Browsing by Subject "GENETIC-VARIATION"

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  • Penteriani, Vincenzo; del Mar Delgado, Maria; Pinchera, Francesco; Naves, Javier; Fernandez-Gil, Alberto; Kojola, Ilpo; Härkönen, Sauli; Norberg, Harri; Frank, Jens; Maria Fedriani, Jose; Sahlen, Veronica; Stoen, Ole-Gunnar; Swenson, Jon E.; Wabakken, Petter; Pellegrini, Mario; Herrero, Stephen; Vicente Lopez-Bao, Jose (2016)
    The media and scientific literature are increasingly reporting an escalation of large carnivore attacks on humans in North America and Europe. Although rare compared to human fatalities by other wildlife, the media often overplay large carnivore attacks on humans, causing increased fear and negative attitudes towards coexisting with and conserving these species. Although large carnivore populations are generally increasing in developed countries, increased numbers are not solely responsible for the observed rise in the number of attacks by large carnivores. Here we show that an increasing number of people are involved in outdoor activities and, when doing so, some people engage in risk-enhancing behaviour that can increase the probability of a risky encounter and a potential attack. About half of the well-documented reported attacks have involved risk-enhancing human behaviours, the most common of which is leaving children unattended. Our study provides unique insight into the causes, and as a result the prevention, of large carnivore attacks on people. Prevention and information that can encourage appropriate human behaviour when sharing the landscape with large carnivores are of paramount importance to reduce both potentially fatal human-carnivore encounters and their consequences to large carnivores.
  • Sánez Tähtisalo, Heini; Ruotsalainen, Sanni; Mars, Nina; Porthan, Kimmo; Oikarinen, Lasse; Virolainen, Juha; Fyhrquist, Frej; Ripatti, Samuli; Kontula, Kimmo K.; Hiltunen, Timo P. (2020)
    Polygenic risk scores (PRSs) for essential hypertension, calculated from>900 genomic loci, were recently found to explain a significant fraction of hypertension heritability and complications. To investigate whether variation of hypertension PRS also captures variation of antihypertensive drug responsiveness, we calculated two different PRSs for both systolic and diastolic blood pressure: one based on the top 793 independent hypertension-associated single nucleotide polymorphisms and another based on over 1 million genome-wide variants. Using our pharmacogenomic GENRES study comprising four different antihypertensive monotherapies (n similar to 200 for all drugs), we identified a weak, but (after Bonferroni correction) statistically nonsignificant association of higher genome-wide PRSs with weaker response to a diuretic. In addition, we noticed a correlation between high genome-wide PRS and electrocardiographic left ventricular hypertrophy. Finally, using data of the Finnish arm of the LIFE study (n=346), we found that PRSs for systolic blood pressure were slightly higher in patients with drug-resistant hypertension than in those with drug-controlled hypertension (p=0.03, not significant after Bonferroni correction). In conclusion, our results indicate that patients with elevated hypertension PRSs may be predisposed to difficult-to-control hypertension and complications thereof. No general association between a high PRS and less efficient drug responsiveness was noticed.
  • Rembeck, Karolina; Alsio, Asa; Christensen, Peer Brehm; Färkkilä, Martti Antero; Langeland, Nina; Buhl, Mads Rauning; Pedersen, Court; Morch, Kristine; Westin, Johan; Lindh, Magnus; Hellstrand, Kristoffer; Norkrans, Gunnar; Lagging, Martin (2012)
  • Silfver, Tarja; Kontro, Merja; Paaso, Ulla; Karvinen, Heini; Keski-Saari, Sarita; Keinanen, Markku; Rousi, Matti; Mikola, Juha (2018)
    Background and aims Differences among plant genotypes can influence ecosystem functioning such as the rate of litter decomposition. Little is known, however, of the strength of genotypic links between litter quality, microbial abundance and litter decomposition within plant populations, or the likelihood that these processes are driven by natural selection. Methods We used 19 Betula pendula genotypes randomly selected from a local population in south-eastern Finland to establish a long-term, 35-month litter decomposition trial on forest ground. We analysed the effect of litter quality (N, phenolics and triterpenoids) of senescent leaves and decomposed litter on microbial abundance and litter mass loss. Results We found that while litter quality and mass loss both had significant genotypic variation, the genotypic variation among silver birch trees in the quantity of bacterial and fungal DNA was marginal. In addition, although the quantity of bacterial DNA at individual tree level was negatively associated with most secondary metabolites of litter and positively with litter N, litter chemistry was not genotypically linked to litter mass loss. Conclusions Contrary to our expectations, these results suggest that natural selection may have limited influence on overall microbial DNA and litter decomposition rate in B. pendula populations by reworking the genetically controlled foliage chemistry of these populations.
