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Sökning: WFRF:(Ohlsson Lina)

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1.
  • AbdelMageed, Manar, et al. (författare)
  • Clinical significance of stem cell biomarkers epcam, lgr5 and lgr4 mrna levels in lymph nodes of colon cancer patients
  • 2022
  • Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 23:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The significance of cancer stem cells (CSCs) in initiation and progression of colon cancer (CC) has been established. In this study, we investigated the utility of measuring mRNA expression levels of CSC markers EpCAM, LGR5 and LGR4 for predicting survival outcome in surgically treated CC patients. Expression levels were determined in 5 CC cell lines, 66 primary CC tumors and 382 regional lymph nodes of 121 CC patients. Prognostic relevance was determined using Kaplan‐Meier survival and Cox regression analyses. CC patients with lymph nodes expressing high levels of EpCAM, LGR5 or LGR4 (higher than a clinical cutoff of 0.07, 0.06 and 2.558 mRNA cop-ies/18S rRNA unit, respectively) had a decreased mean survival time of 32 months for EpCAM and 42 months for both LGR5 and LGR4 at a 12‐year follow‐up (p = 0.022, p = 0.005 and p = 0.011, respec-tively). Additional patients at risk for recurrence were detected when LGR5 was combined with the biomarkers CXCL17 or CEA plus CXCL16. In conclusion, the study underscores LGR5 as a particularly useful prognostic biomarker and illustrates the strength of combining biomarkers detecting different subpopulations of cancer cells and/or cells in the tumor microenvironment for predicting recurrence.
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2.
  • AbdelMageed, Manar, et al. (författare)
  • The chemokine CXCL16 is a new biomarker for lymph node analysis of colon cancer outcome
  • 2019
  • Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 20:22
  • Tidskriftsartikel (refereegranskat)abstract
    • Chemokines are important in the development and progression of tumors. We investigated the expression of CXCL14 and CXCL16 in colon cancer. Expression of mRNA was assessed in primary tumors and lymph nodes and CXCL16 mRNA levels were correlated to patient’s survival. Protein expression was investigated by two-color immunofluorescence and immunomorphometry. CXCL14 and CXCL16 mRNA levels and protein expression were significantly higher in colon cancer primary tumors compared to apparently normal colon tissue. Positive cells were tumor cells, as revealed by anti-CEA and anti-EpCAM staining. CXCL16, but not CXCL14, mRNA levels were significantly higher in hematoxylin and eosin positive (H&E(+)) compared to H&E(−) colon cancer lymph nodes or control nodes (P < 0.0001). CXCL16 mRNA was expressed in 5/5 colon cancer cell lines while CXCL14 was expressed significantly in only one. Kaplan-Meier analysis revealed that colon cancer patients with lymph nodes expressing high or very high levels (7.2 and 11.4 copies/18S rRNA unit, respectively) of CXCL16 mRNA had a decreased mean survival time of 30 and 46 months at the 12-year follow-up (P = 0.04, P = 0.005, respectively). In conclusion, high expression of CXCL16 mRNA in regional lymph nodes of colon cancer patients is a sign of a poor prognosis.
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3.
  • Ali, Haytham, et al. (författare)
  • Detection of lymph node metastasis in colon cancer by ectopically expressed fibroblast markers FOXQ1 and THBS2
  • 2023
  • Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 13
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Approximately 25% of colon cancer (CC) patients having curative surgery will relapse. Therefore, it is crucial to identify patients with increased recurrence risk to offer them adjuvant chemotherapy. Three markers with prominent expression in fibroblasts: forkhead box Q1 (FOXQ1), matrix metalloproteinase-11 (MMP11), and thrombospondin-2 (THBS2), and the fibroblast expressed chemokine CXCL12 were selected for studies because of the critical role of fibroblasts in the microenvironment of the tumor.Methods: The expression levels of the biomarkers were assessed in primary CC tumors, lymph nodes of CC patients and controls, and CC cell lines at mRNA and protein levels by real-time qRT-PCR and immunohistochemistry, respectively.Results: FOXQ1, MMP11, and THBS2 mRNAs were expressed at significantly higher levels in primary tumors compared to normal colon (P=0.002, P<0.0001, and P<0.0001, respectively). In contrast, CXCL12 mRNA levels were higher in normal colon tissue. FOXQ1, MMP11, and THBS2 levels were also expressed at significantly higher levels in metastasis-positive lymph nodes compared to both metastasis-negative- and control nodes (P<0.0001/P=0.002, P<0.0001/P<0.0001, and P<0.0001/P<0.0001, respectively). Immuno-morphometry revealed that 30–40% of the tumor cells expressed FOXQ1, MMP11, and THBS2. FOXQ1 and THBS2 were barely detected in normal colon epithelium (P<0.0001), while MMP11 was expressed in normal colon epithelium at high levels.Discussion: We conclude that CC tumor cells show ectopic expression of FOXQ1 and THBS2 possibly making these tumor cells independent of fibroblast cell support. The high expression levels of these two biomarkers in metastatic lymph nodes suggest that they are potential indicators of patients at risk for recurrence.
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4.
  • Ali, Haytham, et al. (författare)
  • The myeloid cell biomarker EMR1 is ectopically expressed in colon cancer
  • 2021
  • Ingår i: Tumor Biology. - : IOS Press. - 1010-4283 .- 1423-0380. ; 43:1, s. 209-223
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: The microenvironment of colon cancer (CC) is heterogeneous including cells of myeloid lineage affecting tumor growth and metastasis. Two functional subtypes of myeloid cells have been identified; one (M1) is tumor-inhibitory and the other one (M2) is tumor-promoting. Whether the three myeloid markers EMR1, CD206 and CD86 are expressed only in the infiltrating myeloid cells or also in the tumor cells was investigated.METHODS: Expression of the myeloid markers was investigated in CC at the mRNA and protein levels in primary tumors and lymph nodes. mRNA expression was also determined in 5 CC cell lines. Protein expression was investigated by two-color immunofluorescence and consecutive-sections-immune-staining combined with morphometry using specific antibodies for the myeloid cell markers and the epithelial cell markers CEACAM5 and EpCAM.RESULTS: EMR1 and CD86, but not CD206, mRNA levels were significantly higher in CC primary tumors compared to apparently normal colon tissue (P <  0.0001). EMR1 mRNA levels were significantly higher in both hematoxylin-eosin positive (H&E(+)) and H&E(-) lymph nodes of CC patients compared to control nodes (P = 0.03 and P = 0.01, respectively). EMR1 and CD206 mRNAs were expressed in 4/5 and 5/5 CC cell lines, respectively, while CD86 mRNA was not expressed. Immuno-morphometry revealed that about 20% of the tumor cells expressed EMR1 and CD206. Positive cells were tumor cells as revealed by anti-CEACAM5 and anti-EpCAM staining. The number of EMR1, CD206 and CD86 positive cells were significantly increased in CC primary tumors compared to normal colon tissue (P <  0.0001). However, CD206 was also expressed in normal colonocytes. Only EMR1 showed significantly increased numbers of positive tumor cells in H&E(+) nodes compared to H&E(-) nodes (P = 0.001). EMR1 expression in CC tumor cells correlated with CXCL17 expressing tumor cells.CONCLUSION: EMR1, like the chemokine CXCL17, is ectopically expressed in colon cancer possibly in the same cancer cells.
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5.
  • Amirahmadi, Ali, 1994-, et al. (författare)
  • A Masked Language Model for Multi-Source EHR Trajectories Contextual Representation Learning
  • 2023
  • Ingår i: Caring is Sharing - Exploiting the Value in Data for Health and Innovation - Proceedings of MIE 2023. - Amsterdam : IOS Press. - 1879-8365 .- 0926-9630. - 9781643683881 ; 302, s. 609-610, s. 609-610
  • Konferensbidrag (refereegranskat)abstract
    • Using electronic health records data and machine learning to guide future decisions needs to address challenges, including 1) long/short-term dependencies and 2) interactions between diseases and interventions. Bidirectional transformers have effectively addressed the first challenge. Here we tackled the latter challenge by masking one source (e.g., ICD10 codes) and training the transformer to predict it using other sources (e.g., ATC codes).
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6.
  • Bygdell, Maria, et al. (författare)
  • Birth weight and young adult body mass index for predicting the risk of developing adult heart failure in men.
