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- 2019
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Journal article (peer-reviewed)
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- Sliz, E., et al.
(author)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Journal article (peer-reviewed)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 3. |
- Tabassum, R, et al.
(author)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Journal article (peer-reviewed)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 5. |
- Kurki, MI, et al.
(author)
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FinnGen provides genetic insights from a well-phenotyped isolated population
- 2023
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In: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 613:7944, s. 508-
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Journal article (peer-reviewed)abstract
- Population isolates such as those in Finland benefit genetic research because deleterious alleles are often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%). These variants survived the founding bottleneck rather than being distributed over a large number of ultrarare variants. Although this effect is well established in Mendelian genetics, its value in common disease genetics is less explored1,2. FinnGen aims to study the genome and national health register data of 500,000 Finnish individuals. Given the relatively high median age of participants (63 years) and the substantial fraction of hospital-based recruitment, FinnGen is enriched for disease end points. Here we analyse data from 224,737 participants from FinnGen and study 15 diseases that have previously been investigated in large genome-wide association studies (GWASs). We also include meta-analyses of biobank data from Estonia and the United Kingdom. We identified 30 new associations, primarily low-frequency variants, enriched in the Finnish population. A GWAS of 1,932 diseases also identified 2,733 genome-wide significant associations (893 phenome-wide significant (PWS), P < 2.6 × 10–11) at 2,496 (771 PWS) independent loci with 807 (247 PWS) end points. Among these, fine-mapping implicated 148 (73 PWS) coding variants associated with 83 (42 PWS) end points. Moreover, 91 (47 PWS) had an allele frequency of <5% in non-Finnish European individuals, of which 62 (32 PWS) were enriched by more than twofold in Finland. These findings demonstrate the power of bottlenecked populations to find entry points into the biology of common diseases through low-frequency, high impact variants.
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- Kuitunen, M., et al.
(author)
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High IgE levels to -lactalbumin, -lactoglobulin and casein predict less successful cow's milk oral immunotherapy
- 2015
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In: Allergy. European Journal of Allergy and Clinical Immunology. - : Wiley. - 0105-4538 .- 1398-9995. ; 70:8, s. 955-962
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Journal article (peer-reviewed)abstract
- BackgroundA new treatment option for persistent cow's milk allergy (CMA) is oral immunotherapy (OIT). Not all patients develop tolerance during therapy, and markers to identify those who will benefit from it are needed. The objective was to study the IgE and IgG(4) antibody profiles to milk and milk proteins before and after OIT in relation to clinical outcome. MethodsSeventy-six children (5-17years) with challenge-verified CMA were subjected to a 6-month OIT protocol. The treatment aimed at reaching a maintenance dose of 200ml CM (high dose=HD). Those who did not reach target were analysed as a low-dose (LD) group. Sera were characterized before and after OIT regarding serum levels of IgE and IgG(4) to milk and five milk allergen components evaluated together with clinical CMA symptoms and outcome of OIT. ResultsFifty-five (72%) patients reached the maintenance dose (HD) during therapy. High specific IgE levels towards the milk allergens -lactalbumin (P=0.048), -lactoglobulin (P=0.006) and casein (P=0.015) before OIT start were associated with lower maintenance dose reached. Patients who developed desensitization had a larger increase in IgG(4) levels to -lactalbumin (P=0.034), -lactoglobulin (P=0.010), casein (P=0.047) and lactoferrin (P=0.030) during treatment than those who failed. ConclusionsComponent-resolved diagnostics before OIT can help to identify children with lower probability of a successful OIT outcome, as high IgE levels to -lactalbumin, -lactoglobulin and casein are associated with lower maintenance dose reached. An increase in the IgG(4) concentration to milk components during treatment indicated effective desensitization.
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| 14. |
- Obase, Y, et al.