  • Paaso, Ulla; Keski-Saari, Sarita; Keinänen, Markku; Karvinen, Heini; Silfver, Tarja; Rousi, Matti; Mikola, Juha (2017)
    Abundant secondary metabolites, such as condensed tannins, and their interpopulation genotypic variation can remain through plant leaf senescence and affect litter decomposition. Whether the intrapopulation genotypic variation of a more diverse assortment of secondary metabolites equally persists through leaf senescence and litter decomposition is not well understood. We analyzed concentrations of intracellular phenolics, epicuticular flavonoid aglycones, epicuticular triterpenoids, condensed tannins, and lignin in green leaves, senescent leaves and partly decomposed litter of silver birch, Betula pendula. Broad-sense heritability (H-2) and coefficient of genotypic variation (CVG) were estimated for metabolites in senescent leaves and litter using 19 genotypes selected from a B. pendula population in southern Finland. We found that most of the secondary metabolites remained through senescence and decomposition and that their persistence was related to their chemical properties. Intrapopulation H-2 and CVG for intracellular phenolics, epicuticular flavonoid aglycones and condensed tannins were high and remarkably, increased from senescent leaves to decomposed litter. The rank of genotypes in metabolite concentrations was persistent through litter decomposition. Lignin was an exception, however, with a diminishing genotypic variation during decomposition, and the concentrations of lignin and condensed tannins had a negative genotypic correlation in the senescent leaves. Our results show that secondary metabolites and their intrapopulation genotypic variation can for the most part remain through leaf senescence and early decomposition, which is a prerequisite for initial litter quality to predict variation in litter decomposition rates. Persistent genotypic variation also opens an avenue for selection to impact litter decomposition in B. pendula populations through acting on their green foliage secondary chemistry. The negative genotypic correlations and diminishing heritability of lignin concentrations may, however, counteract this process.
  • Batini, Chiara; Hallast, Pille; Zadik, Daniel; Delser, Pierpaolo Maisano; Benazzo, Andrea; Ghirotto, Silvia; Arroyo-Pardo, Eduardo; Cavalleri, Gianpiero L.; de Knijff, Peter; Dupuy, Berit Myhre; Eriksen, Heidi A.; King, Turi E.; Lopez de Munain, Adolfo; Lopez-Parra, Ana M.; Loutradis, Aphrodite; Milasin, Jelena; Novelletto, Andrea; Pamjav, Horolma; Sajantila, Antti; Tolun, Aslihan; Winney, Bruce; Jobling, Mark A. (2015)
    The proportion of Europeans descending from Neolithic farmers similar to 10 thousand years ago (KYA) or Palaeolithic hunter-gatherers has been much debated. The male-specific region of the Ychromosome (MSY) has been widely applied to this question, but unbiased estimates of diversity and time depth have been lacking. Here we show that European patrilineages underwent a recent continent-wide expansion. Resequencing of 3.7Mb of MSY DNA in 334 males, comprising 17 European and Middle Eastern populations, defines a phylogeny containing 5,996 single-nucleotide polymorphisms. Dating indicates that three major lineages (I1, R1a and R1b), accounting for 64% of our sample, have very recent coalescent times, ranging between 3.5 and 7.3 KYA. A continuous swathe of 13/17 populations share similar histories featuring a demographic expansion starting similar to 2.1-4.2 KYA. Our results are compatible with ancient MSY DNA data, and contrast with data on mitochondrial DNA, indicating a widespread male-specific phenomenon that focuses interest on the social structure of Bronze Age Europe.
