Browsing by Subject "GENOTYPE"

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  • Kyöstilä, Kaisa; Syrjä, Pernilla; Lappalainen, Anu K.; Arumilli, Meharji; Hundi, Sruthi; Karkamo, Veera; Viitmaa, Ranno; Hytönen, Marjo K.; Lohi, Hannes (2019)
    Inherited skeletal disorders affect both humans and animals. In the current study, we have performed series of clinical, pathological and genetic examinations to characterize a previously unreported skeletal disease in the Karelian Bear Dog (KBD) breed. The disease was recognized in seven KBD puppies with a variable presentation of skeletal hypomineralization, growth retardation, seizures and movement difficulties. Exome sequencing of one affected dog revealed a homozygous missense variant (c. 1301T > G; p. V434G) in the tissue non-specific alkaline phosphatase gene, ALPL. The identified recessive variant showed full segregation with the disease in a cohort of 509 KBDs with a carrier frequency of 0.17 and was absent from 303 dogs from control breeds. In humans, recessive and dominant ALPL mutations cause hypophosphatasia (HPP), a metabolic bone disease with highly heterogeneous clinical manifestations, ranging from lethal perinatal hypomineralization to a relatively mild dental disease. Our study reports the first naturally occurring HPP in animals, resembling the human infantile form. The canine HPP model may serve as a preclinical model while a genetic test will assist in breeding programs.
  • Drug-Induced Liver Injury Network; Int DILI Consortium iDILIC; Cirulli, Elizabeth T.; Nicoletti, Paola; Laitinen, Tarja (2019)
    BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
  • Wendt, Frank R.; Novroski, Nicole M. M.; Rahikainen, Anna-Liina; Sajantila, Antti; Budowle, Bruce (2019)
    Predicting metabolizer phenotype (MP) is typically performed using data from a single gene. Cytochrome p450 family 2 subfamily D polypeptide 6 (CYP2D6) is considered the primary gene for predicting MP in reference to approximately 30% of marketed drugs and endogenous toxins. CYP2D6 predictions have proven clinically effective but also have well-documented inaccuracies due to relatively high genotype-phenotype discordance in certain populations. Herein, a pathway-driven predictive model employs genetic data from uridine diphosphate glucuronosyltransferase, family 1, polypeptide B7 (UGT2B7), adenosine triphosphate (ATP)-binding cassette, subfamily B, number 1 (ABCB1), opioid receptor mu 1 (OPRM1), and catechol-O-methyltransferase (COMT) to predict the tramadol to primary metabolite ratio (T:M1) and the resulting toxicologically inferred MP (t-MP). These data were then combined with CYP2D6 data to evaluate performance of a fully combinatorial model relative to CYP2D6 alone. These data identify UGT2B7 as a potentially significant explanatory marker for T:M1 variability in a population of tramadol-exposed individuals of Finnish ancestry. Supervised machine learning and feature selection were used to demonstrate that a set of 16 loci from 5 genes can predict t-MP with over 90% accuracy, depending on t-MP category and algorithm, which was significantly greater than predictions made by CYP2D6 alone.
