealed genes involved in KC differentiation in skin grafts and cell cycle regulation related genes in cultured KCs and emphasized the fluctuation of transcription factors and non-coding RNAs associated to sample types. Conclusions The epidermal keratinocytes derived from tissue and cell culture samples showed highly different polyA+ RNA contents. The use of SAMstrt and synthetic RNA based normalization allowed the comparison between tissue and cell culture samples and thus proved to be valuable tools for RNA-seq analysis with translational approach. Transciptomics revealed clear difference both between tissue and cell culture samples and between primary KCs and immortalized HaCaT cells.
  • Majumder, Mamun; Kumar, Ashwini; Heckman, Caroline; Kankainen, Matti; Pesonen, Sari; Jäger , Elke; Karbach , Julia; Joensuu, Timo; Kairemo, Kalevi; Partanen, Kaarina; Alanko, Tuomo; Hemminki, Akseli; Backman, Charlotta; Dienel, Kasper; von Euler, Mikael; Hakonen, Tiina; Juhila, Juuso; Ranki, Tuuli; Vassilev, Lotta; Vuolanto, Antti; Jaderberg, Magnus (BioMed Central Ltd, 2014)
  • Kiljunen, Saija; Pajunen, Maria I; Dilks, Kieran; Storf, Stefanie; Pohlschroder, Mechthild; Savilahti, Harri (BioMed Central Ltd, 2014)
    Abstract Background Archaea share fundamental properties with bacteria and eukaryotes. Yet, they also possess unique attributes, which largely remain poorly characterized. Haloferax volcanii is an aerobic, moderately halophilic archaeon that can be grown in defined media. It serves as an excellent archaeal model organism to study the molecular mechanisms of biological processes and cellular responses to changes in the environment. Studies on haloarchaea have been impeded by the lack of efficient genetic screens that would facilitate the identification of protein functions and respective metabolic pathways. Results Here, we devised an insertion mutagenesis strategy that combined Mu in vitro DNA transposition and homologous-recombination-based gene targeting in H. volcanii. We generated an insertion mutant library, in which the clones contained a single genomic insertion. From the library, we isolated pigmentation-defective and auxotrophic mutants, and the respective insertions pinpointed a number of genes previously known to be involved in carotenoid and amino acid biosynthesis pathways, thus validating the performance of the methodologies used. We also identified mutants that had a transposon insertion in a gene encoding a protein of unknown or putative function, demonstrating that novel roles for non-annotated genes could be assigned. Conclusions We have generated, for the first time, a random genomic insertion mutant library for a halophilic archaeon and used it for efficient gene discovery. The library will facilitate the identification of non-essential genes behind any specific biochemical pathway. It represents a significant step towards achieving a more complete understanding of the unique characteristics of halophilic archaea.
  • Haukkala, Ari; Konttinen, Hanna; Hankonen, Nelli; Perola, Markus; Kääriäinen, Helena; Salomaa, Veikko (BioMed Central, 2015)
    Abstract Background The role and meaning of genetic information has grown considerably in the recent decades. We examined changes in causal beliefs about morbidity as well as the associations between causal beliefs, health behaviors and obesity, and health outcome beliefs from 1982 to 2002. Methods In five population-based risk-factor surveys (the FINRISK Studies) of individuals aged 25 to 64 years conducted from 1982 to 2002 (n = 37,503), respondents chose the most important cause of morbidity from a list of ten alternatives. Health outcome beliefs were assessed with two items. Physical inactivity and smoking status were based on self-reports and obesity was based on measured height and weight. Results The prevalence of those who endorse genetic factors as the most important cause of morbidity increased from 4% in 1982 to 10% in 1992 and remained at that level until 2002. During the study period, lack of exercise and overweight increased, whereas inappropriate diet and stress diminished as causal beliefs about morbidity. Smokers and physically inactive were more likely to endorse genetic than behavioral causes of morbidity, whereas obese respondents were more likely to choose overweight over genetic causes of morbidity. Those who endorse genetic factors as the most important cause had more pessimistic outcome beliefs about health behavior changes, but these outcome beliefs became more positive in all causal belief groups during the study period. Conclusion Despite increased public discussion of genomics, the relative proportion of those who endorse genetic factors as the most important cause of morbidity has remained low. However, within this group beliefs about benefits of health behavior changes have become more positive. This could indicate that increase in genomic health information does not lead to more negative appraisals of efficacy of lifestyle changes.