(author)
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Effects of inhaled corticosteroids on metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 in the airways of asthmatic children
- 2010
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In: International archives of allergy and immunology. - : S. Karger AG. - 1423-0097 .- 1018-2438. ; 151:3, s. 247-254
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Journal article (peer-reviewed)abstract
- <i>Background:</i> The effects of corticosteroids on the level and expression of matrix metalloproteinase-8 (MMP-8; collagenase-2) and tissue inhibitors of metalloproteinases (TIMPs) in airway tissue are poorly characterized in vivo. <i>Methods:</i> We compared MMP-8 and TIMP-1 levels in induced sputum and their expression in airway inflammatory cells of healthy children (n = 27) and of children with newly diagnosed asthma with mild (n = 20) or moderate symptoms (n = 19), before and after 6 months of treatment with inhaled budesonide. <i>Results:</i> At baseline, MMP-8 was higher in asthmatic children with moderate symptoms, TIMP-1 was lower and the MMP-8/TIMP-1 ratio was higher in both groups of asthmatic children compared with controls. Inhaled budesonide increased TIMP-1 levels in both groups of asthmatic children and normalized the MMP-8/TIMP-1 ratio, and this paralleled the improvement in forced expiratory volume in 1 s in children with mild symptoms. At baseline, asthmatic children had significantly more MMP-8-positive macrophages than control children, whereas the number of TIMP-1-positive macrophages was almost the same. Budesonide decreased the percentage of MMP-8-positive macrophages and increased that of TIMP-1-positive macrophages; these changes were significant in asthmatic children with mild symptoms. <i>Conclusions:</i> Inhaled budesonide normalized the MMP-8/TIMP-1 ratio in asthmatic children by upregulation of TIMP-1 production and downregulation of MMP-8 production by airway macrophages. This change may be a biochemical marker of an effect on airway inflammation and possibly of an ongoing remodeling process that should be further investigated using biopsy specimens.
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| 20. |
- Rosendahl, J, et al.
(author)
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A History of Cow's Milk Allergy Is Associated with Lower Vitamin D Status in Schoolchildren
- 2017
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In: Hormone research in paediatrics. - : S. Karger AG. - 1663-2826 .- 1663-2818. ; 88:3-4, s. 244-250
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Journal article (peer-reviewed)abstract
- <b><i>Background/Aims:</i></b> Vitamin D insufficiency is common in children. We aimed to evaluate the main determinants of vitamin D status in Finnish school-aged children, including the history of allergic diseases. <b><i>Methods:</i></b> We conducted a cross-sectional study on 171 ten-year-olds where serum 25-hydroxyvitamin D (25[OH]D) levels were measured, and data on food consumption and use of vitamin D supplements were collected. The history of allergic diseases was evaluated with a validated questionnaire. <b><i>Results:</i></b> Vitamin D insufficiency (<50 nmol/L) was observed in 16% of the children. In children with a history of cow’s milk allergy, the mean 25(OH)D levels were lower than in children without allergy (60.5 ± 12.6 nmol/L vs. 75.5 ± 22.3 nmol/L, <i>p</i> = 0.004). Lack of vitamin D supplementation, female gender, non-Caucasian ethnicity, and a history of milk allergy were associated with lower vitamin D status. <b><i>Conclusion:</i></b> The vitamin D status in our study sample of Finnish schoolchildren was sufficient, which suggests that health policy strategies – such as the recommendation of vitamin D supplementation and the fortification of food products with vitamin D – have been successful in improving vitamin D status in children. Special concern should be given to children with a history of milk allergy to ensure their vitamin D sufficiency.
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| 22. |
- Terho, A M, et al.
(author)
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High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week: a Nordic register study from the CoNARTaS group.
- 2021
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In: Human reproduction (Oxford, England). - : Oxford University Press (OUP). - 1460-2350 .- 0268-1161. ; 36:4, s. 1083-1092
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Journal article (peer-reviewed)abstract
- When do the differences in birth weights become apparent between singletons born after frozen embryo transfer (FET) and fresh embryo transfer (fresh ET)?Mean birth weights after FET become significantly higher starting from gestational week (GW) 33 among boys and from GW 34 among girls.In recent years, there has been a steep rise in recorded FET treatments, enabling widespread use of elective single embryo transfer, thus reducing the risks associated with multiple gestations. However, singletons born after FET are heavier and there is a higher risk of large-for-gestational-age (LGA) (birth weight > 90 percentiles) compared to fresh ET. In contrast, risk of small-for-gestational-age (SGA, birth weight < 10 percentiles) is lower in singletons born after FET compared to fresh ET. The reasons, timing and consequences of these differences remain largely unclear. There is limited evidence about whether this difference in growth develops before the last trimester of pregnancy.This retrospective Nordic register-based cohort study compared singletons born after FET (n=17500) to singletons born after fresh ET (n=69510) and natural conception (NC, n=3311588). All live born singletons born between the years 2000 and 2015 in Denmark, Norway and Sweden at gestational age ≥22weeks were included from