  • Li, Xia; Frechen, Sebastian; Moj, Daniel; Lehr, Thorsten; Taubert, Max; Hsin, Shih-hsuan; Mikus, Gerd; Neuvonen, Pertti J; Olkkola, Klaus; Saari, Teijo; Fuhr, Uwe (2020)
    Background Voriconazole, a first-line antifungal drug, exhibits nonlinear pharmacokinetics (PK), together with large interindividual variability but a narrow therapeutic range, and markedly inhibits cytochrome P450 (CYP) 3A4 in vivo. This causes difficulties in selecting appropriate dosing regimens of voriconazole and coadministered CYP3A4 substrates. Objective This study aimed to investigate the metabolism of voriconazole in detail to better understand dose- and time-dependent alterations in the PK of the drug, to provide the model basis for safe and effective use according to CYP2C19 genotype, and to assess the potential of voriconazole to cause drug-drug interactions (DDIs) with CYP3A4 substrates in more detail. Methods In vitro assays were carried out to explore time-dependent inhibition (TDI) of CYP3A4 by voriconazole. These results were combined with 93 published concentration-time datasets of voriconazole from clinical trials in healthy volunteers to develop a whole-body physiologically based PK (PBPK) model in PK-Sim(R). The model was evaluated quantitatively with the predicted/observed ratio of the area under the plasma concentration-time curve (AUC), maximum concentration (C-max), and trough concentrations for multiple dosings (C-trough), the geometric mean fold error, as well as visually with the comparison of predicted with observed concentration-time datasets over the full range of recommended intravenous and oral dosing regimens. Results The result of the half maximal inhibitory concentration (IC50) shift assay indicated that voriconazole causes TDI of CYP3A4. The PBPK model evaluation demonstrated a good performance of the model, with 71% of predicted/observed aggregate AUC ratios and all aggregateC(max)ratios from 28 evaluation datasets being within a 0.5- to 2-fold range. For those studies reporting CYP2C19 genotype, 89% of aggregate AUC ratios and all aggregateC(max)ratios were inside a 0.5- to 2-fold range of 44 test datasets. The results of model-based simulations showed that the standard oral maintenance dose of voriconazole 200 mg twice daily would be sufficient for CYP2C19 intermediate metabolizers (IMs; *1/*2, *1/*3, *2/*17, and *2/*2/*17) to reach the tentative therapeutic range of > 1-2 mg/L to <5-6 mg/L forC(trough), while 400 mg twice daily might be more suitable for rapid metabolizers (RMs; *1/*17, *17/*17) and normal metabolizers (NMs; *1/*1). When the model was integrated with independently developed CYP3A4 substrate models (midazolam and alfentanil), the observed AUC change of substrates by voriconazole was inside the 90% confidence interval of the predicted AUC change, indicating that CYP3A4 inhibition was appropriately incorporated into the voriconazole model. Conclusions Both the in vitro assay and model-based simulations support TDI of CYP3A4 by voriconazole as a pivotal characteristic of this drug's PK. The PBPK model developed here could support individual dose adjustment of voriconazole according to genetic polymorphisms of CYP2C19, and DDI risk management. The applicability of modeling results for patients remains to be confirmed in future studies.
  • Chawade, Aakash; Armoniene, Rita; Berg, Gunilla; Brazauskas, Gintaras; Frostgard, Gunilla; Geleta, Mulatu; Gorash, Andrii; Henriksson, Tina; Himanen, Kristiina; Ingver, Anne; Johansson, Eva; Jorgensen, Lise Nistrup; Koppel, Mati; Koppel, Reine; Makela, Pirjo; Ortiz, Rodomiro; Podyma, Wieslaw; Roitsch, Thomas; Ronis, Antanas; Svensson, Jan T.; Vallenback, Pernilla; Weih, Martin (2018)
    The Baltic Sea is one of the largest brackish water bodies in the world. Eutrophication is a major concern in the Baltic Sea due to the leakage of nutrients to the sea with agriculture being the primary source. Wheat (Triticum aestivum L.) is the most widely grown crop in the countries surrounding the Baltic Sea and thus promoting sustainable agriculture practices for wheat cultivation will have a major impact on reducing pollution in the Baltic Sea. This approach requires identifying and addressing key challenges for sustainable wheat production in the region. Implementing new technologies for climate-friendly breeding and digital farming across all surrounding countries should promote sustainable intensification of agriculture in the region. In this review, we highlight major challenges for wheat cultivation in the Baltic Sea region and discuss various solutions integrating transnational collaboration for pre-breeding and technology sharing to accelerate development of low input wheat cultivars with improved host plant resistance to pathogen and enhanced adaptability to the changing climate.
  • Vincenzi, Bruno; Napolitano, Andrea; Fiocco, Marta; Mir, Olivier; Rutkowski, Piotr; Blay, Jean-Yves; Reichardt, Peter; Joensuu, Heikki; Fumagalli, Elena; Gennatas, Spyridon; Hindi, Nadia; Nannini, Margherita; Ceruso, Mariella Spalato; Italiano, Antoine; Grignani, Giovanni; Brunello, Antonella; Gasperoni, Silvia; De Pas, Tommaso; Badalamenti, Giuseppe; Pantaleo, Maria A.; van Houdt, Winan J.; IJzerman, Nikki S.; Steeghs, Neeltje; Gelderblom, Hans; Desar, Ingrid M. E.; Falkenhorst, Johanna; Silletta, Marianna; Sbaraglia, Marta; Tonini, Giuseppe; Martin-Broto, Javier; Hohenberger, Peter; Le Cesne, Axel; Jones, Robin L.; Dei Tos, Angelo P.; Gronchi, Alessandro; Bauer, Sebastian; Casali, Paolo G. (2022)
    Purpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopatho-logic variables with survival was evaluated in a large multi-institutional European cohort. Experimental Design: Data from 185 patients were retrospec-tively collected in 23 European GIST reference centers. Propen-sity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Uni-variate and multivariate unweighted and weighted Cox propor-tional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival. Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79- 2.28]. The variables consistently associated with worse survival out-comes were high mitotic index and nongastric tumor location. Conclusions: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.