  • 2022
  • Ingår i: European journal of preventive cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; 29:6, s. 971-978
  • Tidskriftsartikel (refereegranskat)abstract
    • Hospitalizations for heart failure among young adults and middle-aged individuals have increased. The aims of the present study were to evaluate the association between birth weight and risk of adult heart failure and the importance of change from low birth weight to overweight/obesity at young adulthood.We used the population-based body mass index (BMI) Epidemiology Study cohort Gothenburg (n=35659) with birth weight and young adult BMI (20years) available from child healthcare records, school health records, and military conscription register for men born 1945-1961. The cohort includes all children who finished school, which was mandatory, in Gothenburg, Sweden. Information on heart failure diagnosis was retrieved from the National Patient Register and the Cause of Death Register (n=415). In cox regression analyses, there was an inverse association between birth weight and risk of heart failure [hazard ratio (HR) 0.83 per standard deviation (SD), 95% confidence interval (CI) 0.76-0.90], and a direct association for young adult BMI (HR 1.48 per SD, 95% CI 1.36-1.61). Of note, individuals with birth weight in the lowest tertile, who were overweight/obese in young adulthood had a five-fold risk of heart failure (HR 4.95, 95% CI 3.36-7.31) compared with individuals in the middle birth weight tertile who were normal weight at 20years.Birth weight was inversely associated with the risk of hospitalization due to heart failure. The combination of low birth weight and overweight/obesity in young adulthood results in excess risk of heart failure beyond that of low birth weight or young adult overweight/obesity separately. These findings indicate the need of a life course perspective in heart failure prevention and risk assessment.
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7.
  • Bygdell, Maria, et al. (författare)
  • Prevalence of overweight and obesity from 5 to 19 years of age in Gothenburg, Sweden
  • 2021
  • Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 110:12, s. 3349-3355
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim The aim of this study was to present prevalence data for overweight and obesity across school age in a large, recent, population-based cohort of children in Gothenburg, Sweden. Methods We included 66,807 children (48.5% girls) aged 5-18.9 years who had their height and weight measured in school health care 2015-2018. The BMI values were categorised according to the age-dependent cut-offs for overweight and obesity from the International Obesity Task Force (IOTF). Results Overall, the prevalence of overweight and obesity for girls and boys was 18.1% and 18.0%, respectively. We observed increasing proportions of overweight (girls 11.5-17.1% and boys 8.4-17.4%) and obesity (girls 3.0-4.2% and boys 2.7-6.1%) with increasing age (p < 0.001 for trend in both sexes). Moreover, girls had higher prevalence of overweight during ages 5.0 to 8.9 years compared with boys (p < 0.001), while boys had higher prevalence of obesity 15.0-18.9 years compared with girls (p < 0.001). Conclusion In conclusion, we demonstrate increasing prevalence of overweight and obesity across the entire school age range, as well as differences in prevalences between boys and girls, in a population-based sample of 67,000 children in Gothenburg city, Sweden. Continuous monitoring of schoolchildren, together with effective preventive measures, is crucial to curb the obesity epidemic and its consequences.
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8.
  • Cordeddu, Lina, et al. (författare)
  • Severe gastrointestinal dysmotility developed after treatment with gonadotropin-releasing hormone analogs
  • 2015
  • Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 50:3, s. 291-299
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Sporadic cases of abdominal pain and dysmotility has been described after treatment with gonadotropin-releasing hormone (GnRH) analogs. The aim of the present study was to scrutinize for patients with severe gastrointestinal complaints after treatment with GnRH analogs, to describe the expression of antibodies against progonadoliberin-2, GnRH1, GnRH receptor (GnRHR), luteinizing hormone (LH), and LH receptor in serum in these patients, and to search for possible triggers and genetic factors behind the development of this dysmotility. Methods. Patients suffering from prolonged gastrointestinal complaints after treatment with GnRH analogs at the Department of Gastroenterology, Skane University Hospital, were included. GnRHR and LH receptor (LHCGR) genes were exome-sequenced. Serum was analyzed by enzyme-linked immune sorbent assays for the presence of antibodies. Healthy blood donors and women treated with GnRH analogs because of in vitro fertilization (IVF) were used as controls. Results. Seven patients with severe gastrointestinal complaints after GnRH treatment were identified, of whom six suffered from endometriosis. Several variants were found within the 11 exons of LHCGR. The minor allele G, at the single nucleotide polymorphism rs6755901, was detected in homozygosity in two patients (28.5%) who had developed chronic intestinal pseudo-obstruction and in 5.5% of the IVF controls. Three patients expressed IgM antibodies against progonadoliberin-2 and three against GnRH1 (42.9%) when cut off was set to a titer >97.5th percentile in blood donors. Conclusion. A high prevalence of endometriosis, polymorphism in the LHCGR and GnRH1 and progonadoliberin-2 antibodies in serum was found among the patients with severe dysmotility after treatment with GnRH analogs.
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9.
  • Dahlqvist, Johanna, 1979-, et al. (författare)
  • Identification and functional characterization of a novel susceptibility locus for small vessel vasculitis with MPO-ANCA
  • 2022
  • Ingår i: Rheumatology. - Oxford, United Kingdom : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:8, s. 3461-3470
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV). Methods Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay. Results PR3-ANCA(+) AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 x 10(-61), odds ratio (OR) 0.10; rs9277341, P = 1.5 x 10(-44), OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 x 10(-10), OR 2.9). MPO-ANCA(+) AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 x 10(-25), OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 x 10(-7), OR 3.0), the latter a novel susceptibility locus for MPO-ANCA(+) granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele. Conclusion We identified a novel susceptibility locus for MPO-ANCA(+) AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.
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10.
  • Eltorky, Hagar, et al. (författare)
  • LGR6 is a prognostic biomarker for less differentiated tumors in lymph nodes of colon cancer patients
  • 2024
  • Ingår i: Frontiers in Oncology. - : Frontiers Media S.A.. - 2234-943X. ; 14
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The aim was to investigate whether the stem cell marker LGR6 has prognostic value in colon cancer, alone or in combination with the prognostic biomarkers CEA and CXCL16.Methods: LGR6 mRNA levels were determined in 370 half lymph nodes of 121 colon cancer patients. Ability to predict relapse after curative surgery was estimated by Kaplan-Meier survival model and Cox regression analyses.Results: Patients with high LGR6 levels [LGR6(+)] had a decreased mean survival time of 11 months at 5-year follow-up and 47 months at 12-year follow-up, respectively, with hazard ratios of 3.2 and 2.8. LGR6 mRNA analysis added prognostic value to CEA and CXCL16 mRNA analysis. In the poor prognosis groups CEA(+) and CXCL16(+), further division was achieved by LGR6 analysis. LGR6(+) patients had a very poor prognosis. LGR6 also identified a small number of CEA(-), TNM stage I patients who relapsed suggesting stem cell origin of these tumors. LGR6 and LGR5 levels correlated strongly in lymph nodes of stage I and IV patients but not in stage II patients, suggesting that these stem cell markers are differentially regulated.Conclusion: This study highlights LGR6 as a useful prognostic biomarker independently and in combination with CEA, CXCL16 or LGR5 identifying different risk groups.
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11.
  • Gustafsson, Karin L., 1987, et al. (författare)
  • Arginine site 264 in murine estrogen receptor alpha is dispensable for the regulation of the skeleton.
  • 2021
  • Ingår i: American journal of physiology. Endocrinology and metabolism. - 1522-1555. ; 320:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Estrogen protects against bone loss, but is not a suitable treatment due to adverse effects in other tissues. Increased knowledge regarding estrogen signaling in estrogen-responsive tissues is therefore warranted to aid the development of bone-specific estrogen treatments. Estrogen receptor alpha (ERα), the main mediator of estrogenic effects in bone, is widely subjected to posttranslational modifications (PTMs). In vitro studies have shown that methylation at site R260 in the human ERα affects receptor localization and intracellular signaling. The corresponding amino acid R264 in murine ERα has been shown to have a functional role in endothelium in vivo; albeit the methylation of R264 in the murine gene is yet to be empirically demonstrated. The aim of this study was to investigate if R264 in ERα is involved in the regulation of the skeleton in vivo. DXA analysis at three, six, nine, and twelve months of age showed no differences in total body areal BMD between R264A and WT in either female or male mice. Furthermore, analyses using CT demonstrated that trabecular bone mass in tibia and vertebra, and cortical thickness in tibia, were similar between R264A and WT mice. In addition, R264A females displayed a normal estrogen treatment response in trabecular bone mass, as well as in cortical thickness. Furthermore, uterus, thymus, and adipose tissue responded similarly in R264A and WT female mice after estrogen treatment. In conclusion, our novel finding that mutation of R264 in ERα does not affect the regulation of the skeleton, together with the known role of R264 for ERα-mediated endothelial effects, supports the concept that R264 determines tissue specificity of ERα.
