Browsing by Subject "DEFICIENCY"

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  • Toresson, L.; Steiner, J. M.; Razdan, P.; Spodsberg, E.; Olmedal, G.; Suchodolski, J. S.; Spillmann, T. (2018)
    The aim of this study was to compare the efficacies of parenteral and oral cobalamin supplementation protocols in dogs with chronic enteropathies and low cobalamin concentrations. It was hypothesised that both treatments would increase serum cobalamin concentrations significantly. Fifty-three dogs with chronic enteropathies and serum cobalamin concentrations <285 ng/L (reference interval 244-959 ng/L) were enrolled. Dogs were randomised to treatment with either daily oral cobalamin tablets (0.25-1.0 mg cyanocobalamin daily according to body weight) or parenteral cobalamin (0.4-1.2 mg hydroxycobalamin according to body weight). Serum cobalamin concentrations were analysed 28 +/- 5 days and 90 +/- 15 days after initiation of supplementation. After 28 days, all dogs had serum cobalamin concentrations within the reference interval or above. In the parenteral group (n = 26), median (range) cobalamin concentrations were 228 (150-285) ng/L at inclusion, 2107 (725-10,009) ng/L after 28 days and 877 (188-1267) ng/L after 90 days. In the oral group (n = 27), median (range) serum cobalamin concentrations were 245 (150-285) ng/L at inclusion, 975 (564-2385) ng/L after 28 days and 1244 (738-4999) ng/L after 90 days. In both groups, there were significant differences in serum cobalamin concentrations between baseline and 28 days, and between 28 days and 90 days (P <0.001). In conclusion, both parenteral and oral cobalamin supplementation effectively increase serum cobalamin concentrations in dogs with chronic enteropathies and low cobalamin concentrations. (C) 2017 Elsevier Ltd. All rights reserved.
  • Przybyla, Beata; Pinomäki, Anne; Petäjä, Jari; Joutsi-Korhonen, Lotta; Strandberg, Karin; Hillarp, Andreas; Öhlin, Ann-Kristin; Ruutu, Tapani; Volin, Liisa; Lassila, Riitta (2017)
    Background Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. Patients and methods This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII: C) and soluble thrombomodulin (s-TM) at 6-8 time points over three months. Results Overall, PC, AT and FVIII: C increased in parallel after engraftment. Significant correlations between PC and FVIII: C (r = 0.64-0.82, p Conclusion The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.
  • Paakkanen, Riitta; Vauhkonen, Hanna; Eronen, Katja T.; Järvinen, Asko; Seppanen, Mikko; Lokki, Marja-Liisa (2012)
  • Isohanni, Pirjo; Carroll, Christopher J.; Jackson, Christopher B.; Pohjanpelto, Max; Lonnqvist, Tuula; Suomalainen, Anu (2018)
    Mutations in mitochondrial ATP synthase 6 (MT-ATP6) are a frequent cause of NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) or Leigh syndromes, especially a point mutation at nucleotide position 8993. M.8969G > A is a rare MT-ATP6 mutation, previously reported only in three individuals, causing multisystem disorders with mitochondrial myopathy, lactic acidosis, and sideroblastic anemia or IgA nephropathy. We present two siblings with the m.8969G > A mutation and a novel, substantially milder phenotype with lactic acidosis, poor growth, and intellectual disability. Our findings expand the phenotypic spectrum and show that mtDNA mutations should be taken account also with milder, stable phenotypes.