  • Castel, Stephane E.; Cervera, Alejandra; Mohammadi, Pejman; Aguet, Francois; Reverter, Ferran; Wolman, Aaron; Guigo, Roderic; Iossifov, Ivan; Vasileva, Ana; Lappalainen, Tuuli (2018)
    Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit interindividual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.
  • Rodrigues, Ana S. B.; Silva, Sara E.; Marabuto, Eduardo; Silva, Diogo N.; Wilson, Mike R.; Thompson, Vinton; Yurtsever, Selcuk; Halkka, Antti; Borges, Paulo A. V.; Quartau, Jose A.; Paulo, Octavio S.; Seabra, Sofia G. (2014)
  • Barnes, Anna; Isohanni, Matti; Barnett, Jennifer H.; Pietiläinen, Olli; Veijola, Juha; Miettunen, Jouko; Paunio, Tiina; Tanskanen, Paivikki; Ridler, Khanum; Suckling, John; Bullmore, Edward T.; Murray, Graham K.; Jones, Peter B. (2012)
  • Baumert, Jens; Huang, Jie; McKnight, Barbara; Sabater-Lleal, Maria; Steri, Maristella; Chu, Audrey Y.; Trompet, Stella; Lopez, Lorna M.; Fornage, Myriam; Teumer, Alexander; Tang, Weihong; Rudnicka, Alicja R.; Maelarstig, Anders; Hottenga, Jouke-Jan; Kavousi, Maryam; Lahti, Jari; Tanaka, Toshiko; Hayward, Caroline; Huffman, Jennifer E.; Morange, Pierre-Emmanuel; Rose, Lynda M.; Basu, Saonli; Rumley, Ann; Stott, David J.; Buckley, Brendan M.; de Craen, Anton J. M.; Sanna, Serena; Masala, Marco; Biffar, Reiner; Homuth, Georg; Silveira, Angela; Sennblad, Bengt; Goel, Anuj; Watkins, Hugh; Mueller-Nurasyid, Martina; Rueckerl, Regina; Taylor, Kent; Chen, Ming-Huei; de Geus, Eco J. C.; Hofman, Albert; Witteman, Jacqueline C. M.; de Maat, Moniek P. M.; Palotie, Aarno; Davies, Gail; Siscovick, David S.; Kolcic, Ivana; Wild, Sarah H.; Song, Jaejoon; McArdle, Wendy L.; Ford, Ian; Sattar, Naveed; Schlessinger, David; Grotevendt, Anne; Franzosi, Maria Grazia; Illig, Thomas; Waldenberger, Melanie; Lumley, Thomas; Tofler, Geoffrey H.; Willemsen, Gonneke; Uitterlinden, Andre G.; Rivadeneira, Fernando; Räikkönen, Katri; Chasman, Daniel I.; Folsom, Aaron R.; Lowe, Gordon D.; Westendorp, Rudi G. J.; Slagboom, P. Eline; Cucca, Francesco; Wallaschofski, Henri; Strawbridge, Rona J.; Seedorf, Udo; Koenig, Wolfgang; Bis, Joshua C.; Mukamal, Kenneth J.; van Dongen, Jenny; Widen, Elisabeth; Franco, Oscar H.; Starr, John M.; Liu, Kiang; Ferrucci, Luigi; Polasek, Ozren; Wilson, James F.; Oudot-Mellakh, Tiphaine; Campbell, Harry; Navarro, Pau; Bandinelli, Stefania; Eriksson, Johan; Boomsma, Dorret I.; Dehghan, Abbas; Clarke, Robert; Hamsten, Anders; Boerwinkle, Eric; Jukema, J. Wouter; Naitza, Silvia; Ridker, Paul M.; Voezke, Henry; Deary, Ian J.; Reiner, Alexander P.; Tregoueet, David-Alexandre; O'Donnell, Christopher J.; Strachan, David P.; Peters, Annette; Smith, Nicholas L. (2014)
  • Early Growth Genetics Consortium; Vogelezang, Suzanne; Bradfield, Jonathan P.; Ahluwalia, Tarunveer S.; Eriksson, Johan G.; Leinonen, Jaakko T.; Widen, Elisabeth (2020)
    The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values Author summary Although twin studies have shown that body mass index (BMI) is highly heritable, many common genetic variants involved in the development of BMI have not yet been identified, especially in children. We studied associations of more than 40 million genetic variants with childhood BMI in 61,111 children aged between 2 and 10 years. We identified 25 genetic variants that were associated with childhood BMI. Two of these have not been implicated for BMI previously, located close to the genesNEDD4LandSLC45A3. We also show that the genetic background of childhood BMI overlaps with that of birth weight, adult BMI, waist-to-hip-ratio, diastolic blood pressure, type 2 diabetes, and age at menarche. Our results suggest that the biological processes underlying childhood BMI largely overlap with those underlying adult BMI. However, the overlap is not complete. Additionally, the genetic backgrounds of childhood BMI and other cardio-metabolic phenotypes are overlapping. This may mean that the associations of childhood BMI and later cardio-metabolic outcomes are partially explained by shared genetics, but it could also be explained by the strong association of childhood BMI with adult BMI.