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12.
  • Heid, Iris M, et al. (författare)
  • Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
  • Tidskriftsartikel (refereegranskat)abstract
    • Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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13.
  • Heyman, Ellen Tolestam, et al. (författare)
  • Improving Machine Learning 30-Day Mortality Prediction by Discounting Surprising Deaths
  • 2021
  • Ingår i: Journal of Emergency Medicine. - Philadelphia, PA : Elsevier BV. - 0736-4679 .- 1090-1280. ; 61:6, s. 763-773
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Machine learning (ML) is an emerging tool for predicting need of end-of-life discussion and palliative care, by using mortality as a proxy. But deaths, unforeseen by emergency physicians at time of the emergency department (ED) visit, might have a weaker association with the ED visit.OBJECTIVES: To develop an ML algorithm that predicts unsurprising deaths within 30 days after ED discharge.METHODS: In this retrospective registry study, we included all ED attendances within the Swedish region of Halland in 2015 and 2016. All registered deaths within 30 days after ED discharge were classified as either "surprising" or "unsurprising" by an adjudicating committee with three senior specialists in emergency medicine. ML algorithms were developed for the death subclasses by using Logistic Regression (LR), Random Forest (RF), and Support Vector Machine (SVM).RESULTS: Of all 30-day deaths (n = 148), 76% (n = 113) were not surprising to the adjudicating committee. The most common diseases were advanced stage cancer, multidisease/frailty, and dementia. By using LR, RF, and SVM, mean area under the receiver operating characteristic curve (ROC-AUC) of unsurprising deaths in the test set were 0.950 (SD 0.008), 0.944 (SD 0.007), and 0.949 (SD 0.007), respectively. For all mortality, the ROC-AUCs for LR, RF, and SVM were 0.924 (SD 0.012), 0.922 (SD 0.009), and 0.931 (SD 0.008). The difference in prediction performance between all and unsurprising death was statistically significant (P < .001) for all three models.CONCLUSION: In patients discharged to home from the ED, three-quarters of all 30-day deaths did not surprise an adjudicating committee with emergency medicine specialists. When only unsurprising deaths were included, ML mortality prediction improved significantly.
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14.
  • Jiang, Yiwen, et al. (författare)
  • Membrane estrogen receptor alpha signaling modulates the sensitivity to estradiol treatment in a dose- and tissue- dependent manner
  • 2023
  • Ingår i: Scientific Reports. - 2045-2322. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Estradiol (E2) affects both reproductive and non-reproductive tissues, and the sensitivity to different doses of E2 varies between tissues. Membrane estrogen receptor alpha (mER alpha)-initiated signaling plays a tissue-specific role in mediating E2 effects, however, it is unclear if mER alpha signaling modulates E2 sensitivity. To determine this, we treated ovariectomized C451A females, lacking mER alpha signaling, and wildtype (WT) littermates with physiological (0.05 mu g/mouse/day (low); 0.6 mu g/mouse/day (medium)) or supraphysiological (6 mu g/mouse/day (high)) doses of E2 (17 beta-estradiol-3-benzoate) for three weeks. Low-dose treatment increased uterus weight in WT, but not C451A mice, while non-reproductive tissues (gonadal fat, thymus, trabecular and cortical bone) were unaffected in both genotypes. Medium-dose treatment increased uterus weight and bone mass and decreased thymus and gonadal fat weights in WT mice. Uterus weight was also increased in C451A mice, but the response was significantly attenuated (- 85%) compared to WT mice, and no effects were triggered in non-reproductive tissues. High-dose treatment effects in thymus and trabecular bone were significantly blunted (- 34% and - 64%, respectively) in C451A compared to WT mice, and responses in cortical bone and gonadal fat were similar between genotypes. Interestingly, the high dose effect in uterus was enhanced (+ 26%) in C451A compared to WT mice. In conclusion, loss of mER alpha signaling reduces the sensitivity to physiological E2 treatment in both non-reproductive tissues and uterus. Furthermore, the E2 effect after high-dose treatment in uterus is enhanced in the absence of mER alpha, suggesting a protective effect of mER alpha signaling in this tissue against supraphysiological E2 levels.
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15.
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16.
  • Knudsen, Kasper Jermiin, et al. (författare)
  • ERG promotes the maintenance of hematopoietic stem cells by restricting their differentiation.
  • 2015
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 1549-5477 .- 0890-9369. ; 29:18, s. 1915-1929
  • Tidskriftsartikel (refereegranskat)abstract
    • The balance between self-renewal and differentiation is crucial for the maintenance of hematopoietic stem cells (HSCs). Whereas numerous gene regulatory factors have been shown to control HSC self-renewal or drive their differentiation, we have relatively few insights into transcription factors that serve to restrict HSC differentiation. In the present work, we identify ETS (E-twenty-six)-related gene (ERG) as a critical factor protecting HSCs from differentiation. Specifically, loss of Erg accelerates HSC differentiation by >20-fold, thus leading to rapid depletion of immunophenotypic and functional HSCs. Molecularly, we could demonstrate that ERG, in addition to promoting the expression of HSC self-renewal genes, also represses a group of MYC targets, thereby explaining why Erg loss closely mimics Myc overexpression. Consistently, the BET domain inhibitor CPI-203, known to repress Myc expression, confers a partial phenotypic rescue. In summary, ERG plays a critical role in coordinating the balance between self-renewal and differentiation of HSCs.
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17.
  • Lango Allen, Hana, et al. (författare)
  • Hundreds of variants clustered in genomic loci and biological pathways affect human height.
  • 2010
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
  • Tidskriftsartikel (refereegranskat)abstract
    • Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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18.
  • Lawenius, Lina, et al. (författare)
  • A probiotic mix partially protects against castration-induced bone loss in male mice
  • 2022
  • Ingår i: Journal of Endocrinology. - 0022-0795. ; 254:2, s. 91-101
  • Tidskriftsartikel (refereegranskat)abstract
    • Studies in postmenopausal women and ovariectomized mice show that the probiotic mix Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312 and DSM 15313 (L. Mix) can protect from bone loss caused by sex steroid deficiency. Whether probiotic bacteria can protect bone also in sex steroid-deficient males is less studied. We used the orchiectomized mouse as a model for age-dependent bone loss caused by decreasing sex hormone levels in males. We treated 10-week-old male mice with either vehicle (veh) or L. Mix for 6 weeks, starting 2 weeks before orchiectomy (orx) or sham surgery. Importantly, mice treated with L. Mix had a general increase in total body bone mineral density (BMD) and lean mass (P ≤ 0.05) compared with veh-treated mice. Detailed computer tomography analysis of dissected bones showed increased trabecular BMD of the distal metaphyseal region of the femur in L. Mix compared to veh-treated orx mice (+8.0%, P ≤ 0.05). In the vertebra, L. Mix treatment increased trabecular bone volume fraction BV/TV (+11.5%, P ≤ 0.05) compared to veh in orx mice. Also, L. Mix increased the levels of short-chain fatty acids (SCFAs) such as propionate and acetate and important intermediates in SCFA synthesis such as succinate and lactate in the cecal content of male mice. In conclusion, L. Mix treatment resulted in a general increase in BMD in adult male mice and prevented trabecular bone loss in femur and vertebra of orx mice. These bone protective effects of L. Mix were associated with increased levels of SCFAs in the cecal content of male mice. © 2022 The authors
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19.