  • Mäkitie, R. E.; Niinimäki, R.; Kakko, S.; Honkanen, T.; Kovanen, P. E.; Mäkitie, O. (2018)
    This study explores bone marrow function in patients with defective WNT1 signaling. Bone marrow samples showed increased reticulin and altered granulopoiesis while overall hematopoiesis was normal. Findings did not associate with severity of osteoporosis. These observations provide new insight into the role of WNT signaling in bone marrow homeostasis. WNT signaling regulates bone homeostasis and survival and self-renewal of hematopoietic stem cells. Aberrant activation may lead to osteoporosis and bone marrow pathology. We aimed to explore bone marrow findings in a large family with early-onset osteoporosis due to a heterozygous WNT1 mutation. We analyzed peripheral blood samples, and bone marrow aspirates and biopsies from 10 subjects with WNT1 mutation p.C218G. One subject was previously diagnosed with idiopathic myelofibrosis and others had no previously diagnosed hematologic disorders. The findings were correlated with the skeletal phenotype, as evaluated by number of peripheral and spinal fractures and bone mineral density. Peripheral blood samples showed no abnormalities in cell counts, morphology or distributions but mild increase in platelet count. Bone marrow aspirates (from 8/10 subjects) showed mild decrease in bone marrow iron storages in 6 and variation in cell distributions in 5 subjects. Bone marrow biopsies (from 6/10 subjects) showed increased bone marrow reticulin (grade MF-2 in the myelofibrosis subject and grade MF-1 in 4 others), and an increase in overall, and a shift towards early-phase, granulopoiesis. The bone marrow findings did not associate with the severity of skeletal phenotype. Defective WNT signaling associates with a mild increase in bone marrow reticulin and may predispose to myelofibrosis, while overall hematopoiesis and peripheral blood values are unaltered in individuals with a WNT1 mutation. In this family with WNT1 osteoporosis, bone marrow findings were not related to the severity of osteoporosis.
  • Rodrigues, Ana Paula C.; Camargo, Andre F.; Andjelkovic, Ana; Jacobs, Howard T.; Oliveira, Marcos T. (2018)
    The xenotopic expression of the alternative oxidase AOX from the tunicate Ciona intestinalis in diverse models of human disease partially alleviates the phenotypic effects of mitochondrial respiratory chain defects. AOX is a non-proton pumping, mitochondrial inner membrane-bound, single-subunit enzyme that can bypass electron transport through the cytochrome segment, providing an additional site for ubiquinone reoxidation and oxygen reduction upon respiratory chain overload. We set out to investigate whether AOX expression in Drosophila could counteract the effects of mitochondrial DNA (mtDNA) replication defects caused by disturbances in the mtDNA helicase or DNA polymerase gamma. We observed that the developmental arrest imposed by either the expression of mutant forms of these enzymes or their knockdown was not rescued by AOX. Considering also the inability of AOX to ameliorate the phenotype of tko(25t), a fly mutant with mitochondrial translation deficiency, we infer that this alternative enzyme may not be applicable to cases of mitochondrial gene expression defects. Finding the limitations of AOX applicability will help establish the parameters for the future putative use of this enzyme in gene therapies for human mitochondrial diseases.
  • Mäkitaipale, Johanna; Sievänen, Harri; Sankari, Satu; Vapaavuori, Outi (2019)
    During the winter time in Finland, sunlight is inadequate for vitamin D synthesis. Many pet rabbits live as house rabbits with limited outdoor access even during summer and may therefore be dependent on dietary sources of vitamin D. The aims of this study were to report the serum 25-hydroxyvitamin D concentrations in Finnish pet rabbits and to identify factors that influence vitamin D status. Serum 25-hydroxyvitamin D concentrations from 140 pet rabbits were determined using a vitamin D enzyme immunoassay (EIA) kit. Eleven rabbits were excluded from the statistical analysis because of unclear dietary data. The remaining 129 rabbits were divided into groups depending on outdoor access during summer (no access n = 26, periodic n = 57, regular n = 46) as well as daily diet: little or no hay and commercial rabbit food = 1 dl (n = 35). The range of serum 25-hydroxyvitamin D concentration was from 4.5 to 67.5 ng/ml with a mean of 26.1 ng/ml. Statistical general linear model adjusted for weight, age and season indicated that diet was associated with vitamin D concentrations (p = 0.001), but outdoor access during summer was not (p = 0.41). Mean 25-hydroxyvitamin D concentration was significantly higher in the rabbits receiving a lot of hay and commercial food >= 1 dl (33.9 +/- 13.2 ng/ml) than in rabbits in other diet groups (24.0 +/- 8.5 ng/ml, 21.7 +/- 8.1 ng/ml, and 22.2 +/- 18.0 ng/ml, respectively). This investigation showed wide variation in 25-hydroxyvitamin D concentrations among Finnish pet rabbits. Diet remains a main source since outdoor access seems to be too limited to provide adequate vitamin D synthesis for most of them, and the use of vitamin D supplements is rare.