  • Johnson, Nichola; Dudbridge, Frank; Orr, Nick; Gibson, Lorna; Jones, Michael E; Schoemaker, Minouk J; Folkerd, Elizabeth J; Haynes, Ben P; Hopper, John L; Southey, Melissa C; Dite, Gillian S; Apicella, Carmel; Schmidt, Marjanka K; Broeks, Annegien; Van’t Veer, Laura J; Atsma, Femke; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Ekici, Arif B; Renner, Stefan P; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Guénel, Pascal; Truong, Therese; Cordina, Emilie; Menegaux, Florence; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Milne, Roger; Zamora, M P; Arias Perez, Jose I; Benitez, Javier; Bernstein, Leslie; Anton-Culver, Hoda; Ziogas, Argyrios; Clarke Dur, Christina; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Dieffenbach, Aida K; Meindl, Alfons; Heil, Joerg; Bartram, Claus R; Schmutzler, Rita K; Brauch, Hiltrud; Justenhoven, Christina; Ko, Yon-Dschun; The GENICA (Gene Environment Interaction and Breast Cancer in Germany) Network; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Dörk, Thilo; Bogdanova, Natalia V; Antonenkova, Natalia N; Lindblom, Annika; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Chenevix-Trench, Georgia; Beesley, Jonathan; kConFab Investigators; Australian Ovarian Cancer Study Group; Wu, Anna H; Van den Berg, David; Tseng, Chiu-Chen; Lambrechts, Diether; Smeets, Dominiek; Neven, Patrick; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Pensotti, Valeria; Couch, Fergus J; Olson, Janet E; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Haiman, Chris; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Soucy, Penny; Teo, Soo; Yip, Cheng H; Phuah, Sze Y; Cornes, Belinda K; Kristensen, Vessela N; Grenaker Alnæs, Grethe; Børresen-Dale, Anne-Lise; Zheng, Wei; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna M; Devillee, Peter; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Sherman, Mark E; Hall, Per; Schoof, Nils; Hooning, Maartje; Hollestelle, Antoinette; Oldenburg, Rogier A; Tilanus-Linthorst, Madeleine; Liu, Jianjun; Cox, Angie; Brock, Ian W; Reed, Malcolm WR; Cross, Simon S; Blot, William; Signorello, Lisa B; Pharoah, Paul DP; Dunning, Alison M; Shah, Mitul; Kang, Daehee; Noh, Dong-Young; Park, Sue K; Choi, Ji-Yeob; Hartman, Mikael; Miao, Hui; Lim, Wei Y; Tang, Anthony; Hamann, Ute; Försti, Asta; Rüdiger, Thomas; Ulmer, Hans U; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Slager, Susan; Toland, Amanda E; Vachon, Celine; Yannoukakos, Drakoulis; Shen, Chen-Yang; Yu, Jyh-Cherng; Huang, Chiun-Sheng; Hou, Ming-Feng; González-Neira, Anna; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Jean; Easton, Douglas F; García-Closas, Montserrat; Dowsett, Mitch; Ashworth, Alan; Swerdlow, Anthony J; Peto, Julian; dos Santos Silva, Isabel; Fletcher, Olivia (BioMed Central Ltd, 2014)
    Abstract Introduction We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P trend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P trend = 0.005) but not cases (P trend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P het = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; P trend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; P trend = 0.29). Conclusions To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
  • Johnson, Nichola; Dudbridge, Frank; Orr, Nick; Gibson, Lorna; Jones, Michael E; Schoemaker, Minouk J; Folkerd, Elizabeth J; Haynes, Ben P; Hopper, John L; Southey, Melissa C; Dite, Gillian S; Apicella, Carmel; Schmidt, Marjanka K; Broeks, Annegien; Van’t Veer, Laura J; Atsma, Femke; Muir, Kenneth; Lophatananon, Artitaya; Fasching, Peter A; Beckmann, Matthias W; Ekici, Arif B; Renner, Stefan P; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael; Miller, Nicola; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Guénel, Pascal; Truong, Therese; Cordina, Emilie; Menegaux, Florence; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Milne, Roger; Zamora, M P; Arias Perez, Jose I; Benitez, Javier; Bernstein, Leslie; Anton-Culver, Hoda; Ziogas, Argyrios; Clarke Dur, Christina; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Dieffenbach, Aida K; Meindl, Alfons; Heil, Joerg; Bartram, Claus R; Schmutzler, Rita