  • Lawenius, Lina, et al. (författare)
  • Development of a synbiotic that protects against ovariectomy-induced trabecular bone loss
  • 2022
  • Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 322:4
  • Tidskriftsartikel (refereegranskat)abstract
    • The gut microbiome has the capacity to regulate bone mass. The aim of this study was to develop a nutritional synbiotic dietary assemblage at an optimal dose to maintain bone mass in ovariectomized (Ovx) mice. We performed genomic analyses and in vitro experiments in a large collection of bacterial and fungal strains (>4,000) derived from fresh fruit and vegetables to identify candidates with the synergistic capacity to produce bone-protective short-chain fatty acids (SCFA) and vitamin K2. The candidate SBD111-A, composed of Lactiplantibacillus plantarum, Levilactobacillus brevis, Leuconostoc mesenteroides, Pseudomonas fluorescens, and Pichia kudriavzevii together with prebiotic dietary fibers, produced high levels of SCFA in vitro and protected against Ovx-induced trabecular bone loss in a dose-dependent manner in mice. Metagenomic sequencing revealed that SBD111-A changed the taxonomic composition and enriched specific pathways for synthesis of bone-protective SCFA, vitamin K2, and branched-chain amino acids in the gut microbiome. NEW & NOTEWORTHY We performed genomic analyses and in vitro experiments in a collection of bacterial and fungal strains. We identified a combination (SBD111-A) that produced high levels of SCFA in vitro and protected against ovariectomy-induced bone loss in a dose-dependent manner in mice. Metagenomic sequencing revealed that SBD111-A changed the taxonomic composition and function of the gut microbiome and enriched pathways for synthesis of bone-protective SCFA, vitamin K2, and branched-chain amino acids.
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20.
  • Lawenius, Lina, et al. (författare)
  • Pasteurized Akkermansia muciniphila protects from fat mass gain but not from bone loss
  • 2020
  • Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 318:4
  • Tidskriftsartikel (refereegranskat)abstract
    • Probiotic bacteria can protect from ovariectomy (ovx)-induced bone loss in mice. Akkermansia muciniphila is considered to have probiotic potential due to its beneficial effect on obesity and insulin resistance. The purpose of the present study was to determine if treatment with pasteurized Akkermansia muciniphila (pAkk) could prevent ovx-induced bone loss. Mice were treated with vehicle or pAkk for 4 wk, starting 3 days before ovx or sham surgery. Treatment with pAkk reduced fat mass accumulation confirming earlier findings. However, treatment with pAkk decreased trabecular and cortical bone mass in femur and vertebra of gonadal intact mice and did not protect from ovx-induced bone loss. Treatment with pAkk increased serum parathyroid hormone (PTH) levels and increased expression of the calcium transporter Trpv5 in kidney suggesting increased reabsorption of calcium in the kidneys. Serum amyloid A 3 (SAA3) can suppress bone formation and mediate the effects of PTH on bone resorption and bone loss in mice and treatment with pAkk increased serum levels of SAA3 and gene expression of Saa3 in colon. Moreover, regulatory T cells can be protective of bone and pAkk-treated mice had decreased number of regulatory T cells in mesenteric lymph nodes and bone marrow. In conclusion, treatment with pAkk protected from ovx-induced fat mass gain but not from bone loss and reduced bone mass in gonadal intact mice. Our findings with pAkk differ from some probiotics that have been shown to protect bone mass, demonstrating that not all prebiotic and probiotic factors have the same effect on bone.
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21.
  • Lawenius, Lina, et al. (författare)
  • Transplantation of gut microbiota from old mice into young healthy mice reduces lean mass but not bone mass
  • 2023
  • Ingår i: Gut Microbes. - 1949-0976. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Aging is associated with low bone and lean mass as well as alterations in the gut microbiota (GM). In this study, we determined whether the reduced bone mass and relative lean mass observed in old mice could be transferred to healthy young mice by GM transplantation (GMT). GM from old (21-month-old) and young adult (5-month-old) donors was used to colonize germ-free (GF) mice in three separate studies involving still growing 5- or 11-week-old recipients and 17-week-old recipients with minimal bone growth. The GM of the recipient mice was similar to that of the donors, demonstrating successful GMT. GM from old mice did not have statistically significant effects on bone mass or bone strength, but significantly reduced the lean mass percentage of still growing recipient mice when compared with recipients of GM from young adult mice. The levels of propionate in the cecum of mice receiving old donor GM were significantly lower than those in mice receiving young adult donor GM. Bacteroides ovatus was enriched in the microbiota of recipient mice harboring GM from young adult donors. The presence of B. ovatus was not only significantly associated with high lean mass percentage in mice, but also with lean mass adjusted for fat mass in the large human HUNT cohort. In conclusion, GM from old mice reduces lean mass percentage but not bone mass in young, healthy, still growing recipient mice. Future studies are warranted to determine whether GM from young mice improves the musculoskeletal phenotype of frail elderly recipient mice.
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22.
  • Lilja, Lina, et al. (författare)
  • Low Birth Weight as an Early-Life Risk Factor for Adult Stroke Among Men
  • 2021
  • Ingår i: Journal of Pediatrics. - : Elsevier BV. - 0022-3476. ; 237
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective To evaluate the association between birth weight and the risk of adult stroke in men, independent of body mass index (BMI) at young adult age. Study design We included 35 659 men born between 1945 and 1961 from the BMI Epidemiology Study with data on birth weight together with BMI in childhood (8 years) and young adulthood (20 years). Information on stroke events (1184 first stroke events; 905 ischemic stroke [IS] events and 234 intracerebral hemorrhage [ICH] events) was retrieved from national registers in Sweden. Results Birth weight was inversely associated with the risk of stroke (IS, ICH and uncategorized together; hazard ratio [HR], 0.88 per SD increase, 95% CI, 0.84-0.93), IS, and ICH in a linear manner, independent of young adultBMI. This association was maintained when the analysis was restricted to individuals within the normal birth weight range only. Moreover, individuals with a birth weight in the lowest tertile followed by overweight at 20 years had an 81% greater risk of stroke (HR, 1.81; 95% CI, 1.29; 2.54), compared with a reference group of individuals with birth weight in the middle tertile who were of normal weight at age 20 years. Conclusions We demonstrate an inverse association between birth weight and the risk of adult stroke, IS, and ICH independent of young adult BMI. These findings suggest that low birth weight should be included in assessments of stroke risk in adults.
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23.
  • Lilja, Lina, et al. (författare)
  • Overweight in childhood and young adulthood increases the risk for adult thromboembolic events
  • 2023
  • Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 293:5, s. 615-623
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundApproximately one third of thromboembolic (TE) events are related to obesity, but to which extent elevated body mass index (BMI) during the distinct periods of childhood and puberty contributes is not known. We aimed to evaluate the impact of high BMI during childhood and puberty for the risk of adult venous and arterial thromboembolic events (VTE, ATE, respectively) in men. MethodsWe included 37,672 men from the BMI Epidemiology Study (BEST) Gothenburg with data on weight and height in childhood, young adult age, and on pubertal BMI change. Information on outcomes (VTE [n = 1683], ATE [n = 144], or any first TE event [VTE or ATE; n = 1780]) was retrieved from Swedish national registers. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions. ResultsBoth BMI at 8 years of age and the pubertal BMI change were associated with VTE, independently of each other (BMI at 8: HR 1.06 per standard deviation [SD] increase, 95% CI, 1.01;1.11; pubertal BMI change: HR 1.11 per SD increase, 95% CI, 1.06;1.16). Individuals with normal weight during childhood followed by young adult overweight (HR 1.40, 95% CI, 1.15;1.72), and individuals with overweight at both childhood and young adult age (HR 1.48, 95% CI, 1.14;1.92), had a significantly increased risk of VTE in adult life, compared with the normal weight reference group. Individuals with overweight in childhood and in young adult age had increased risk of ATE and TE. ConclusionYoung adult overweight was a strong determinant, and childhood overweight a moderate determinant, of the risk of VTE in adult men.
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24.