  • Konstari, Sanna; Sares-Jäske, Laura; Heliövaara, Markku; Rissanen, Harri; Knekt, Paul; Arokoski, Jari; Sundvall, Jouko; Karppinen, Jaro (2019)
    Objectives To study whether low dietary magnesium (Mg) intake and serum high sensitivity C-reactive protein (hs-CRP) predict the development of clinical knee osteoarthritis (OA). Methods The cohort consisted of 4,953 participants of a national health examination survey who were free of knee and hip OA at baseline. Information on the incidence of knee OA leading to hospitalization was drawn from the National Care Register for Health Care. During the follow-up of 10 years, 123 participants developed incident knee OA. Dietary magnesium intake was assessed on the basis of a food frequency questionnaire from the preceding year. We used Cox's proportional hazards model to estimate the strength of the association between the tertiles of dietary Mg intake and incident knee OA, adjusted for baseline age, gender, energy intake, BMI, history of physical workload, leisure time physical activity, injuries, knee complaints, the use of Mg supplements, and serum hs-CRP levels. Results At baseline, dietary Mg intake was inversely associated with serum hs-CRP even after adjustment for all the potential confounding factors. During the follow-up, the adjusted hazard ratios (with their 95% confidence intervals) for incident knee OA in dietary Mg intake tertiles were 1.00, 1.28 (0.78-2.10), and 1.38 (0.73-2.62); the p value for trend was 0.31. Serum hs-CRP level at baseline did not predict incident knee OA. Conclusions The results do not support the hypothesis that low dietary Mg intake contributes to the development of clinical knee OA, although Mg intake is inversely associated with serum hs-CRP level.
  • Tani, Haruna; Mito, Takayuki; Velagapudi, Vidya; Ishikawa, Kaori; Umehara, Moe; Nakada, Kazuto; Suomalainen, Anu; Hayashi, Jun-Ichi (2019)
    In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality. Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation. Given that foetal livers function to produce erythroblasts in mouse embryos, growth retardation in foetal livers directly induced depletion of erythroblasts. By contrast, mitochondrial respiration defects in foetal livers also induced depletion of erythroblasts as a consequence of the inhibition of erythroblast differentiation, resulting in the manifestation of anaemia in Shmt2-knockout E13.5 embryos.
  • Mäki-Nevala, Satu; Valo, Satu; Ristimaki, Ari; Sarhadi, Virinder; Knuutila, Sakari; Nyström, Minna; Renkonen-Sinisalo, Laura; Lepistö, Anna; Mecklin, Jukka-Pekka; Peltomäki, Päivi (2019)
    Background: DNA mismatch repair (MMR) defects are a major factor in colorectal tumorigenesis in Lynch syndrome (LS) and 15% of sporadic cases. Some adenomas from carriers of inherited MMR gene mutations have intact MMR protein expression implying other mechanisms accelerating tumorigenesis. We determined roles of DNA methylation changes and somatic mutations in cancer-associated genes as tumorigenic events in LS-associated colorectal adenomas with intact MMR. Methods: We investigated 122 archival colorectal specimens of normal mucosae, adenomas and carcinomas from 57 LS patients. MMR-deficient (MMR-D, n 49) and MMR-proficient (MMR-P, n 18) adenomas were of particular interest and were interrogated by methylation-specific multiplex ligation-dependent probe amplification and Ion Torrent sequencing. Findings: Promoter methylation of CpG island methylator phenotype (CIMP)-associated marker genes and selected colorectal cancer (CRC)-associated tumor suppressor genes (TSGs) increased and LINE-1 methylation decreased from normal mucosa to MMR-P adenomas to MMR-D adenomas. Methylation differences were statistically significant when either adenoma group was compared with normal mucosa, but not between MMR-P and MMR-D adenomas. Significantly increased methylation was found in multiple CIMP marker genes (1612, NEUROGI,CRABP1, and CDKN2A) and TSGs (SERPI and SFRP2) in MMR-P adenomas already. Furthermore, certain CRC-associated somatic mutations, such as KRAS, were prevalent in MMR-P adenomas. Interpretation: We conclude that DNA methylation changes and somatic mutations of cancer-associated genes might serve as an alternative pathway accelerating LS-associated tumorigenesis in the presence of proficient MMR. Fund: Jane and Aatos Erkko Foundation, Academy of Finland, Cancer Foundation Finland, Sigrid juselius Foundation, and HiL1FE. (C) 2019 Published by Elsevier B.V.