K; Brauch, Hiltrud; Justenhoven, Christina; Ko, Yon-Dschun; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Matsuo, Keitaro; Dörk, Thilo; Bogdanova, Natalia V; Antonenkova, Natalia N; Lindblom, Annika; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Chenevix-Trench, Georgia; Beesley, Jonathan; Wu, Anna H; Van den Berg, David; Tseng, Chiu-Chen; Lambrechts, Diether; Smeets, Dominiek; Neven, Patrick; Wildiers, Hans; Chang-Claude, Jenny; Rudolph, Anja; Nickels, Stefan; Flesch-Janys, Dieter; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Pensotti, Valeria; Couch, Fergus J; Olson, Janet E; Wang, Xianshu; Fredericksen, Zachary; Pankratz, Vernon S; Giles, Graham G; Severi, Gianluca; Baglietto, Laura; Haiman, Chris; Simard, Jacques; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Soucy, Penny; Teo, Soo; Yip, Cheng H; Phuah, Sze Y; Cornes, Belinda K; Kristensen, Vessela N; Grenaker Alnæs, Grethe; Børresen-Dale, Anne-Lise; Zheng, Wei; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna M; Devillee, Peter; Figueroa, Jonine; Chanock, Stephen J; Lissowska, Jolanta; Sherman, Mark E; Hall, Per; Schoof, Nils; Hooning, Maartje; Hollestelle, Antoinette; Oldenburg, Rogier A; Tilanus-Linthorst, Madeleine; Liu, Jianjun; Cox, Angie; Brock, Ian W; Reed, Malcolm W; Cross, Simon S; Blot, William; Signorello, Lisa B; Pharoah, Paul D; Dunning, Alison M; Shah, Mitul; Kang, Daehee; Noh, Dong-Young; Park, Sue K; Choi, Ji-Yeob; Hartman, Mikael; Miao, Hui; Lim, Wei Y; Tang, Anthony; Hamann, Ute; Försti, Asta; Rüdiger, Thomas; Ulmer, Hans U; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Slager, Susan; Toland, Amanda E; Vachon, Celine; Yannoukakos, Drakoulis; Shen, Chen-Yang; Yu, Jyh-Cherng; Huang, Chiun-Sheng; Hou, Ming-Feng; González-Neira, Anna; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Luccarini, Craig; Dennis, Joe; Michailidou, Kyriaki; Bolla, Manjeet K; Wang, Jean; Easton, Douglas F; García-Closas, Montserrat; Dowsett, Mitch; Ashworth, Alan; Swerdlow, Anthony J; Peto, Julian; dos Santos Silva, Isabel; Fletcher, Olivia (BioMed Central, 2014)
    Abstract Introduction We have previously shown that a tag single nucleotide polymorphism (rs10235235), which maps to the CYP3A locus (7q22.1), was associated with a reduction in premenopausal urinary estrone glucuronide levels and a modest reduction in risk of breast cancer in women age ≤50 years. Methods We further investigated the association of rs10235235 with breast cancer risk in a large case control study of 47,346 cases and 47,570 controls from 52 studies participating in the Breast Cancer Association Consortium. Genotyping of rs10235235 was conducted using a custom Illumina Infinium array. Stratified analyses were conducted to determine whether this association was modified by age at diagnosis, ethnicity, age at menarche or tumor characteristics. Results We confirmed the association of rs10235235 with breast cancer risk for women of European ancestry but found no evidence that this association differed with age at diagnosis. Heterozygote and homozygote odds ratios (ORs) were OR = 0.98 (95% CI 0.94, 1.01; P = 0.2) and OR = 0.80 (95% CI 0.69, 0.93; P = 0.004), respectively (P trend = 0.02). There was no evidence of effect modification by tumor characteristics. rs10235235 was, however, associated with age at menarche in controls (P trend = 0.005) but not cases (P trend = 0.97). Consequently the association between rs10235235 and breast cancer risk differed according to age at menarche (P het = 0.02); the rare allele of rs10235235 was associated with a reduction in breast cancer risk for women who had their menarche age ≥15 years (ORhet = 0.84, 95% CI 0.75, 0.94; ORhom = 0.81, 95% CI 0.51, 1.30; P trend = 0.002) but not for those who had their menarche age ≤11 years (ORhet = 1.06, 95% CI 0.95, 1.19, ORhom = 1.07, 95% CI 0.67, 1.72; P trend = 0.29). Conclusions To our knowledge rs10235235 is the first single nucleotide polymorphism to be associated with both breast cancer risk and age at menarche consistent with the well-documented association between later age at menarche and a reduction in breast cancer risk. These associations are likely mediated via an effect on circulating hormone levels.