  • McFadyen, Charles A.; Zeiler, Frederick A.; Newcombe, Virginia; Synnot, Anneliese; Steyerberg, Ewout; Gruen, Russel L.; Rosand, Jonathan; Palotie, Aarno; Maas, Andrew I. R.; Menon, David K. (2021)
    The mortality of traumatic brain injury (TBI) has been largely static despite advances in monitoring and imaging techniques. Substantial variance exists in outcome, not fully accounted for by baseline characteristics or injury severity, and genetic factors likely play a role in this variance. The aims of this systematic review were to examine the evidence for a link between the apolipoprotein E4 (APOE4) polymorphism and TBI outcomes and where possible, to quantify the effect size via meta-analysis. We searched EMBASE, MEDLINE, CINAHL, and gray literature in December 2017. We included studies of APOE genotype in relation to functional adult TBI outcomes. Methodological quality was assessed using the Quality in Prognostic Studies Risk of Bias Assessment Instrument and the prognostic studies adaptation of the Grading of Recommendations Assessment, Development and Evaluation tool. In addition, we contacted investigators and included an additional 160 patients whose data had not been made available for previous analyses, giving a total sample size of 2593 patients. Meta-analysis demonstrated higher odds of a favorable outcome following TBI in those not possessing an ApoE e4 allele compared with e4 carriers and homozygotes (odds ratio 1.39, 95% confidence interval 1.05 to 1.84; p = 0.02). The influence of APOE4 on neuropsychological functioning following TBI remained uncertain, with multiple conflicting studies. We conclude that the ApoE e4 allele confers a small risk of poor outcome following TBI, with analysis by TBI severity not possible based on the currently available published data. Further research into the long-term neuropsychological impact and risk of dementia is warranted.
  • Eck, Jenalle L.; Kytoviita, Minna-Maarit; Laine, Anna-Liisa (2022)
    While pathogenic and mutualistic microbes are ubiquitous across ecosystems and often co-occur within hosts, how they interact to determine patterns of disease in genetically diverse wild populations is unknown. To test whether microbial mutualists provide protection against pathogens, and whether this varies among host genotypes, we conducted a field experiment in three naturally occurring epidemics of a fungal pathogen, Podosphaera plantaginis, infecting a host plant, Plantago lanceolata, in the angstrom land Islands, Finland. In each population, we collected epidemiological data on experimental plants from six allopatric populations that had been inoculated with a mixture of mutualistic arbuscular mycorrhizal fungi or a nonmycorrhizal control. Inoculation with arbuscular mycorrhizal fungi increased growth in plants from every population, but also increased host infection rate. Mycorrhizal effects on disease severity varied among host genotypes and strengthened over time during the epidemic. Host genotypes that were more susceptible to the pathogen received stronger protective effects from inoculation. Our results show that arbuscular mycorrhizal fungi introduce both benefits and risks to host plants, and shift patterns of infection in host populations under pathogen attack. Understanding how mutualists alter host susceptibility to disease will be important for predicting infection outcomes in ecological communities and in agriculture.