  • Toresson, L.; Steiner, J. M.; Spodsberg, E.; Olmedal, G.; Suchodolski, J. S.; Lidbury, J. A.; Spillmann, T. (2019)
    The objective of this study was to compare the effects of parenteral (PE) versus oral (PO) cobalamin supplementation on serum methylmalonic acid (MMA) and homocysteine (HCY) concentrations in dogs with hypocobalaminaemia. Thirty-six dogs with serum cobalamin concentrations below 285 ng/L (reference interval (RI): 244-959 ng/L) were treated with PO (0.25-1.0 mg daily) or PE cobalamin (0.25-1.2 mg/injection) using a block-randomized schedule. Serum MMA and HCY concentrations were analysed at day 0, 28 and 90 after start of supplementation. There was no significant difference between the PO and PE group regarding serum MMA or HCY concentrations at any time point. Median (range, P comparing baseline and 28 days, P comparing 28 days and 90 days) serum MMA concentrations (nmol/L; RI 415-1193) were 932 (566-2468) in the PO and 943 (508-1900) in the PE group at baseline, respectively, 705 (386-1465, P
  • Trotta, Luca; Hautala, Timo; Hamalainen, Sari; Syrjanen, Jaana; Viskari, Hanna; Almusa, Henrikki; Lepisto, Maija; Kaustio, Meri; Porkka, Kimmo; Palotie, Aarno; Seppanen, Mikko; Saarela, Janna (2016)
    Antibody class-switch recombination and somatic hypermutation critically depend on the function of activation-induced cytidine deaminase (AID). Rare variants in its gene AICDA have been reported to cause autosomal recessive AID deficiency (autosomal recessive hyper-IgM syndrome type 2 (HIGM2)). Exome sequencing of a multicase Finnish family with an HIGM2 phenotype identified a rare, homozygous, variant (c.416T > C, p.(Met139Thr)) in the AICDA gene, found to be significantly enriched in the Finnish population compared with other populations of European origin (38.56-fold, P <0.001). The population history of Finland, characterized by a restricted number of founders, isolation and several population bottlenecks, has caused enrichment of certain rare disease-causing variants and losses of others, as part of a phenomenon called the Finnish Disease Heritage. Accordingly, rare founder mutations cause the majority of observed Finnish cases in these mostly autosomal recessive disorders that consequently are more frequent in Finland than elsewhere. Screening of all currently known Finnish patients with an HIGM2 phenotype showed them to be homozygous for p.(Met139Thr). All the Finnish p.(Met139Thr) carriers with available data on their geographic descent originated from the eastern and northeastern parts of Finland. They were observed to share more of their genome identity by descent (IBD) than Finns in general (P <0.001), and they all carried a 207.5-kb ancestral haplotype containing the variant. In conclusion, the identified p.(Met139Thr) variant is significantly enriched in Finns and explains all thus far found AID deficiencies in Finland.