  • Ollikainen, Miina; Ismail, Khadeeja; Gervin, Kristina; Kyllönen, Anjuska; Hakkarainen, Antti; Lundbom, Jesper; Järvinen, Elina A; Harris, Jennifer R; Lundbom, Nina; Rissanen, Aila; Lyle, Robert; Pietiläinen, Kirsi H; Kaprio, Jaakko (BioMed Central, 2015)
    Abstract Background The current epidemic of obesity and associated diseases calls for swift actions to better understand the mechanisms by which genetics and environmental factors affect metabolic health in humans. Monozygotic (MZ) twin pairs showing discordance for obesity suggest that epigenetic influences represent one such mechanism. We studied genome-wide leukocyte DNA methylation variation in 30 clinically healthy young adult MZ twin pairs discordant for body mass index (BMI; average within-pair BMI difference: 5.4 ± 2.0 kg/m2). Results There were no differentially methylated cytosine-guanine (CpG) sites between the co-twins discordant for BMI. However, stratification of the twin pairs based on the level of liver fat accumulation revealed two epigenetically highly different groups. Significant DNA methylation differences (n = 1,236 CpG sites (CpGs)) between the co-twins were only observed if the heavier co-twins had excessive liver fat (n = 13 twin pairs). This unhealthy pattern of obesity was coupled with insulin resistance and low-grade inflammation. The differentially methylated CpGs included 23 genes known to be associated with obesity, liver fat, type 2 diabetes mellitus (T2DM) and metabolic syndrome, and potential novel metabolic genes. Differentially methylated CpG sites were overrepresented at promoters, insulators, and heterochromatic and repressed regions. Based on predictions by overlapping histone marks, repressed and weakly transcribed sites were significantly more often hypomethylated, whereas sites with strong enhancers and active promoters were hypermethylated. Further, significant clustering of differentially methylated genes in vitamin, amino acid, fatty acid, sulfur, and renin-angiotensin metabolism pathways was observed. Conclusions The methylome in leukocytes is altered in obesity associated with metabolic disturbances, and our findings indicate several novel candidate genes and pathways in obesity and obesity-related complications.
  • Arason, Adalgeir; Gunnarsson, Haukur; Johannesdottir, Gudrun; Jonasson, Kristjan; Bendahl, Pär-Ola; Gillanders, Elizabeth M; Agnarsson, Bjarni A; Jönsson, Göran; Pylkäs, Katri; Mustonen, Aki; Heikkinen, Tuomas; Aittomäki, Kristiina; Blomqvist, Carl; Melin, Beatrice; Johannsson, Oskar TH; Møller, Pål; Winqvist, Robert; Nevanlinna, Heli; Borg, Åke; Barkardottir, Rosa B (BioMed Central Ltd, 2010)
    Abstract Introduction: A significant proportion of high-risk breast cancer families are not explained by mutations in known genes. Recent genome-wide searches (GWS) have not revealed any single major locus reminiscent of BRCA1 and BRCA2, indicating that still unidentified genes may explain relatively few families each or interact in a way obscure to linkage analyses. This has drawn attention to possible benefits of studying populations where genetic heterogeneity might be reduced. We thus performed a GWS for linkage on nine Icelandic multiple-case non-BRCA1/2 families of desirable size for mapping highly penetrant loci. To follow up suggestive loci, an additional 13 families from other Nordic countries were genotyped for selected markers. Methods: GWS was performed using 811 microsatellite markers providing about five centiMorgan (cM) resolution. Multipoint logarithm of odds (LOD) scores were calculated using parametric and nonparametric methods. For selected markers and cases, tumour tissue was compared to normal tissue to look for allelic loss indicative of a tumour suppressor gene. Results: The three highest signals were located at chromosomes 6q, 2p and 14q. One family contributed suggestive LOD scores (LOD 2.63 to 3.03, dominant model) at all these regions, without consistent evidence of a tumour suppressor gene. Haplotypes in nine affected family members mapped the loci to 2p23.2 to p21, 6q14.2 to q23.2 and 14q21.3 to q24.3. No evidence of a highly penetrant locus was found among the remaining families. The heterogeneity LOD (HLOD) at the 6q, 2p and 14q loci in all families was 3.27, 1.66 and 1.24, respectively. The subset of 13 Nordic families showed supportive HLODs at chromosome 6q (ranging from 0.34 to 1.37 by country subset). The 2p and 14q loci overlap with regions indicated by large families in previous GWS studies of breast cancer. Conclusions: Chromosomes 2p, 6q and 14q are candidate sites for genes contributing together to high breast cancer risk. A polygenic model is supported, suggesting the joint effect of genes in contributing to breast cancer risk to be rather common in non-BRCA1/2 families. For genetic counselling it would seem important to resolve the mode of genetic interaction.