  • Pan, Bohu; Ren, Luyao; Onuchic, Vitor; Guan, Meijian; Kusko, Rebecca; Bruinsma, Steve; Trigg, Len; Scherer, Andreas; Ning, Baitang; Zhang, Chaoyang; Glidewell-Kenney, Christine; Xiao, Chunlin; Donaldson, Eric; Sedlazeck, Fritz J.; Schroth, Gary; Yavas, Gokhan; Grunenwald, Haiying; Chen, Haodong; Meinholz, Heather; Meehan, Joe; Wang, Jing; Yang, Jingcheng; Foox, Jonathan; Shang, Jun; Miclaus, Kelci; Dong, Lianhua; Shi, Leming; Mohiyuddin, Marghoob; Pirooznia, Mehdi; Gong, Ping; Golshani, Rooz; Wolfinger, Russ; Lababidi, Samir; Sahraeian, Sayed Mohammad Ebrahim; Sherry, Steve; Han, Tao; Chen, Tao; Shi, Tieliu; Hou, Wanwan; Ge, Weigong; Zou, Wen; Guo, Wenjing; Bao, Wenjun; Xiao, Wenzhong; Fan, Xiaohui; Gondo, Yoichi; Yu, Ying; Zhao, Yongmei; Su, Zhenqiang; Liu, Zhichao; Tong, Weida; Xiao, Wenming; Zook, Justin M.; Zheng, Yuanting; Hong, Huixiao (2022)
    Background: Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. Results: To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30x. Conclusions: Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.
  • Garcia-Romero, Noemi; Gonzalez-Tejedo, Carmen; Carrion-Navarro, Josefa; Esteban-Rubio, Susana; Rackov, Gorjana; Rodriguez-Fanjul, Vanessa; Oliver-De La Cruz, Jorge; Prat-Acin, Ricardo; Peris-Celda, Maria; Blesa, David; Ramirez-Jimenez, Laura; Sanchez-Gomez, Pilar; Perona, Rosario; Escobedo-Lucea, Carmen; Belda-Iniesta, Cristobal; Ayuso-Sacido, Angel (2016)
    Human gliomas harbour cancer stem cells (CSCs) that evolve along the course of the disease, forming highly heterogeneous subpopulations within the tumour mass. These cells possess self-renewal properties and appear to contribute to tumour initiation, metastasis and resistance to therapy. CSC cultures isolated from surgical samples are considered the best preclinical in vitro model for primary human gliomas. However, it is not yet well characterized to which extent their biological and functional properties change during in vitro passaging in the serum-free culture conditions. Here, we demonstrate that our CSC-enriched cultures harboured from one to several CSC clones from the human glioma sample. When xenotransplanted into mouse brain, these cells generated tumours that reproduced at least three different dissemination patterns found in original tumours. Along the passages in culture, CSCs displayed increased expression of stem cell markers, different ratios of chromosomal instability events, and a varied response to drug treatment. Our findings highlight the need for better characterization of CSC-enriched cultures in the context of their evolution in vitro, in order to uncover their full potential as preclinical models in the studies aimed at identifying molecular biomarkers and developing new therapeutic approaches of human gliomas.
  • Koponen, Mikael; Havulinna, Aki S.; Marjamaa, Annukka; Tuiskula, Annukka M.; Salomaa, Veikko; Laitinen-Forsblom, Päivi J.; Piippo, Kirsi; Toivonen, Lauri; Kontula, Kimmo; Viitasalo, Matti; Swan, Heikki (2018)
    Background: Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). We studied factors affecting the clinical course of genetically confirmed patients, in particular those not receiving beta-blocker treatment. In addition, an attempt was made to associate risk of events to specific types of KCNQ1 and KCNH2 mutations. Methods: A follow-up study covering a mean of 18.6 +/- 6.1 years was conducted in 867 genetically confirmed LQT1 and LQT2 patients and 654 non-carrier relatives aged 18-40 years. Cox regression models were used to evaluate the contribution of clinical and genetic risk factors to cardiac events. Results: In mutation carriers, risk factors for cardiac events before initiation of beta-blocker included LQT2 genotype (hazard ratio [HR] = 2.1, p = 0.002), female gender (HR = 3.2, p <0.001), a cardiac event before the age of 18 years (HR = 5.9, p <0.001), and QTc >= 500 ms (vs <470 ms, HR = 2.7, p = 0.001). LQT1 patients carrying the KCNQ1 D317N mutation were at higher risk (HR = 3.0-3.9, p <0.001-0.03) compared to G589D, c. 1129-2A > G and other KCNQ1 mutation carriers after adjusting for gender, QTc duration, and cardiac events before age 18. KCNH2 c. 453delC, L552S and R176W mutations associated with lower risk (HR = 0.11-0.23, p <0.001) than other KCNH2 mutations. Conclusions: LQT2 (compared to LQT1), female gender, a cardiac event before age 18, and long QT interval increased the risk of cardiac events in LQTS patients aged 18 to 40 years. The nature of the underlying mutation may be associated with risk variation in both LQT1 and LQT2. The identification of high-risk and low-risk mutations may enhance risk stratification.