  • Alegre, Sara; Pascual, Jesús; Trotta, Andrea; Angeleri, Martina; Rahikainen, Moona; Brosche, Mikael; Moffatt, Barbara; Kangasjärvi, Saijaliisa (2020)
    Trans-methylation reactions are intrinsic to cellular metabolism in all living organisms. In land plants, a range of substrate-specific methyltransferases catalyze the methylation of DNA, RNA, proteins, cell wall components and numerous species-specific metabolites, thereby providing means for growth and acclimation in various terrestrial habitats. Trans-methylation reactions consume vast amounts of S-adenosyl-L-methionine (SAM) as a methyl donor in several cellular compartments. The inhibitory reaction by-product, S-adenosyl-L-homocysteine (SAH), is continuously removed by SAH hydrolase (SAHH), which essentially maintains trans-methylation reactions in all living cells. Here we report on the evolutionary conservation and post-translational control of SAHH in land plants. We provide evidence suggesting that SAHH forms oligomeric protein complexes in phylogenetically divergent land plants and that the predominant protein complex is composed by a tetramer of the enzyme. Analysis of light-stress-induced adjustments of SAHH in Arabidopsis thaliana and Physcomitrella patens further suggests that regulatory actions may take place on the levels of protein complex formation and phosphorylation of this metabolically central enzyme. Collectively, these data suggest that plant adaptation to terrestrial environments involved evolution of regulatory mechanisms that adjust the trans-methylation machinery in response to environmental cues.
  • Justice, Anne E.; Winkler, Thomas W.; Feitosa, Mary F.; Graff, Misa; Fisher, Virginia A.; Young, Kristin; Barata, Llilda; Deng, Xuan; Czajkowski, Jacek; Hadley, David; Ngwa, Julius S.; Ahluwalia, Tarunveer S.; Chu, Audrey Y.; Heard-Costa, Nancy L.; Lim, Elise; Perez, Jeremiah; Eicher, John D.; Kutalik, Zoltan; Xue, Luting; Mahajan, Anubha; Renstrom, Frida; Wu, Joseph; Qi, Qibin; Ahmad, Shafqat; Alfred, Tamuno; Amin, Najaf; Bielak, Lawrence F.; Bonnefond, Amelie; Bragg, Jennifer; Cadby, Gemma; Chittani, Martina; Coggeshall, Scott; Corre, Tanguy; Direk, Nese; Eriksson, Joel; Fischer, Krista; Gorski, Mathias; Harder, Marie Neergaard; Horikoshi, Momoko; Huang, Tao; Huffman, Jennifer E.; Jackson, Anne U.; Justesen, Johanne Marie; Kanoni, Stavroula; Kinnunen, Leena; Kleber, Marcus E.; Komulainen, Pirjo; Kumari, Meena; Lim, Unhee; Luan, Jian'an; Lyytikainen, Leo-Pekka; Mangino, Massimo; Manichaikul, Ani; Marten, Jonathan; Middelberg, Rita P. S.; Mueller-Nurasyid, Martina; Navarro, Pau; Perusse, Louis; Pervjakova, Natalia; Sarti, Cinzia; Smith, Albert Vernon; Smith, Jennifer A.; Stancakova, Alena; Strawbridge, Rona J.; Stringham, Heather M.; Sung, Yun Ju; Tanaka, Toshiko; Teumer, Alexander; Trompet, Stella; van der Laan, Sander W.; van der Most, Peter J.; Van Vliet-Ostaptchouk, Jana V.; Vedantam, Sailaja L.; Verweij, Niek; Vink, Jacqueline M.; Vitart, Veronique; Wu, Ying; Yengo, Loic; Zhang, Weihua; Zhao, Jing Hua; Zimmermann, Martina E.; Zubair, Niha; Abecasis, Goncalo R.; Adair, Linda S.; Afaq, Saima; Afzal, Uzma; Bakker, Stephan J. L.; Bartz, Traci M.; Beilby, John; Bergman, Richard N.; Bergmann, Sven; Biffar, Reiner; Blangero, John; Boerwinkle, Eric; Bonnycastle, Lori L.; Bottinger, Erwin; Braga, Daniele; Buckley, Brendan M.; Buyske, Steve; Campbell, Harry; Chambers, John C.; Collins, Francis S.; Curran, Joanne E.; de Borst, Gert J.; de Craen, Anton J. M.; de Geus, Eco J. C.; Dedoussis, George; Delgado, Graciela E.; den Ruijter, Hester M.; Eiriksdottir, Gudny; Eriksson, Anna L.; Esko, Tonu; Faul, Jessica D.; Ford, Ian; Forrester, Terrence; Gertow, Karl; Gigante, Bruna; Glorioso, Nicola; Gong, Jian; Grallert, Harald; Grammer, Tanja