  • Lallukka, Susanna; Luukkonen, Panu K.; Zhou, You; Isokuortti, Elina; Leivonen, Marja; Juuti, Anne; Hakkarainen, Antti; Orho-Melander, Marju; Lundbom, Nina; Olkkonen, Vesa M.; Lassila, Riitta; Yki-Järvinen, Hannele (2017)
    Increased liver fat may be caused by insulin resistance and adipose tissue inflammation or by the common I148M variant in PNPLA3 at rs738409, which lacks both of these features. We hypothesised that obesity/insulin resistance rather than liver fat increases circulating coagulation factor activities. We measured plasma prothrombin time (PT, Owren method), activated partial thromboplastin time (APTT), activities of several coagulation factors, VWF:RCo and fibrinogen, and D-dimer concentration in 92 subjects divided into groups based on insulin sensitivity [insulin-resistant ('IR') versus insulin-sensitive ('IS')] and PNPLA3 genotype (PNPLA3(148MM/MI) vs PNPLA3(148II)). Liver fat content (H-1-MRS) was similarly increased in 'IR' (13 +/- 1%) and PNPLA3(148MM/MI) (12 +/- 2%) as compared to 'IS' (6 +/- 1%, p
  • Castel, Guillaume; Chevenet, Francois; Razzauti, Maria; Murri, Severine; Marianneau, Philippe; Cosson, Jean-Francois; Tordo, Noel; Plyusnin, Alexander (2019)
    Puumala virus is an RNA virus hosted by the bank vole (Myodes glareolus) and is today present in most European countries. Whilst it is generally accepted that hantaviruses have been tightly co-evolving with their hosts, Puumala virus (PUUV) evolutionary history is still controversial and so far has not been studied at the whole European level. This study attempts to reconstruct the phylogeographical spread of modern PUUV throughout Europe during the last postglacial period in the light of an upgraded dataset of complete PUUV small (S) segment sequences and by using most recent computational approaches. Taking advantage of the knowledge on the past migrations of its host, we identified at least three potential independent dispersal routes of PUUV during postglacial recolonization of Europe by the bank vole. From the Alpe-Adrian region (Balkan, Austria, and Hungary) to Western European countries (Germany, France, Belgium, and Netherland), and South Scandinavia. From the vicinity of Carpathian Mountains to the Baltic countries and to Poland, Russia, and Finland. The dissemination towards Denmark and North Scandinavia is more hypothetical and probably involved several independent streams from south and north Fennoscandia.