  • Ohlsson, Claes, 1965, et al. (författare)
  • Mild stimulatory effect of a probiotic mix on bone mass when treatment is initiated 1.5 weeks after ovariectomy in mice
  • 2021
  • Ingår i: American Journal of Physiology-Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 320:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Studies in humans and rodents show that probiotic bacteria can protect from bone loss caused by sex steroid deficiency. We showed earlier that a mixture of three probiotic bacteria, Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312, and DSM 15313 (L. mix), protects mice from ovariectomy (ovx)-induced bone loss when treatment was started 2 wk before sham and ovx surgery. In addition, the same probiotic treatment protected against lumbar spine bone loss in early postmenopausal women. In the present study, we wanted to evaluate the therapeutic potential of L. mix by starting treatment 1.5 wk after ovx when most of the rapid bone loss as a result of estrogen deficiency has already occurred. Treatment with L. mix for 5.5 wk increased the trabecular thickness but not the trabecular number in the proximal metaphyseal region of tibia compared with vehicle treatment. Cortical thickness and cortical area of the middiaphyseal part of the tibia were significantly decreased in ovx mice but not in L. mix-treated ovx mice. The bone-protective effects of L. mix in ovx mice were associated with a protection against ovx-induced reduction of the frequency of regulatory T-cells and of the expression of Tgfb in the bone marrow. In conclusion, the probiotic L. mix exerted a mild stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 wk after ovariectomy in mice. This effect was associated with effects on bone-protecting regulatory T-cells. The results suggest that L. mix may exert beneficial effects on bone mass when treatment is started after ovariectomy. NEW & NOTEWORTHY The probiotic L. mix exerted a mild stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 wk after ovariectomy in mice. This effect was associated with effects on bone-protecting regulatory T-cells. The results suggest that L. mix may exert beneficial effects on bone mass when treatment is started after ovariectomy.
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25.
  • Ohlsson, Lina, et al. (författare)
  • Allocating colorectal cancer patients to different risk categories by using a five-biomarker mRNA combination in lymph node analysis
  • 2020
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 15:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and aims: Curative surgery saves approximate to 50% of all patients with colorectal cancer (CRC) while remaining patients have synchronous or will develop metachronous metastases. Presently, the single most important prognostic factor is histopathological detection of disseminated tumor cells in regional lymph nodes. However, the routine method has several limitations. The aim was to identify biomarker mRNAs that could be combined in a formula that would allow better prediction of patients' survival after surgery.Methods: Screening for biomarker mRNAs overexpressed in CRC was performed by genome-wide hybridization bead array, with verification by qRT-PCR. Specific qRT-PCR assays with copy standards were developed for 5 selected genes and mRNA expression levels determined in lymph nodes from 174 CRC patients (517 nodes) and 24 control patients (118 nodes). Prognostic value of biomarker mRNAs was estimated. A cut-off was set using univariate Cox regression analysis and used for calculation of differences between patient groups in disease-free survival 12 years after surgery (Kaplan-Meier survival model) and risk for recurrent disease (Cox's regression analysis). A formula was constructed for evaluation of the prognostic value of the biomarkers in combination.Results: Two new biomarkers, SLC35D3 and POSTN with prognostic value were identified. SLC35D3 was expressed in the epithelium derived tumor cells and POSTN in fibroblasts. Combined with CEACAM5, KLK6 and MUC2 they could be used to identify risk groups. A formula was constructed using CEACAM5 as denominator for KLK6, SLC35D3 and MUC2 and 18S rRNA as denominator for POSTN. The formula yielded 5 categories (-1, 0, 1, 2, 3). Categories (-1 and 0) had good prognosis, categories (1 and 2) relatively poor prognosis and category (3) very poor prognosis.Conclusion: Lymph node analysis using 5 selected biomarker mRNAs and 18S rRNA in combination allowed allocation of CRC patients to different risk categories with respect to recurrent disease.
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26.
  • Ohlsson, Lina, 1981- (författare)
  • Biomarker mRNAs for staging and prognosis of colorectal cancer
  • 2011
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Mesenteric lymph node (ln) metastasis is the single most important prognostic characteristic in colorectal cancer (CRC). The ln status is used for staging and is a decisive selection criterion for postoperative adjuvant therapy. However, it is difficult to accurately determine ln status by routine histopathology (H&E). Thus, ~25% of CRC patients, who by H&E are considered to lack tumor cells in their lns, i.e. stage I+II, die from CRC.To explore the utility of biomarker mRNA analysis for staging and prognosis of CRC, lns were collected at surgery and mRNA levels for fourteen biomarkers, including carcinoembryonic antigen (CEA), kallikrein 6 (KLK6), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CEACAM1-S, CEACAM6 and mucin 2 (MUC2), were determined by quantitative RT-PCR with RNA copy standards. Results were compared to routine H&E analysis.The biomarkers were analyzed for capacity to detect disseminated tumor cells in lns. mRNA levels were determined in CRC- and control lns, primary tumor, normal colon, immune cells and fibroblasts. Lack of expression in immune cells and fibroblasts and high and homogenous expression in primary tumors showed to be the determining factors. CEA fulfilled these criteria best, followed by KLK6, CK20, GCC, and MUC2.Utility of the biomarker mRNAs for staging and prognosis was examined in 174 CRC patients. CEA was the best predictor of disease-free survival time after surgery with a 71 months difference between CEA(+) and CEA(-) patients and a hazard ratio of 5.1 for risk of recurrence for CEA(+) patients. CEA, CK20 and MUC2 were more sensitive than H&E in that these biomarkers identified patients who succumbed from recurrent CRC although H&E analysis had failed to detect the disseminated tumor cells. Combined analysis of CEA and MUC2 mRNAs improved prediction of outcome. Patients with high risk for recurrence had low MUC2/CEA ratios.KLK6 mRNA was identified as a potential progression marker by genome-wide microarray analysis of gene expression. It was found to be ectopically expressed in CRC tumor cells. KLK6(+) lns was an indicator of poor prognosis (hazard ratio 3.7). Notably, the actual level was of importance for outcome. The higher the KLK6 mRNA levels the greater the risk of recurrence. At the 90thpercentile the hazard risk ratio for KLK6(+) patients was 5.6. KLK6 positivity in lns with low numbers of tumor cells, as indicated by low CEA mRNA levels, indicated poor prognosis (hazard ratio 2.8). Thus, KLK6 adds prognostic information to CEA analysis.Increased levels of mRNA for the proinflammatory cytokine interferon- and the down-regulatory cytokine interleukin-10 in lns of CRC patients suggested ongoing immune reactions against the infiltrating tumor cells. Elevated TGF-1 levels correlated weakly with survival, suggesting protection by the antiproliferative effect of TGF-1 in sporadic cases.CEA mRNA was the best single biomarker for staging and prediction of disease-free survival time and risk of recurrence after surgery. In addition to CEA, KLK6 positivity and low MUC2/CEA ratio correlate with poor prognosis. Thus, CEA, MUC2 and KLK6 mRNAs form a strong "trio" for staging and prediction of outcome for CRC patients.
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27.
  • Ohlsson, Lina, et al. (författare)
  • Biomarker selection for detection of occult tumour cells in lymph nodes of colorectal cancer patients using real-time quantitative RT-PCR
  • 2006
  • Ingår i: British Journal of Cancer. - London : Harcourt Publishers. - 0007-0920 .- 1532-1827. ; 95:2, s. 218-225
  • Tidskriftsartikel (refereegranskat)abstract
    • Accurate identification of lymph node involvement is critical for successful treatment of patients with colorectal carcinoma (CRC). Real-time quantitative RT–PCR with a specific probe and RNA copy standard for biomarker mRNA has proven very powerful for detection of disseminated tumour cells. Which properties of biomarker mRNAs are important for identification of disseminated CRC cells? Seven biomarker candidates, CEA, CEACAM1-S/L, CEACAM6, CEACAM7-1/2, MUC2, MMP7 and CK20, were compared in a test-set of lymph nodes from 51 CRC patients (Dukes' A–D) and 10 controls. Normal colon epithelial cells, primary tumours, and different immune cells were also analysed. The biomarkers were ranked according to: (1) detection of haematoxylin/eosin positive nodes, (2) detection of Dukes' A and B patients, who developed metastases during a 54 months follow-up period and (3) identification of patients with Dukes' C and D tumours using the highest value of control nodes as cutoff. The following properties appear to be of importance; (a) no expression in immune cells, (b) relatively high and constant expression in tumour tissue irrespective of Dukes' stage and (c) no or weak downregulation in tumours compared to normal tissue. CEA fulfilled these criteria best, followed by CK20 and MUC2.
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28.