B.; Grarup, Niels; Haitjema, Saskia; Hallmans, Goran; Hamsten, Anders; Hansen, Torben; Harris, Tamara B.; Hartman, Catharina A.; Hassinen, Maija; Hastie, Nicholas D.; Heath, Andrew C.; Hernandez, Dena; Hindorff, Lucia; Hocking, Lynne J.; Hollensted, Mette; Holmen, Oddgeir L.; Homuth, Georg; Hottenga, Jouke Jan; Huang, Jie; Hung, Joseph; Hutri-Kahonen, Nina; Ingelsson, Erik; James, Alan L.; Jansson, John-Olov; Jarvelin, Marjo-Riitta; Jhun, Min A.; Jorgensen, Marit E.; Juonala, Markus; Kahonen, Mika; Karlsson, Magnus; Koistinen, Heikki A.; Kolcic, Ivana; Kolovou, Genovefa; Kooperberg, Charles; Kramer, Bernhard K.; Kuusisto, Johanna; Kvaloy, Kirsti; Lakka, Timo A.; Langenberg, Claudia; Launer, Lenore J.; Leander, Karin; Lee, Nanette R.; Lind, Lars; Lindgren, Cecilia M.; Linneberg, Allan; Lobbens, Stephane; Loh, Marie; Lorentzon, Mattias; Luben, Robert; Lubke, Gitta; Ludolph-Donislawski, Anja; Lupoli, Sara; Madden, Pamela A. F.; Mannikko, Reija; Marques-Vidal, Pedro; Martin, Nicholas G.; McKenzie, Colin A.; McKnight, Barbara; Mellstrom, Dan; Menni, Cristina; Montgomery, Grant W.; Musk, A. W. (Bill); Narisu, Narisu; Nauck, Matthias; Nolte, Ilja M.; Oldehinkel, Albertine J.; Olden, Matthias; Ong, Ken K.; Padmanabhan, Sandosh; Peyser, Patricia A.; Pisinger, Charlotta; Porteous, David J.; Raitakari, Olli T.; Rankinen, Tuomo; Rao, D. C.; Rasmussen-Torvik, Laura J.; Rawal, Rajesh; Rice, Treva; Ridker, Paul M.; Rose, Lynda M.; Bien, Stephanie A.; Rudan, Igor; Sanna, Serena; Sarzynski, Mark A.; Sattar, Naveed; Savonen, Kai; Schlessinger, David; Scholtens, Salome; Schurmann, Claudia; Scott, Robert A.; Sennblad, Bengt; Siemelink, Marten A.; Silbernagel, Gunther; Slagboom, P. Eline; Snieder, Harold; Staessen, Jan A.; Stott, David J.; Swertz, Morris A.; Swift, Amy J.; Taylor, Kent D.; Tayo, Bamidele O.; Thorand, Barbara; Thuillier, Dorothee; Tuomilehto, Jaakko; Uitterlinden, Andre G.; Vandenput, Liesbeth; Vohl, Marie-Claude; Volzke, Henry; Vonk, Judith M.; Waeber, Gerard; Waldenberger, Melanie; Westendorp, R. G. J.; Wild, Sarah; Willemsen, Gonneke; Wolffenbuttel, Bruce H. R.; Wong, Andrew; Wright, Alan F.; Zhao, Wei; Zillikens, M. Carola; Baldassarre, Damiano; Balkau, Beverley; Bandinelli, Stefania; Boger, Carsten A.; Boomsma, Dorret I.; Bouchard, Claude; Bruinenberg, Marcel; Chasman, Daniel I.; Chen, Yii-Der Ida; Chines, Peter S.; Cooper, Richard S.; Cucca, Francesco; Cusi, Daniele; de Faire, Ulf; Ferrucci, Luigi; Franks, Paul W.; Froguel, Philippe; Gordon-Larsen, Penny; Grabe, Hans-Jorgen; Gudnason, Vilmundur; Haiman, Christopher A.; Hayward, Caroline; Hveem, Kristian; Johnson, Andrew D.; Jukema, Wouter; Kardia, Sharon L. R.; Kivimaki, Mika; Kooner, Jaspal S.; Kuh, Diana; Laakso, Markku; Lehtimaki, Terho; Le Marchand, Loic; Marz, Winfried; McCarthy, Mark I.; Metspalu, Andres; Morris, Andrew P.; Ohlsson, Claes; Palmer, Lyle J.; Pasterkamp, Gerard; Pedersen, Oluf; Peters, Annette; Peters, Ulrike; Polasek, Ozren; Psaty, Bruce M.; Qi, Lu; Rauramaa, Rainer; Smith, Blair H.; Sorensen, Thorkild I. A.; Strauch, Konstantin; Tiemeier, Henning; Tremoli, Elena; Van der Harst, Pim; Vestergaard, Henrik; Vollenweider, Peter; Wareham, Nicholas J.; Weir, David R.; Whitfield, John B.; Wilson, James F.; Tyrrell, Jessica; Frayling, Timothy M.; Barroso, Ines; Boehnke, Michael; Deloukas, Panagiotis; Fox, Caroline S.; Hirschhorn, Joel N.; Hunter, David J.; Spector, Tim D.; Strachan, David P.; van Duijn, Cornelia M.; Heid, Iris M.; Mohlke, Karen L.; Marchini, Jonathan; Loos, Ruth J. F.; Kilpelainen, Tuomas O.; Liu, Ching-Ti; Borecki, Ingrid B.; North, Kari E.; Cupples, L. Adrienne (2017)
    Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.