  • Duarte, Gustavo Turqueto; Pandey, Prashant K.; Vaid, Neha; Alseekh, Saleh; Fernie, Alisdair R.; Nikoloski, Zoran; Laitinen, Roosa A. E. (2021)
    Nitrogen (N) is fundamental to plant growth, development and yield. Genes underlying N utilization and assimilation are well-characterized, but mechanisms underpinning plasticity of different phenotypes in response to N remain elusive. Here, using Arabidopsis thaliana accessions, we dissected the genetic architecture of plasticity in early and late rosette diameter, flowering time and yield, in response to three levels of N in the soil. Furthermore, we found that the plasticity in levels of primary metabolites were related with the plasticities of the studied traits. Genome-wide association analysis identified three significant associations for phenotypic plasticity, one for early rosette diameter and two for flowering time. We confirmed that the gene At1g19880, hereafter named as PLASTICITY OF ROSETTE TO NITROGEN 1 (PROTON1), encoding for a regulator of chromatin condensation 1 (RCC1) family protein, conferred plasticity of rosette diameter in response to N. Treatment of PROTON1 T-DNA line with salt implied that the reduced plasticity of early rosette diameter was not a general growth response to stress. We further showed that plasticities of growth and flowering-related traits differed between environmental cues, indicating decoupled genetic programs regulating these traits. Our findings provide a prospective to identify genes that stabilize performance under fluctuating environments.
  • Taurisano, Paolo; Romano, Raffaella; Mancini, Marina; Di Giorgio, Annabella; Antonucci, Linda A.; Fazio, Leonardo; Rampino, Antonio; Quarto, Tiziana; Gelao, Barbara; Porcelli, Annamaria; Papazacharias, Apostolos; Ursini, Gianluca; Caforio, Grazia; Masellis, Rita; Niccoli-Asabella, Artor; Todarello, Orlando; Popolizio, Teresa; Rubini, Giuseppe; Blasi, Giuseppe; Bertolino, Alessandro (2014)
  • Waldenstrom, Jesper; Hellstrand, Kristoffer; Westin, Johan; Nilsson, Staffan; Christensen, Peer; Färkkilä, Martti; Morch, Kristine; Langeland, Nina; Norkrans, Gunnar; Lagging, Martin (2021)
    Objectives: Despite recombinant interferon-lambda 4 (IFN-lambda 4) demonstrating anti-viral activity in vitro and the ancestral functional gene (IFNL4) being conserved in all other primates, there has been speculation that IFN-?A may be detrimental in humans. In light of recent rekindled interest in humoral immunity, this study aimed at evaluating the impact of baseline characteristics, including IFNL4, on antibody levels to hepatitis C virus (HCV). Materials and methods: Pretreatment sera from 279 well-characterized North European Caucasians with chronic HCV genotype 2 or 3 infection having undergone liver biopsy were analyzed regarding IFNL4 (rs12979860) and anti-HCV antibody levels using a commercially available assay. Results: Patients producing IFN-lambda 4 had higher signal to cut-off (S/CO) anti-HCV antibody ratios as compared with those lacking IFN-lambda 4 (IFNL4(rs1)(2979860) CT/TT versus CC, p Conclusions: To our knowledge, this is the first report that demonstrates that the ability to produce IFN-lambda 4, in addition to male gender, absent/mild steatosis, and lower viral load, augments antibody levels against HCV. This indicates that IFN-lambda 4 may be associated with T helper cell 2 (Th2) immune skewing, which might have clinical implications beyond HCV infection.
  • Waldenstrom, Jesper; Westin, Johan; Nystrom, Kristina; Christensen, Peer; Dalgard, Olav; Farkkila, Martti; Lindahl, Karin; Nilsson, Staffan; Norkrans, Gunnar; Krarup, Henrik; Norrgren, Hans; Buhl, Mads Rauning; Stenmark, Stephan; Lagging, Martin (2016)
    In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naive patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-alpha (pegIFN-alpha), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-alpha, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-alpha. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log(10) IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log(10) IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-alpha and thus shortened treatment duration (P <0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P <0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an antiviral effect differently regulated across IL28B genotypes.