  • Ohlsson, Lina, et al. (författare)
  • CEACAM5, KLK6, SLC35D3, POSTN, and MUC2 mRNA Analysis Improves Detection and Allows Characterization of Tumor Cells in Lymph Nodes of Patients Who Have Colon Cancer
  • 2021
  • Ingår i: Diseases of the Colon & Rectum. - : Lippincott Williams & Wilkins. - 0012-3706 .- 1530-0358. ; 64:11, s. 1354-1363
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Lymph node metastasis is the single most important prognostic risk factor for recurrence in patients with colon cancer who have undergone curative surgery. The routine method for detecting disseminated tumor cells in lymph nodes is microscopic examination of one or a few hematoxylin and eosin-stained tissue sections by a trained pathologist. This method, however, is insensitive mainly because less than 1% of the lymph node volume is examined, leading to misclassification.OBJECTIVE: This study aimed to investigate whether analysis of a selected group of biomarker mRNAs improves detection and characterization of lymph node metastases/micrometastases compared with the routine method.DESIGN: This study is a side-by-side comparison of biomarker mRNA analysis and histopathology of 185 lymph nodes from patients with colon cancer representing stages I to IV, and an investigation of the importance of lymph node tissue volume for tumor cell detection.SETTINGS: This is a collaborative study between a high-volume central hospital and a preclinical university institution.PATIENTS: Fifty-seven patients who had undergone tumor resection for colon cancer were included.MAIN OUTCOME MEASURES: The primary outcomes measured were mRNA copies per 18S rRNA copy of CEACAM5, KLK6, SLC35D3, POSTN, and MUC2 by multiplex assay and metastases/micrometastases detected by histopathology.RESULTS: The number of tumor cell-positive lymph nodes was 1.33-fold higher based on CEACAM5 mRNA levels compared with histopathological examination. Increasing the tissue volume analyzed for CEACAM5 levels from an 80-µm section to half a lymph node increased the number of positive nodes from 34 of 107 to 80 of 107 (p < 0.0001). Similarly, the number of positive nodes for the aggressiveness marker KLK6 increased from 9 of 107 to 24 of 107.LIMITATIONS: Only a limited number of individual lymph nodes per patient was available for analysis.CONCLUSIONS: mRNA analysis of CEACAM5, KLK6, and SLC35D3 improves the detection of tumor cells in lymph nodes from patients surgically treated for colon cancer, and, together with POSTN and MUC2, it further allows characterization of the tumor cells with respect to aggressiveness and the tumor cell environment. See Video Abstract at https://links.lww.com/DCR/B650.
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29.
  • Ohlsson, Lina, et al. (författare)
  • Detection of Tumor Cells in Lymph Nodes of Colon Cancer Patients Using Real-Time Quantitative Reverse Transcription-Polymerase Chain Reaction
  • 2009
  • Ingår i: Colorectal Cancer. - NEW YORK : Springer Netherlands. - 9781402095443 - 9781402095450 ; , s. 257-268
  • Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
    • Colorectal cancer is ranked third in worldwide incidence for women and fourth for men representing ͌ 9% of the world cancer or approximately 1 million new cases for 2002 (Parkin et al., 2005). Two thirds of colorectal cancers are located in the colon and one third in the rectum. At diagnosis approximately one third of all patients with colorectal cancer has lymph node positive disease, one third has lymph node-negative disease, and one third has distant metas-tases (Benson et al., 2004). The principal curative treatment for colorectal cancer is surgery. Adjuvant chemotherapy given to lymph node positive colon cancer patients has been shown to increase the survival rate (Haydon, 2003). In rectal cancer patients preoperative irradiation therapy is given to reduce local recurrences and has also been shown to improve survival (Folkesson et al., 2005). Still with these improved treatment modalities only approximately half the number of patients will survive for 5 years. For example, Swedish results for the time period 1995–1999 show a 5-years relative survival of ≈ 57% for both genders (Birgisson et al., 2005).Tumor stage, based on histopathologi-cal examination of the resected specimen, and perioperative findings predict survival. Relative 5-year survival in Dukes' A (T1-2N0M0, Stage I) is 90–95%, Dukes' B (T3-4N0M0, Stage II) 60–80%, Dukes' C (anyTN1-2M0, Stage III) 40–60% and Dukes' D (anyTN0-2M1, Stage IV) < 5% (Staib et al., 2002). Besides distant metas-tases the most important prognostic indicator is the status of the regional lymphatic field showing presence or absence of tumor cells in regional lymph nodes. Given the importance of correctly identifying Dukes' C patients, i.e., patients with lymph node involvement who are eligible for chemotherapy, we have focused on improving the methods for detecting disseminated tumor cells in regional lymph nodes.
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30.
  • Ohlsson, Lina, et al. (författare)
  • Ectopic expression of the chemokine CXCL17 in colon cancer cells
  • 2016
  • Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 114:6, s. 697-703
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: The novel chemokine CXCL17 acts as chemoattractant for monocytes, macrophages and dendritic cells. CXCL17 also has a role in angiogenesis of importance for tumour development. Methods: Expression of CXCL17, CXCL10, CXCL9 and CCL2 was assessed in primary colon cancer tumours, colon carcinoma cell lines and normal colon tissue at mRNA and protein levels by real-time qRT-PCR, immunohistochemistry, two-colour immunofluorescence and immunomorphometry. Results: CXCL17 mRNA was expressed at 8000 times higher levels in primary tumours than in normal colon (P<0.0001). CXCL17 protein was seen in 17.2% of cells in tumours as compared with 0.07% in normal colon (P = 0.0002). CXCL10, CXCL9 and CCL2 mRNAs were elevated in tumours but did not reach the levels of CXCL17. CXCL17 and CCL2 mRNA levels were significantly correlated in tumours. Concordant with the mRNA results, CXCL10-and CXCL9-positive cells were detected in tumour tissue, but at significantly lower numbers than CXCL17. Two-colour immunofluorescence and single-colour staining of consecutive sections for CXCL17 and the epithelial cell markers carcinoembryonic antigen and BerEP4 demonstrated that colon carcinoma tumour cells indeed expressed CXCL17. Conclusions: CXCL17 is ectopically expressed in primary colon cancer tumours. As CXCL17 enhances angiogenesis and attracts immune cells, its expression could be informative for prognosis in colon cancer patients.
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31.
  • Ohlsson, Lina, et al. (författare)
  • Evaluating macrophage migration inhibitory factor 1 expression as a prognostic biomarker in colon cancer
  • 2020
  • Ingår i: Tumor Biology. - : Sage Publications. - 1010-4283 .- 1423-0380. ; 42:6
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Several studies indicate that macrophage migration inhibitory factor 1 plays a role for tumor progression in colon cancer. We investigated whether determination of migration inhibitory factor 1 mRNA expression levels in lymph nodes of colon cancer patients could be used as a prognostic marker.METHODS: Expression levels of migration inhibitory factor 1 and carcinoembryonic antigen mRNAs were assessed in primary tumors and regional lymph nodes of 123 colon cancer patients (stages I-IV), and in colon cancer- and immune cell lines using quantitative reverse transcriptase-polymerase chain reaction. Expression of migration inhibitory factor 1 protein was investigated by two-color immunohistochemistry and immunomorphometry.RESULTS: Migration inhibitory factor 1 mRNA was expressed at 60 times higher levels in primary colon cancer tumors compared to normal colonic tissue (medians 8.2 and 0.2 mRNA copies/18S rRNA unit; p < .0001). A highly significant difference in mRNA expression levels was found between hematoxylin-eosin positive lymph nodes and hematoxylin-eosin negative lymph nodes (p < .0001). Migration inhibitory factor 1 and carcinoembryonic antigen proteins were simultaneously expressed in many colon cancer-tumor cells. Kaplan-Meier survival model and hazard ratio analysis, using a cutoff level at 2.19 mRNA copies/18S rRNA unit, revealed that patients with lymph nodes expressing high levels of migration inhibitory factor 1 mRNA had a 3.5-fold (p = .04) higher risk for recurrence, associated with a small, but significant, difference in mean survival time (7 months, p = .03) at 12 years of follow-up.CONCLUSION: Although migration inhibitory factor 1 mRNA expression levels were related to severity of disease and lymph node analysis revealed that colon cancer patients with high levels had a shorter survival time after surgery than those with low levels, the difference was small and probably not useful in clinical practice.
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32.