  • IPSYCH Grp; FinnGen Consortium; Fadista, Joao; Skotte, Line; Karjalainen, Juha; Abner, Erik; Sorensen, Erik; Ullum, Henrik; Werge, Thomas; Esko, Tonu; Milani, Lili; Palotie, Aarno; Daly, Mark; Melbye, Mads; Feenstra, Bjarke; Geller, Frank (2022)
    Hernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. In this study we identify 65,492 cases for five hernia types in the UK Biobank and perform genome-wide association study scans for these five types and two combined groups. Our results show associated variants in all scans. Inguinal hernia has the most associations and we conduct a follow-up study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans are collapsed into 81 independent loci. Further testing shows that 26 loci are associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analyses identify several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology. Hernias involve protrusion of an organ or tissue through its surrounding cavity. Here the authors carry out GWAS for five types of hernia and find 81 variants, most of which are associated with inguinal hernia; downstream analysis suggests an important role for connective tissue morphology.
  • Viinamaki, Jenni; Ojanpera, Ilkka (2016)
    There is a constant demand for the quantification of drug metabolites within post-mortem toxicology. Especially electrospray ionization-mass spectrometry techniques necessitate that calibration is carried out using primary reference standards due to the non-uniform ionization efficiency between parent drugs and their metabolites. As reference standards for metabolites are not readily available and their costs are high, alternative methods for immediate quantification are required. In this study, ultra-high performance liquid chromatography coupled with photodiode array detection and corona charged aerosol detection was utilized for the concurrent quantification of 23 drug metabolites using the corresponding parent drug for calibration. Based on this secondary calibration, the quantitative results for the N-demethylated metabolites by each detector were similar to those obtained by the ordinary calibration using reference standards. For O-demethylated metabolites, the differences in detector response caused somewhat larger biases using the secondary calibration. Using the validated secondary calibration, the blood sample data gathered from 633 post-mortem cases was retrospectively reprocessed to discover the combined metabolite-parent concentrations and metabolite to parent ratios for six toxicologically relevant drugs. These results, representing all causes of death, were compared to published data from therapeutic drug monitoring and post-mortem toxicology. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Koivusaari, Katariina; Syrjälä, Essi; Niinistö, Sari; Takkinen, Hanna-Mari; Ahonen, Suvi; Åkerlund, Mari; Korhonen, Tuuli E.; Toppari, Jorma; Ilonen, Jorma; Peltonen, Jaakko; Nevalainen, Jaakko; Knip, Mikael; Alatossava, Tapani; Veijola, Riitta; Virtanen, Suvi M (2020)
    Several prospective studies have shown an association between cows’ milk consumption and the risk of islet autoimmunity and/or type 1 diabetes. We wanted to study whether processing of milk plays a role. A population-based birth cohort of 6081 children with HLA-DQB1-conferred risk to type 1 diabetes was followed until the age of 15 years. We included 5545 children in the analyses. Food records were completed at the ages of 3 and 6 months and 1, 2, 3, 4 and 6 years, and diabetes-associated autoantibodies were measured at 3–12-month intervals. For milk products in the food composition database, we used conventional and processing-based classifications. We analysed the data using a joint model for longitudinal and time-to-event data. By the age of 6 years, islet autoimmunity developed in 246 children. Consumption of all cows’ milk products together (energy-adjusted hazard ratio 1·06; 95 % CI 1·02, 1·11; P = 0·003), non-fermented milk products (1·06; 95 % CI 1·01, 1·10; P = 0·011) and fermented milk products (1·35; 95 % CI 1·10, 1·67; P = 0·005) was associated with an increased risk of islet autoimmunity. The early milk consumption was not associated with the risk beyond 6 years. We observed no clear differences based on milk homogenisation and heat treatment. Our results are consistent with the previous studies, which indicate that high milk consumption may cause islet autoimmunity in children at increased genetic risk. The study did not identify any specific type of milk processing that would clearly stand out as a sole risk factor apart from other milk products.
