| 1. |
- Kiiskinen, Tuomo, et al.
(författare)
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Genetic predictors of lifelong medication-use patterns in cardiometabolic diseases
- 2023
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 29:1, s. 209-218
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the genetic determinants of medication use in preventing cardiometabolic diseases. Using the Finnish nationwide drug purchase registry with follow-up since 1995, we performed genome-wide association analyses of longitudinal patterns of medication use in hyperlipidemia, hypertension and type 2 diabetes in up to 193,933 individuals (55% women) in the FinnGen study. In meta-analyses of up to 567,671 individuals combining FinnGen with the Estonian Biobank and the UK Biobank, we discovered 333 independent loci (P < 5 × 10–9) associated with medication use. Fine-mapping revealed 494 95% credible sets associated with the total number of medication purchases, changes in medication combinations or treatment discontinuation, including 46 credible sets in 40 loci not associated with the underlying treatment targets. The polygenic risk scores (PRS) for cardiometabolic risk factors were strongly associated with the medication-use behavior. A medication-use enhanced multitrait PRS for coronary artery disease matched the performance of a risk factor-based multitrait coronary artery disease PRS in an independent sample (UK Biobank, n = 343,676). In summary, we demonstrate medication-based strategies for identifying cardiometabolic risk loci and provide genome-wide tools for preventing cardiovascular diseases.
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| 2. |
- Gronroos, Toni, et al.
(författare)
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Clinicopathological features and prognostic value of SOX11 in childhood acute lymphoblastic leukemia
- 2020
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Acute lymphoblastic leukemia is marked by aberrant transcriptional features that alter cell differentiation, self-renewal, and proliferative features. We sought to identify the transcription factors exhibiting altered and subtype-specific expression patterns in B-ALL and report here that SOX11, a developmental and neuronal transcription factor, is aberrantly expressed in the ETV6-RUNX1 and TCF3-PBX1 subtypes of acute B-cell leukemias. We show that a high expression of SOX11 leads to alterations of gene expression that are typically associated with cell adhesion, migration, and differentiation. A high expression is associated with DNA hypomethylation at the SOX11 locus and a favorable outcome. The results indicate that SOX11 expression marks a group of patients with good outcomes and thereby prompts further study of its use as a biomarker.
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| 3. |
- Mäkinen, Artturi, et al.
(författare)
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Expression of BCL6 in paediatric B-cell acute lymphoblastic leukaemia and association with prognosis
- 2021
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Ingår i: Pathology. - : Elsevier BV. - 0031-3025 .- 1465-3931. ; 53:7, s. 875-882
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Tidskriftsartikel (refereegranskat)abstract
- B-cell lineage acute lymphoblastic leukaemia (B-ALL) is the most common paediatric malignancy. Transcription factor B-cell lymphoma 6 (BCL6) is essential to germinal centre formation and antibody affinity maturation and plays a major role in mature B-cell malignancies. More recently, it was shown to act as a critical downstream regulator in pre-BCR+ B-ALL. We investigated the expression of the BCL6 protein in a population-based cohort of paediatric B-ALL cases and detected moderate to strong positivity through immunohistochemistry in 7% of cases (8/117); however, only two of eight BCL6 cases (25%) co-expressed the ZAP70 protein. In light of these data, the subtype with active pre-BCR signalling constitutes a rare entity in paediatric B-ALL. In three independent larger cohorts with gene expression data, high BCL6 mRNA levels were associated with the TCF3-PBX1, Ph-like, NUTM1, MEF2D and PAX5-alt subgroups and the ‘metagene’ signature for pre-BCR-associated genes. However, higher-than-median BCL6 mRNA level alone was associated with favourable event free survival in the Nordic paediatric cohort, indicating that using BCL6 as a diagnostic marker requires careful design, and evaluation of protein level is needed alongside the genetic or transcriptomic data.
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