  • Fitak, Robert Rodgers; Mohandesan, Elmira; Corander, Jukka; Yadamsuren, Adiya; Chuluunbat, Battsetseg; Abdelhadi, Omer; Raziq, Abdul; Nagy, Peter; Walzer, Chris; Faye, Bernard; Burger, Pamela Anna (2020)
    Domestication begins with the selection of animals showing less fear of humans. In most domesticates, selection signals for tameness have been superimposed by intensive breeding for economical or other desirable traits. Old World camels, conversely, have maintained high genetic variation and lack secondary bottlenecks associated with breed development. By re-sequencing multiple genomes from dromedaries, Bactrian camels, and their endangered wild relatives, here we show that positive selection for candidate genes underlying traits collectively referred to as 'domestication syndrome' is consistent with neural crest deficiencies and altered thyroid hormone-based signaling. Comparing our results with other domestic species, we postulate that the core set of domestication genes is considerably smaller than the pan-domestication set - and overlapping genes are likely a result of chance and redundancy. These results, along with the extensive genomic resources provided, are an important contribution to understanding the evolutionary history of camels and the genomic features of their domestication. Robert R. Fitak et al. investigate the genetic basis for domestication in camels. They found that the positive selection of candidate domestication genes is consistent with neural crest deficiencies and altered thyroid hormone-based signaling. Their work provides insights to the evolutionary history of camels and genetics of domestication.
  • Nozal, Pilar; Bernabeu-Herrero, Maria E.; Uzonyi, Barbara; Szilagyi, Agnes; Hyvarinen, Satu; Prohaszka, Zoltan; Jokiranta, T. Sakari; Sanchez-Corral, Pilar; Lopez-Trascasa, Margarita; Jozsi, Mihaly (2016)
    Factor H (FH) autoantibodies are present in 6-10% of atypical hemolytic uremic syndrome (aHUS) patients, most of whom have homozygous deficiency of the FH-related protein FHR-1. Although the pathogenic role of the autoantibodies is established, little is known about their molecular characteristics and changes over time. Here, we describe the specificity and other immunological features of anti-FH autoantibodies in the Spanish and Hungarian aHUS cohorts. A total of 19 patients were included and serial samples of 14 of them were available. FH autoantibodies from FHR-1 deficient patients (n = 13) mainly recognized FH, its SCR19-20 fragment and FHR-1, but autoantibody specificity in patients who are homoor heterozygous for the CFHR1 gene (n = 6) was heterogeneous. No significant changes apart from total antibody titer were observed during follow-up in each patient. Fine epitope mapping with recombinant FH SCR19-20 containing single amino acid mutations showed significantly reduced binding in 6 out of 14 patients. In most cases, autoantibody binding to residues 1183-1189 and 1210-1215 was impaired, revealing a major common autoantibody epitope. Avidities showed variations between patients, but in most cases the avidity index did not change upon time. Most autoantibodies were IgG3, and all but three presented only with kappa or with lambda light chains. Although the pathogenic role of anti-FH autoantibodies in aHUS is well established, this study shows autoantibody heterogeneity among patients, but no significant variation in their characteristics over time in each patient. The presence of a single light chain in 16 out of 19 patients and the limited number of recognized epitopes suggest a restricted autoantibody response in most patients. (C) 2015 Elsevier Ltd. All rights reserved.