the population-based Committee of Nordic ART and Safety (CoNARTaS) study population.Children born after FET were compared to those born after fresh ET and NC for mean birth weight and proportion of LGA and SGA for each GW at birth. Chi-square test and tests for relative proportions were used to compare categorical variables and Student's t-test was used to compare continuous variables. Adjusted odds ratios (aORs) for LGA and SGA were calculated using logistic regressions, adjusting for year of birth, maternal age, parity, BMI, chronic hypertension, diabetes, smoking and offspring sex.Mean birth weights were significantly higher after FET compared to fresh ET starting from GW 33 (range from 75g to 228g by week) for boys and starting from GW 34 (range from 90g to 236g by week) for girls. Boys born after FET had a significantly higher proportion of LGA (11.0-15.1%) at birth between GW 36 and 42, compared to those born after fresh ET (7.1-9.4%) (range from P<0.001 to P=0.048 by week). For girls born after FET, the difference was seen between GW 37 and 42 (10.6-13.4%) compared to those born after fresh ET (6.6-8.0%) (range from P<0.001 to P=0.009 by week).The proportion of SGA was significantly lower among boys born after FET (7.6-8.7%) compared to fresh ET (11.9-13.6%) between GW 36 and 42 (range from P<0.001 to P=0.016 by week). For girls born after FET, the difference was seen between GW 38 and 42 (7.0-9.3%) compared to those born after fresh ET (13.0-14.6%) (P<0.001). The proportion of LGA (12.3-15.1%) was significantly higher for boys born after FET between GW 38 and 41 (P<0.001) and for girls born after FET (12.6-13.4%) between GW 37 and 40 (range from P<0.001 to P=0.018 by week), compared to naturally conceived boys (9.7-9.9%) and girls (9.0-10.0%). All singletons born after FET had a higher risk of LGA compared to singletons born after fresh ET (aOR 1.87, 95% CI 1.76-1.98) and singletons born after NC (aOR 1.28, 95% CI 1.22-1.35).There may be residual confounding factors that we were not able to control for, most importantly the causes of preterm birth, which may also influence foetal growth. A further limitation is that we have no knowledge on growth patterns between implantation and GW 22. Finally, the number of children born extremely preterm or post-term was limited even in this large study population.This is, to date, the largest study on birth weights among preterm and term ART singletons with a population-based design and NC control group. The results suggest that the freeze-thaw process is associated with higher birthweights and greater risk of LGA at least in the last trimester of pregnancy. This is an important aspect of the safety profile of ART. More research is needed on the long-term outcome of these children.The CoNARTaS collaboration has received the following funding: the Nordic Trial Alliance: a pilot project jointly funded by the Nordic Council of Ministers and NordForsk [71450], the Central Norway Regional Health Authorities [46045000], the Norwegian Cancer Society [182356-2016], the Nordic Federation of Obstetrics and Gynaecology [NF13041, NF15058, NF16026 and NF17043], the Interreg Öresund-Kattegat-Skagerrak European Regional Development Fund (ReproUnion project) and the Research Council of Norway's Centre of Excellence funding scheme [262700]. None of the authors have any competing interests to declare.ISRCTN11780826.
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| 23. |
- Berntson, L., et al.
(author)
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Incidence of juvenile idiopathic arthritis in the Nordic countries : A population based study with special reference to the validity of the ILAR and EULAR criteria
- 2003
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In: Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 30:10, s. 2275-2282
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To find the incidence of juvenile arthritis according to the ILAR and EULAR criteria within defined areas in the Nordic countries, and to study the validity of the ILAR and EULAR criteria from this perspective. METHOD: A longitudinal, prospective, population based study with patients enrolled according to the ILAR and EULAR criteria. Twenty doctors in Iceland, Norway, Sweden, Denmark, and Finland collected data from the incidence cases within their catchment areas over a period of 1.5 years, beginning July 1, 1997. Clinical and serological data from the first year of the disease were collected. RESULTS: In the whole group of 315 patients, the incidence rate was 15 per 100,000 children/year (95% CI 13-17) according to the ILAR criteria, varying from 7 (1-13) in Iceland, 19 (7-31) and 23 (10-36) from 2 different regions in Norway, and 9 (5-12) and 16 (9-23) from 2 different areas in Denmark, to 15 (12-18) in Sweden and 21/100,000/year (15-26) in the Helsinki region in Finland. An early peak in distribution for age of onset was found in girls but not in boys. The number of antinuclear antibody (ANA) positive children in the whole group, made up of children who had undergone at least one analyzed ANA test, was 123/315 (39%). Girls were ANA positive in 83/197 (42%) and boys in 40/118 (34%). Uveitis developed in 27/315 (8.6%) children during the first 6 months of the disease. CONCLUSION: Incidence rates of juvenile arthritis for areas within the Nordic countries were in accord with previous data. The ILAR criteria present slightly higher incidence rates, with a shorter disease duration for inclusion, compared to the EULAR criteria. Patients in one subgroup in either of the criteria sets do not necessarily belong to the expected subgroup in the other set of criteria; e.g., for juvenile ankylosing spondylitis (EULAR) and enthesitis related arthritis (ILAR). Our epidemiological findings are a reminder to be aware of possible new subgroups in children with juvenile arthritis.