  • Akinrinade, Oyediran; Heliö, Tiina; Deprez, Ronald H. Lekanne; Jongbloed, Jan D. H.; Boven, Ludolf G.; van den Berg, Maarten P.; Pinto, Yigal M.; Alastalo, Tero-Pekka; Myllykangas, Samuel; van Spaendonck-Zwarts, Karin; van Tintelen, J. Peter; van der Zwaag, Paul A.; Koskenvuo, Juha (2019)
    Recent advancements in next generation sequencing (NGS) technology have led to the identification of the giant sarcomere gene, titin (TTN), as a major human disease gene. Truncating variants of TTN (TTNtv) especially in the A-band region account for 20% of dilated cardiomyopathy (DCM) cases. Much attention has been focused on assessment and interpretation of TTNtv in human disease; however, missense and non-frameshifting insertions/deletions (NFS-INDELs) are difficult to assess and interpret in clinical diagnostic workflow. Targeted sequencing covering all exons of TTN was performed on a cohort of 530 primary DCM patients from three cardiogenetic centres across Europe. Using stringent bioinformatic filtering, twenty-nine and two rare TTN missense and NFS-INDELs variants predicted deleterious were identified in 6.98% and 0.38% of DCM patients, respectively. However, when compared with those identified in the largest available reference population database, no significant enrichment of such variants was identified in DCM patients. Moreover, DCM patients and reference individuals had comparable frequencies of splice-region missense variants with predicted splicing alteration. DCM patients and reference populations had comparable frequencies of rare predicted deleterious TTN missense variants including splice-region missense variants suggesting that these variants are not independently causative for DCM. Hence, these variants should be classified as likely benign in the clinical diagnostic workflow, although a modifier effect cannot be excluded at this stage.
  • Kelemen, Linda E.; Earp, Madalene; Fridley, Brooke L.; Chenevix-Trench, Georgia; Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.; Hein, Alexander; Lambrechts, Diether; Lambrechts, Sandrina; Van Nieuwenhuysen, Els; Vergote, Ignace; Rossing, Mary Anne; Doherty, Jennifer A.; Chang-Claude, Jenny; Behrens, Sabine; Moysich, Kirsten B.; Cannioto, Rikki; Lele, Shashikant; Odunsi, Kunle; Goodman, Marc T.; Shvetsov, Yurii B.; Thompson, Pamela J.; Wilkens, Lynne R.; Doerk, Thilo; Antonenkova, Natalia; Bogdanova, Natalia; Hillemanns, Peter; Runnebaum, Ingo B.; du Bois, Andreas; Harter, Philipp; Heitz, Florian; Schwaab, Ira; Butzow, Ralf; Pelttari, Liisa M.; Nevanlinna, Heli; Modugno, Francesmary; Edwards, Robert P.; Kelley, Joseph L.; Ness, Roberta B.; Karlan, Beth Y.; Lester, Jenny; Orsulic, Sandra; Walsh, Christine; Kjaer, Susanne K.; Jensen, Allan; Cunningham, Julie M.; Vierkant, Robert A.; Giles, Graham G.; Bruinsma, Fiona (2018)
    Thymidylate synthase (TYMS) is a crucial enzyme for DNA synthesis. TYMS expression is regulated by its antisense mRNA, ENOSF1. Disrupted regulation may promote uncontrolled DNA synthesis and tumor growth. We sought to replicate our previously reported association between rs495139 in the TYMS-ENOSF1 3' gene region and increased risk of mucinous ovarian carcinoma (MOC) in an independent sample. Genotypes from 24,351 controls to 15,000 women with invasive OC, including 665 MOC, were available. We estimated per-allele odds ratios (OR) and 95% confidence intervals (CI) using unconditional logistic regression, and meta-analysis when combining these data with our previous report. The association between rs495139 and MOC was not significant in the independent sample (OR = 1.09; 95% CI = 0.97-1.22; p = 0.15; N = 665 cases). Meta-analysis suggested a weak association (OR = 1.13; 95% CI = 1.03-1.24; p = 0.01; N = 1019 cases). No significant association with risk of other OC histologic types was observed (p = 0.05 for tumor heterogeneity). In expression quantitative trait locus (eQTL) analysis, the rs495139 allele was positively associated with ENOSF1 mRNA expression in normal tissues of the gastrointestinal system, particularly esophageal mucosa (r = 0.51, p = 1.7 x 10(-28)), and nonsignificantly in five MOC tumors. The association results, along with inconclusive tumor eQTL findings, suggest that a true effect of rs495139 might be small.