  • Rendo, Veronica; Kundu, Snehangshu; Rameika, Natallia; Ljungstrom, Viktor; Svensson, Richard; Palin, Kimmo; Aaltonen, Lauri; Stoimenov, Ivaylo; Sjöblom, Tobias (2020)
    Therapies targeting somatic bystander genetic events represent a new avenue for cancer treatment. We recently identified a subset of colorectal cancer (CRC) patients who are heterozygous for a wild-type and a low activity allele (NAT2*6) but lack the wild-type allele in their tumors due to loss of heterozygosity (LOH) at 8p22. These tumors were sensitive to treatment with a cytotoxic substrate of NAT2 (6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl)pyrazin-2-amine, APA), and pointed to NAT2 loss being a therapeutically exploitable vulnerability of CRC tumors. To better estimate the total number of treatable CRC patients, we here determined whether tumor cells retaining also other NAT2 low activity variants after LOH respond to APA treatment. The prevalent low activity alleles NAT2*5 and NAT2*14, but not NAT2*7, were found to be low metabolizers with high sensitivity to APA. By analysis of two different CRC patient cohorts, we detected heterozygosity for NAT2 alleles targetable by APA, along with allelic imbalances pointing to LOH, in similar to 24% of tumors. Finally, to haplotype the NAT2 locus in tumor and patient-matched normal samples in a clinical setting, we develop and demonstrate a long-read sequencing based assay. In total,>79.000 CRC patients per year fulfil genetic criteria for high sensitivity to a NAT2 LOH therapy and their eligibility can be assessed by clinical sequencing.
  • Blatter, Robert; Tschupp, Benjamin; Aretz, Stefan; Bernstein, Inge; Colas, Chrystelle; Evans, D. Gareth; Genuardi, Maurizio; Hes, Frederik J.; Hueneburg, Robert; Jarvinen, Heikki; Lalloo, Fiona; Moeslein, Gabriela; Renkonen-Sinisalo, Laura; Resta, Nicoletta; Spier, Isabel; Varvara, Dora; Vasen, Hans; Latchford, Andrew R.; Heinimann, Karl (2020)
    Purpose Juvenile polyposis syndrome (JPS) is a rare, autosomal-dominantly inherited cancer predisposition caused in approximately 50% of cases by pathogenic germline variants in SMAD4 and BMPR1A. We aimed to gather detailed clinical and molecular genetic information on JPS disease expression to provide a basis for management guidelines and establish open access variant databases. Methods We performed a retrospective, questionnaire-based European multicenter survey on and established a cohort of SMAD4/BMPR1A pathogenic variant carriers from the medical literature. Results We analyzed questionnaire-based data on 221 JPS patients (126 kindreds) from ten European centers and retrieved literature-based information on 473 patients. Compared with BMPR1A carriers, SMAD4 carriers displayed anemia twice as often (58% vs. 26%), and exclusively showed overlap symptoms with hemorrhagic telangiectasia (32%) and an increased prevalence (39% vs. 13%) of gastric juvenile polyps. Cancer, reported in 15% of JPS patients (median age 41 years), mainly occurred in the colorectum (overall: 62%, SMAD4: 58%, BMPR1A: 88%) and the stomach (overall: 21%; SMAD4: 27%, BMPR1A: 0%). Conclusion This comprehensive retrospective study on genotype-phenotype correlations in 694 JPS patients corroborates previous observations on JPS in general and SMAD4 carriers in particular, facilitates recommendations for clinical management, and provides the basis for open access variant SMAD4 and BMPR1A databases.
  • Impola, Ulla; Turpeinen, Hannu; Alakulppi, Noora; Linjama, Tiina; Volin, Liisa; Niittyvuopio, Riitta; Partanen, Jukka; Koskela, Satu (2014)
    Successful allogeneic hematopoietic stem cell transplantation (HSCT) depends not only on good HLA match but also on T-cell mediated graft-versus-leukemia (GyL) effect. Natural killer (NK) cells are able to kill malignant cells by receiving activation signal from the killer-cell immunoglobulin-like receptors (KIR) recognizing HLA molecules on a cancer cell. It has been recently reported that the risk of relapse in allogeneic hematopoietic stem cell transplantation (HSCT) is reduced in acute myeloid leukemia (AML) patients whose donors have several activating KIR genes or KIR B-motifs in unrelated donor setting, obviously due to enhanced GyL effect by NK cells. We studied the effect on relapse rate of donor KIR haplotypes in the HLA-identical adult sibling HSCT, done in a single center, in Helsinki University Central Hospital, Helsinki, Finland. Altogether, 134 patients with 6 different diagnoses were identified. Their donors were KIR genotyped using the Luminex and the SSP techniques. The clinical endpoint, that is, occurrence of relapse, was compared with the presence or absence of single KIR genes. Also, time from transplantation to relapse was analyzed. The patients with AML whose donors have KIR2DL2 or KIR2DS2 had statistically significantly longer relapse-free survival (P = 0.015). Our data support previous reports that donors with KIR B-haplotype defining genes have a lower occurrence of relapse in HSCT of AML patients. Determination of donor KIR haplotypes could be a useful addition for a risk assessment of HSCT especially in AML patients.