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| 24. |
- Berntson, L., et al.
(author)
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The influence of heredity for psoriasis on the ILAR classification of juvenile idiopathic arthritis
- 2002
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In: Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 29:11, s. 2454-2458
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To evaluate how heredity for psoriasis influences classification according to the International League of Associations for Rheumatology (ILAR). Heredity for psoriasis is currently both an exclusion and an inclusion criterion for different types of childhood arthritis according to ILAR classification criteria. METHODS: Twenty physicians in 5 Nordic countries prospectively collected data from the incident cases in their catchment areas over an 18 month period beginning July 1, 1997. Clinical and serological data from the first year of disease were collected. RESULTS: Of the 321 patients included who could be classified according to ILAR criteria for childhood arthritis, 50 (15.6%) patients were excluded from 55 classification events and fulfilled criteria for "other arthritis 1" i.e., did not fulfill criteria for any of the other classification categories, primarily because of heredity for psoriasis. If psoriasis in second degree relatives was disregarded as an exclusion criterion, only 8.7% of the patients remained in the "other arthritis 1" subgroup. For 20.6% of the whole group, heredity for psoriasis in a first or second degree relative (or both) and its distribution among arthritis subgroups did not differ except for juvenile psoriatic arthritis. CONCLUSION: We suggest that second degree heredity for psoriasis be withdrawn as an exclusion criterion from the ILAR criteria.
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| 25. |
- Chernyaeva, Larisa, et al.
(author)
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Reduced binding of apoE4 to complement factor H promotes amyloid-β oligomerization and neuroinflammation
- 2023
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In: EMBO Reports. - 1469-221X. ; 24:7
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Journal article (peer-reviewed)abstract
- The APOE4 variant of apolipoprotein E (apoE) is the most prevalent genetic risk allele associated with late-onset Alzheimer's disease (AD). ApoE interacts with complement regulator factor H (FH), but the role of this interaction in AD pathogenesis is unknown. Here we elucidate the mechanism by which isoform-specific binding of apoE to FH alters Aβ1-42-mediated neurotoxicity and clearance. Flow cytometry and transcriptomic analysis reveal that apoE and FH reduce binding of Aβ1-42 to complement receptor 3 (CR3) and subsequent phagocytosis by microglia which alters expression of genes involved in AD. Moreover, FH forms complement-resistant oligomers with apoE/Aβ1-42 complexes and the formation of these complexes is isoform specific with apoE2 and apoE3 showing higher affinity to FH than apoE4. These FH/apoE complexes reduce Aβ1-42 oligomerization and toxicity, and colocalize with complement activator C1q deposited on Aβ plaques in the brain. These findings provide an important mechanistic insight into AD pathogenesis and explain how the strongest genetic risk factor for AD predisposes for neuroinflammation in the early stages of the disease pathology.
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| 26. |
- Natarajan, K., et al.
(author)
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Potential expansion of second generation Fischer Tropsch biodiesel production in Finland
- 2012
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In: NWBC 2012 - 4th Nordic Wood Biorefinery Conference. - : VTT Technical Research Centre of Finland. ; , s. 277-278
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Conference paper (peer-reviewed)abstract
- The Finnish biofuel industry is undergoing a major change in particular second generation Fischer Tropsch (FT) biodiesel production. However, efficient geographical energy planning is essential to optimally allocate the limited natural resources between biomass based industries. Therefore, a decision tool was formulated which includes three different models: (1) a spatial model that estimates the amount of biomass supply and industrial residues available for energy production, (2) an energy demand model calculates the amount of heat and transport fuel that can be delivered to the customers, (3) an optimization model that minimizes the complete costs of biodiesel supply chain from biomass supply to biodiesel delivery at the fuel stations to determine the optimal location, size and configurations of FT biodiesel production plants in Finland. Model results show that five cost-optimal biodiesel production plant locations of 390 MWfeedstock are needed to be built to meet the 2020 renewable energy share in transport (25.2 PJ). The unit cost of FT biodiesel produced in Finland could range between 1.1 and 1.4 €/l2011 without heat sales. © NWBC 2012.All rights reserved.
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