  • Ohlsson, Lina, et al. (författare)
  • Lymph node CEA and MUC2 mRNA as useful predictors of outcome in colorectal cancer
  • 2012
  • Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 130:8, s. 1833-1843
  • Tidskriftsartikel (refereegranskat)abstract
    • The aim was to explore the utility for staging and prognostic impact of carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CUB (complement protein subcomponents C1r/C1s, urchin embryonic growth factor, and bone morphogenic protein 1) containing domain protein 1 (CDCP1) and mucin 2 (MUC2) mRNA levels in mesenteric lymph nodes of colorectal cancer (CRC) patients. Lymph nodes were collected at surgery and bisected; one half was subjected to biomarker mRNA analysis using real-time quantitative RT-PCR and the other half to routine histopathology. Lymph nodes from 174 CRC patients and 24 controls were analyzed. The median follow-up time was 59 (range 17-131) months. Cut-off levels were defined by analyzing quintiles by Cox regression model. CEA mRNA showed the best discriminating power between patients with recurrence in CRC after surgery and patients who were apparently disease-free (p = 0.015). The risk of recurrence for the CEA(+) patients was 4.6 times greater than for the CEA(-) patients (p < 0.0001). The other biomarkers gave lower hazard ratios. Cumulative survival analysis demonstrated that the average survival time was 99 months for CEA(-) patients compared to 39 months for CEA(+) patients, a difference of 60 months (p < 0.0001). Six to nine percent of the Stage I and Stage II patients [H&E(-)] had CEA(+), CK20(+), GCC(+) and/or MUC2(+) lymph nodes. Two of these patients died from recurrent CRC. Low lymph node MUC2/CEA mRNA ratio identified patients with high risk for recurrence (p = 0.011). Thus, quantitative reverse transcriptase-polymerase chain reaction of CEA mRNA is a sensitive method to identify tumor cells in lymph nodes of CRC patients and, in combination with MUC2 mRNA, allows improved prediction of clinical outcome.
  •  
33.
  • Ohlsson, Lina, et al. (författare)
  • Lymph node tissue kallikrein-related peptidase 6 mRNA : a progression marker for colorectal cancer
  • 2012
  • Ingår i: British Journal of Cancer. - : Nature Publishing Group. - 0007-0920 .- 1532-1827. ; 107:1, s. 150-157
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:A most important characteristic feature for poor prognosis in colorectal cancer (CRC) is the presence of lymph node metastasis. Determination of carcinoembryonic antigen (CEA) mRNA levels in lymph nodes has proven powerful for quantification of disseminated tumour cells. Here, we investigate the utility of human tissue kallikrein-related peptidase 6 (KLK6) mRNA as a progression biomarker to complement CEA mRNA, for improved selection of patients in need of adjuvant therapy and intensified follow-up after surgery.Methods:Lymph nodes of pTNM stage I-IV CRC- (166 patients/503 lymph nodes) and control (23/108) patients were collected at surgery and analysed by quantitative RT–PCR.Results:Lymph node KLK6 positivity was an indicator of poor outcome (hazard ratio 3.7). Risk of recurrence and cancer death increased with KLK6 lymph node levels. Patients with KLK6 lymph node levels above the 90th percentile had a hazard ratio of 6.5 and 76 months shorter average survival time compared to patients with KLK6 negative nodes. The KLK6 positivity in lymph nodes with few tumour cells, that is, low CEA mRNA levels, also indicated poor prognosis (hazard ratio 2.8).Conclusion:In CRC patients, lymph node KLK6 positivity indicated presence of aggressive tumour cells associated with poor prognosis and high risk of tumour recurrence.
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34.
  •  
35.
  • Sandhu, Kuljeet Singh, et al. (författare)
  • Nonallelic transvection of multiple imprinted loci is organized by the H19 imprinting control region during germline development
  • 2009
  • Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 23:22, s. 2598-2603
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent observations highlight that the mammalian genome extensively communicates with itself via long-range chromatin interactions. The causal link between such chromatin cross-talk and epigenetic states is, however, poorly understood. We identify here a network of physically juxtaposed regions from the entire genome with the common denominator of being genomically imprinted. Moreover, CTCF-binding sites within the H19 imprinting control region (ICR) not only determine the physical proximity among imprinted domains, but also transvect allele-specific epigenetic states, identified by replication timing patterns, to interacting, nonallelic imprinted regions during germline development. We conclude that one locus can directly or indirectly pleiotropically influence epigenetic states of multiple regions on other chromosomes with which it interacts.
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36.
  • Scheffler, Julia M., et al. (författare)
  • Interleukin 17A: a Janus-faced regulator of osteoporosis
  • 2020
  • Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10
  • Tidskriftsartikel (refereegranskat)abstract
    • Interleukin (IL)-17A is a well-described mediator of bone resorption in inflammatory diseases, and postmenopausal osteoporosis is associated with increased serum levels of IL-17A. Ovariectomy (OVX) can be used as a model to study bone loss induced by estrogen deficiency and the role of IL-17A in osteoporosis development has previously been investigated using various methods to inhibit IL-17A signaling in this model. However, the studies show opposing results. While some publications reported IL-17A as a mediator of OVX-induced osteoporosis, others found a bone-protective role for IL-17 receptor signaling. In this study, we provide an explanation for the discrepancies in previous literature and show for the first time that loss of IL-17A has differential effects on OVX-induced osteoporosis; with IL-17A being important for cortical but not trabecular bone loss. Interestingly, the decrease in trabecular bone after OVX in IL-17A knock-out mice, was accompanied by increased adipogenesis depicted by elevated leptin levels. Additionally, the bone marrow adipose tissue expanded, and the bone-turnover decreased in ovariectomized mice lacking IL-17A compared to ovariectomized WT mice. Our results increase the understanding of how IL-17A signaling influences bone remodeling in the different bone compartments, which isof importance for the development of new treatments of post-menopausal osteoporosis. © 2020, The Author(s).
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37.
  • Schrage, Benedikt, et al. (författare)
  • Lower socioeconomic status predicts higher mortality and morbidity in patients with heart failure
  • 2021
  • Ingår i: Heart. - : BMJ PUBLISHING GROUP. - 1355-6037 .- 1468-201X. ; 107:3, s. 229-236
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective It is not fully understood whether and how socioeconomic status (SES) has a prognostic impact in patients with heart failure (HF). We assessed SES and its association with patient characteristics and outcomes in a contemporary and well-characterised HF cohort. Methods Socioeconomic risk factors (SERF) were defined in the Swedish HF Registry based on income (low vs high according to the annual median value), education level (no degree/compulsory school vs university/secondary school) and living arrangement (living alone vs cohabitating). Results Of 44 631 patients, 21% had no, 33% one, 30% two and 16% three SERF. Patient characteristics strongly and independently associated with lower SES were female sex and no specialist referral. Additional independent associations were older age, more severe HF, heavier comorbidity burden, use of diuretics and less use of HF devices. Lower SES was associated with higher risk of HF hospitalisation/mortality, and overall cardiovascular and non-cardiovascular events. These associations persisted after extensive adjustment for patient characteristics, treatments and care. The magnitude of the association increased linearly with the increasing number of coexistent SERF: HR (95% CI) 1.09 (1.05 to 1.13) for one, 1.16 (1.12 to 1.20) for two and 1.22 (1.18 to 1.28) for three SERF (p<0.01). Conclusions In a contemporary and well-characterised HF cohort and after comprehensive adjustment for confounders, lower SES was linked with multiple factors such as less use of HF devices and age, but most strongly with female sex and lack of specialist referral; and associated with greater risk of morbidity/mortality.
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38.
  • Sjöberg, Christina, 1963, et al. (författare)
  • Treatment with fall-risk-increasing and fracture-preventing drugs before and after a hip fracture: an observational study.
  • 2010
  • Ingår i: Drugs & aging. - : Springer Science and Business Media LLC. - 1170-229X. ; 27:8, s. 653-661
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Hip fracture is a common diagnosis in the older population, with often serious consequences. Drug treatment may be of significance for both falls and fractures. OBJECTIVE: To investigate drug treatment in older hip fracture patients, focusing on use of fall-risk-increasing and fracture-preventing drugs before and after the fracture. METHODS: This was an observational study conducted in Sahlgrenska University Hospital, Gothenburg, Sweden. The participants were 100 consecutive hip fracture patients aged > or =65 years with a median age of 86 (range 66-97) years. Seventy-three patients were female, and 87 patients had at least one strong risk factor for a fracture. Four patients died during the hospital stay, and a further 18 died within 6 months after discharge. Treatment with fall-risk-increasing and fracture-preventing drugs at admission to hospital, at discharge and 6 months after the hip fracture was measured. RESULTS: The numbers of patients treated with fall-risk-increasing drugs were 93 (93%), 96 (100%) and 73 (94%) at admission, discharge and 6-month follow-up, respectively. The median (range) number of such drugs was 3 (0-9), 4 (1-10) and 3 (0-10), respectively. A total of 17 (17%), 32 (33%) and 29 (37%) patients were treated with fracture-preventing drugs, predominantly calcium plus vitamin D, at admission, discharge and 6-month follow-up, respectively. Five patients (5%) used bisphosphonates or selective estrogen receptor modulators at admission. No additional patients had these drugs prescribed during the hospital stay. At 6-month follow-up, four more patients were treated with bisphosphonates. CONCLUSIONS: Treatment with fall-risk-increasing drugs was extensive among older hip fracture patients both before and after the fracture. The proportion of patients with fracture-preventing drugs was low at admission and increased slightly during the follow-up period. Hence, drug treatment in older hip fracture patients can be improved regarding both fall-risk-increasing drugs and fracture-preventing drugs.