  • Hirvinen, Mari; Heiskanen, Raita; Oksanen, Minna; Pesonen, Saila; Liikanen, Ilkka; Joensuu, Timo; Kanerva, Anna; Cerullo, Vincenzo; Hemminki, Akseli (2013)
  • Skaga, Erlend; Kulesskiy, Evgeny; Potdar, Swapnil; Panagopoulos, Ioannis; Micci, Francesca; Langmoen, Iver A.; Sandberg, Cecilie J.; Vik-Mo, Einar O. (2022)
    Serum-free culturing of patient-derived glioblastoma biopsies enrich for glioblastoma stem cells (GSCs) and is recognized as a disease-relevant model system in glioblastoma (GBM). We hypothesized that the temozolomide (TMZ) drug sensitivity of patient-derived GSC cultures correlates to clinical sensitivity patterns and has clinical predictive value in a cohort of GBM patients. To this aim, we established 51 individual GSC cultures from surgical biopsies from both treatment-naive primary and pretreated recurrent GBM patients. The cultures were evaluated for sensitivity to TMZ over a dosing range achievable in normal clinical practice. Drug efficacy was quantified by the drug sensitivity score. MGMT-methylation status was investigated by pyrosequencing. Correlative, contin-gency, and survival analyses were performed for associations between experimental and clinical data. We found a heterogeneous response to temozolomide in the GSC culture cohort. There were significant differences in the sensitivity to TMZ between the newly diagnosed and the TMZ-treated recurrent disease (p
  • Dobewall, Henrik; Savelieva, Kateryna; Seppälä, Ilkka; Knafo-Noam, Ariel; Hakulinen, Christian; Elovainio, Marko; Keltikangas-Jarvinen, Liisa; Pulkki-Råback, Laura; Raitakari, Olli T.; Lehtimäki, Terho; Hintsanen, Mirka (2019)
    Background Genomic analysis of the child might offer new potential to illuminate human parenting. We examined whether offspring (G2) genome-wide genotype variation (SNPs) is associated with their mother's (G1) emotional warmth and intolerance, indicating a gene-environment correlation. If this association is stronger than between G2 ' s genes and their emotional warmth and intolerance toward their own children, then this would indicate the presence of an evocative gene-environment correlation. To further understand how G1 mother's parenting has been evoked by genetically influenced characteristics of the child (G2), we examined whether child (G2) temperament partially accounted for the association between offspring genes and parental responses. Methods Participants were from the Young Finns Study. G1 mothers (N = 2,349; mean age 39 years) self-reported the emotional warmth and intolerance toward G2 in 1980 when the participants were from 3 to 18 years old. G2 participants answered the same parenting scales in 2007/2012 (N = 1,378; mean age = 38 years in 2007; 59% female) when their children were on average 11 years old. Offspring temperament traits were self-reported in 1992 (G2 age range 15-30 years). Estimation of the phenotypic variance explained by the SNPs of G2 was done by genome-wide complex trait analysis with restricted maximum likelihood (GCTA-GREML). Results Results showed that the SNPs of a child (G2) explained 22.6% of the phenotypic variance of maternal intolerance (G1; p-value = .039). G2 temperament trait negative emotionality explained only 2.4% points of this association. G2 genes did not explain G1 emotional warmth or G2 ' s own emotional warmth and intolerance. However, further analyses of a combined measure of both G1 parenting scales found genetic effects. Parent or child gender did not moderate the observed associations. Conclusions Presented genome-wide evidence is pointing to the important role a child plays in affecting and shaping his/her family environment, though the underlying mechanisms remain unclear.