  • Partanen, Terhi; Chen, Jie; Lehtonen, Johanna; Kuismin, Outi; Rusanen, Harri; Vapalahti, Olli; Vaheri, Antti; Anttila, Veli-Jukka; Bode, Michaela; Hautala, Nina; Vuorinen, Tytti; Glumoff, Virpi; Kraatari, Minna; Åström, Pirjo; Saarela, Janna; Kauma, Heikki; Lorenzo, Lazaro; Casanova, Jean-Laurent; Zhang, Shen-Ying; Seppänen, Mikko; Hautala, Timo (2020)
    Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%,p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-lambda and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.
  • Mantula, Paula S.; Outinen, Tuula K.; Jaatinen, Pia; Hämäläinen, Mari; Huhtala, Heini; Pörsti, Ilkka H.; Vaheri, Antti; Mustonen, Jukka T.; Mäkelä, Satu M. (2018)
    Background Puumala hantavirus (PUUV) infected patients typically suffer from acute kidney injury (AKI). Adipokines have inflammation modulating functions in acute diseases including AKI. We examined plasma levels of three adipokines (resistin, leptin, and adiponectin) in acute PUUV infection and their associations with disease severity. Methods This study included 79 patients hospitalized due to acute PUUV infection. Plasma resistin, leptin, adiponectin, as well as IL-6 and CRP, were measured at the acute phase, recovery phase and one year after hospitalization. Results Plasma resistin levels were significantly higher in the acute phase compared to the recovery phase and one year after (median resistin 28 pg/mL (11-107) vs. 17 pg/mL (7-36) vs. 14 pg/mL (7-31), p= 353.6 mu mol/L) (OR 1.08, 95% CI 1.02-1.14). Neither plasma leptin nor adiponectin level had any correlation with creatinine concentration or the amount of albuminuria. Conclusions Plasma resistin independently associates with the severity of AKI in acute PUUV infection. The association of resistin with the amount of albuminuria suggests that the level of plasma resistin is not only influenced by renal clearance but could have some role in the pathogenesis of AKI during PUUV infection.
  • Robciuc, Marius R.; Metso, Jari; Sima, Anca; Ehnholm, Christian; Jauhiainen, Matti (2010)
    Background: phospholipid transfer protein (PLTP) plays important roles in lipoprotein metabolism and atherosclerosis and is expressed by macrophages and macrophage foam cells (MFCs). The aim of the present study was to determine whether the major protein from HDL, apoA-I, affects PLTP derived from MFCs. Results: as cell model we used human THP-1 monocytes incubated with acetylated LDL, to generate MFC. The addition of apoA-I to the cell media increased apoE secretion from the cells, in a concentration dependent fashion, without affecting cellular apoE levels. In contrast, apoA-I had no effect on PLTP synthesis and secretion, but strongly induced the PLTP activity in the media. ApoA-I also increased phospholipid transfer activity of PLTP isolated from human plasma. This effect was dependent on apoA-I concentration but independent on apoA-I lipidation status. ApoE, ApoA-II and apoA-IV, but not immunoglobulins or bovine serum albumin, also increased PLTP activity. We also report that apoA-I protects PLTP from heat inactivation. Conclusion: apoA-I enhances the phospholipid transfer activity of PLTP secreted from macrophage foam cells without affecting the PLTP mass.