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39.
  • Sjöberg, Klas, et al. (författare)
  • Vitamin D levels in microscopic colitis.
  • 2013
  • Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 48:8, s. 987-988
  • Tidskriftsartikel (refereegranskat)
  •  
40.
  • Speliotes, Elizabeth K., et al. (författare)
  • Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
  • 2010
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
  • Tidskriftsartikel (refereegranskat)abstract
    • Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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41.
  • Svensson, Johan, 1964, et al. (författare)
  • Bone-Derived IGF-I Regulates Radial Bone Growth in Adult Male Mice
  • 2023
  • Ingår i: Endocrinology. - 0013-7227. ; 164:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Insulin-like growth factor-I (IGF-I) levels, which are reduced by age, and cortical bone dimensions are major determinants of fracture risk in elderly subjects. Inactivation of liver-derived circulating IGF-I results in reduced periosteal bone expansion in young and older mice. In mice with lifelong depletion of IGF-I in osteoblast lineage cells, the long bones display reduced cortical bone width. However, it has not previously been investigated whether inducible inactivation of IGF-I locally in bone in adult/old mice affects the bone phenotype. Adult tamoxifen-inducible inactivation of IGF-I using a CAGG-CreER mouse model (inducible IGF-I-KO mice) substantially reduced IGF-I expression in bone (-55%) but not in liver. Serum IGF-I and body weight were unchanged. We used this inducible mouse model to assess the effect of local IGF-I on the skeleton in adult male mice, avoiding confounding developmental effects. After tamoxifen-induced inactivation of the IGF-I gene at 9 months of age, the skeletal phenotype was determined at 14 months of age. Computed tomography analyses of tibia revealed that the mid-diaphyseal cortical periosteal and endosteal circumferences and calculated bone strength parameters were decreased in inducible IGF-I-KO mice compared with controls. Furthermore, 3-point bending showed reduced tibia cortical bone stiffness in inducible IGF-I-KO mice. In contrast, the tibia and vertebral trabecular bone volume fraction was unchanged. In conclusion, inactivation of IGF-I in cortical bone with unchanged liver-derived IGF-I in older male mice resulted in reduced radial growth of cortical bone. This suggests that not only circulating IGF-I but also locally derived IGF-I regulates the cortical bone phenotype in older mice.
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42.
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43.
  • Vimaleswaran, Karani S, et al. (författare)
  • Association of vitamin D status with arterial blood pressure and hypertension risk: a mendelian randomisation study.
  • 2014
  • Ingår i: The lancet. Diabetes & endocrinology. - 2213-8595 .- 2213-8587. ; 2:9, s. 719-29
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Low plasma 25-hydroxyvitamin D (25[OH]D) concentration is associated with high arterial blood pressure and hypertension risk, but whether this association is causal is unknown. We used a mendelian randomisation approach to test whether 25(OH)D concentration is causally associated with blood pressure and hypertension risk. Methods In this mendelian randomisation study, we generated an allele score (25[OH]D synthesis score) based on variants of genes that affect 25(OH)D synthesis or substrate availability (CYP2R1 and DHCR7), which we used as a proxy for 25(OH)D concentration. We meta-analysed data for up to 108173 individuals from 35 studies in the D-CarDia collaboration to investigate associations between the allele score and blood pressure measurements. We complemented these analyses with previously published summary statistics from the International Consortium on Blood Pressure (ICBP), the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and the Global Blood Pressure Genetics (Global BPGen) consortium. Findings In phenotypic analyses (up to n=49363), increased 25(OH)D concentration was associated with decreased systolic blood pressure (β per 10% increase, −0·12 mm Hg, 95% CI −0·20 to −0·04; p=0·003) and reduced odds of hypertension (odds ratio [OR] 0·98, 95% CI 0·97–0·99; p=0·0003), but not with decreased diastolic blood pressure (β per 10% increase, −0·02 mm Hg, −0·08 to 0·03; p=0·37). In meta-analyses in which we combined data from D-CarDia and the ICBP (n=146581, after exclusion of overlapping studies), each 25(OH)D-increasing allele of the synthesis score was associated with a change of −0·10 mm Hg in systolic blood pressure (−0·21 to −0·0001; p=0·0498) and a change of −0·08 mm Hg in diastolic blood pressure (−0·15 to −0·02; p=0·01). When D-CarDia and consortia data for hypertension were meta-analysed together (n=142255), the synthesis score was associated with a reduced odds of hypertension (OR per allele, 0·98, 0·96–0·99; p=0·001). In instrumental variable analysis, each 10% increase in genetically instrumented 25(OH)D concentration was associated with a change of −0·29 mm Hg in diastolic blood pressure (−0·52 to −0·07; p=0·01), a change of −0·37 mm Hg in systolic blood pressure (−0·73 to 0·003; p=0·052), and an 8·1% decreased odds of hypertension (OR 0·92, 0·87–0·97; p=0·002). Interpretation Increased plasma concentrations of 25(OH)D might reduce the risk of hypertension. This finding warrants further investigation in an independent, similarly powered study.
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44.
  • Yang, Jian, et al. (författare)
  • FTO genotype is associated with phenotypic variability of body mass index
  • 2012
  • Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 490:7419, s. 267-272
  • Tidskriftsartikel (refereegranskat)abstract
    • There is evidence across several species for genetic control of phenotypic variation of complex traits(1-4), such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using similar to 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype)(5-7), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of similar to 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI8, possibly mediated by DNA methylation(9,10). Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
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45.
  • Zheng, Tenghao, et al. (författare)
  • Human Leukocyte Antigen Signatures as Pathophysiological Discriminants of Microscopic Colitis Subtypes
  • 2024
  • Ingår i: Journal of Crohn's and Colitis. - : OXFORD UNIV PRESS. - 1873-9946 .- 1876-4479. ; 18:3, s. 349-359
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Aims: Microscopic colitis [MC] is currently regarded as an inflammatory bowel disease that manifests as two subtypes: collagenous colitis [CC] and lymphocytic colitis [LC]. Whether these represent a clinical continuum or distinct entities is, however, an open question. Genetic investigations may contribute important insight into their respective pathophysiologies. Methods: We conducted a genome-wide association study [GWAS] meta-analysis in 1498 CC, 373 LC patients, and 13 487 controls from Europe and the USA, combined with publicly available MC GWAS data from UK Biobank and FinnGen [2599 MC cases and 552 343 controls in total]. Human leukocyte antigen [HLA] alleles and polymorphic residues were imputed and tested for association, including conditional analyses for the identification of key causative variants and residues. Genetic correlations with other traits and diagnoses were also studied. Results: We detected strong HLA association with CC, and conditional analyses highlighted the DRB1*03:01 allele and its residues Y26, N77, and R74 as key to this association (best p = 1.4 × 10-23, odds ratio [OR] = 1.96). Nominally significant genetic correlations were detected between CC and pneumonia [rg = 0.77; p = 0.048] and oesophageal diseases [rg = 0.45, p = 0.023]. An additional locus was identified in MC GWAS analyses near the CLEC16A and RMI2 genes on chromosome 16 [rs35099084, p = 2.0 × 10-8, OR = 1.31]. No significant association was detected for LC. Conclusion: Our results suggest CC and LC have distinct pathophysiological underpinnings, characterised by an HLA predisposing role only in CC. This challenges existing classifications, eventually calling for a re-evaluation of the utility of MC umbrella definitions.
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