| 1. |
- Edgren, Gustaf, et al.
(författare)
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The new Scandinavian Donations and Transfusions database (SCANDAT2) : a blood safety resource with added versatility
- 2015
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Ingår i: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 55:7, s. 1600-1606
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundRisks of transfusion-transmitted disease are currently at a record low in the developed world. Still, available methods for blood surveillance might not be sufficient to detect transmission of diseases with unknown etiologies or with very long incubation periods. Study Design and MethodsWe have previously created the anonymized Scandinavian Donations and Transfusions (SCANDAT) database, containing data on blood donors, blood transfusions, and transfused patients, with complete follow-up of donors and patients for a range of health outcomes. Here we describe the re-creation of SCANDAT with updated, identifiable data. We collected computerized data on blood donations and transfusions from blood banks covering all of Sweden and Denmark. After data cleaning, two structurally identical databases were created and the entire database was linked with nationwide health outcomes registers to attain complete follow-up for up to 47 years regarding hospital care, cancer, and death. ResultsAfter removal of erroneous records, the database contained 25,523,334 donation records, 21,318,794 transfusion records, and 3,692,653 unique persons with valid identification, presently followed over 40 million person-years, with possibility for future extension. Data quality is generally high with 96% of all transfusions being traceable to their respective donation(s) and a very high (>97%) concordance with official statistics on annual number of blood donations and transfusions. ConclusionsIt is possible to create a binational, nationwide database with almost 50 years of follow-up of blood donors and transfused patients for a range of health outcomes. We aim to use this database for further studies of donor health, transfusion-associated risks, and transfusion-transmitted disease.
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| 2. |
- Edgren, Gustaf, et al.
(författare)
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Transmission of Neurodegenerative Disorders Through Blood Transfusion A Cohort Study
- 2016
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Ingår i: Annals of Internal Medicine. - 0003-4819 .- 1539-3704. ; 165:5, s. 316-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aggregation of misfolded proteins in the brain occurs in several neurodegenerative disorders. Aberrant protein aggregation is inducible in rodents and primates by intracerebral inoculation. Possible transfusion transmission of neurodegenerative diseases has important public health implications. Objective: To investigate possible transfusion transmission of neurodegenerative disorders. Design: Retrospective cohort study. Setting: Nationwide registers of transfusions in Sweden and Denmark. Participants: 1 465 845 patients who received transfusions between 1968 and 2012. Measurements: Multivariable Cox regression models were used to estimate hazard ratios for dementia of any type, Alzheimer disease, and Parkinson disease in patients receiving blood transfusions from donors who were later diagnosed with any of these diseases versus patients who received blood from healthy donors. Whether excess occurrence of neurodegenerative disease occurred among recipients of blood from a subset of donors was also investigated. As a positive control, transmission of chronic hepatitis before and after implementation of hepatitis C virus screening was assessed. Results: Among included patients, 2.9% received a transfusion from a donor diagnosed with one of the studied neurodegenerative diseases. No evidence of transmission of any of these diseases was found, regardless of approach. The hazard ratio for dementia in recipients of blood from donors with dementia versus recipients of blood from healthy donors was 1.04 (95% CI, 0.99 to 1.09). Corresponding estimates for Alzheimer disease and Parkinson disease were 0.99 (CI, 0.85 to 1.15) and 0.94 (CI, 0.78 to 1.14), respectively. Hepatitis transmission was detected before but not after implementation of hepatitis C virus screening. Limitation: Observational study design, underascertainment of the outcome, and possible insufficient statistical power. Conclusion: The data provide no evidence for the transmission of neurodegenerative diseases and suggest that if transmission does occur, it is rare.
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| 3. |
- Halmin, Marit, et al.
(författare)
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Epidemiology of Massive Transfusion : A Binational Study From Sweden and Denmark
- 2016
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Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 44:3, s. 468-477
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Tidskriftsartikel (refereegranskat)abstract
- Objective: There is an increasing focus on massive transfusion, but there is a paucity of comprehensive descriptions of the massively transfused patients and their outcomes. The objective of this study is to describe the incidence rate of massive transfusion, patient characteristics, and the mortality of massively transfused patients. Design: Descriptive cohort study. Setting: Nationwide study with data from Sweden and Denmark. Patients: The study was based on the Scandinavian Donations and Transfusions database, including all patients receiving 10 or more red cell concentrate transfusions in Sweden from 1987 and in Denmark from 1996. A total of 92,057 patients were included. Patients were followed until the end of 2012. Measurements and Main Results: Descriptive statistics were used to characterize the patients and indications. Post transfusion mortality was expressed as crude 30-day mortality and as long-term mortality using the Kaplan-Meier method and using standardized mortality ratios. The incidence of massive transfusion was higher in Denmark (4.5 per 10,000) than in Sweden (2.5 per 10,000). The most common indication for massive transfusion was major surgery (61.2%) followed by trauma (15.4%). Massive transfusion due to obstetrical bleeding constituted only 1.8%. The overall 5-year mortality was very high (54.6%), however with large differences between indication groups, ranging from 91.1% among those transfused for a malignant disease without surgery to 1.7% among patients transfused for obstetrical bleeding. The early standardized mortality ratios were high and decreased thereafter, but remained elevated throughout the time period. Conclusions: This large-scale study based on nationwide data from Sweden and Denmark describes the complete range of massive transfusion. We report a nonnegligible incidence and both a high absolute mortality and high standardized mortality ratio. The general pattern was similar for Sweden and Denmark, and we believe that similar patterns may be found in other high-resource countries. The study provides a relevant background for clinicians and researchers for designing future studies in this field.
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| 4. |
- Moslemi, Camous, et al.
(författare)
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A large cohort study of the effects of Lewis, ABO, 13 other blood groups, and secretor status on COVID-19 susceptibility, severity, and long COVID-19
- 2023
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Ingår i: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 63:1, s. 47-58
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies have reported Blood type O to confer a lower risk of SARS-CoV-2 infection, while secretor status and other blood groups have been suspected to have a similar effect as well. Study design and methods: To determine whether any other blood groups influence testing positive for SARS-CoV-2, COVID-19 severity, or prolonged COVID-19, we used a large cohort of 650,156 Danish blood donors with varying available data for secretor status and blood groups ABO, Rh, Colton, Duffy, Diego, Dombrock, Kell, Kidd, Knops, Lewis, Lutheran, MNS, P1PK, Vel, and Yt. Of these, 36,068 tested positive for SARS-CoV-2 whereas 614,088 tested negative between 2020-02-17 and 2021-08-04. Associations between infection and blood groups were assessed using logistic regression models with sex and age as covariates. Results: The Lewis blood group antigen Lea displayed strongly reduced SARS-CoV-2 susceptibility OR 0.85 CI[0.79–0.93] p <.001. Compared to blood type O, the blood types B, A, and AB were found more susceptible toward infection with ORs 1.1 CI[1.06–1.14] p <.001, 1.17 CI[1.14–1.2] p <.001, and 1.2 CI[1.14–1.26] p <.001, respectively. No susceptibility associations were found for the other 13 blood groups investigated. There was no association between any blood groups and COVID-19 hospitalization or long COVID-19. No secretor status associations were found. Discussion: This study uncovers a new association to reduced SARS-CoV-2 susceptibility for Lewis type Lea and confirms the previous link to blood group O. The new association to Lea could be explained by a link between mucosal microbiome and SARS-CoV-2.
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| 5. |
- Moslemi, Camous, et al.
(författare)
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Genetic prediction of 33 blood group phenotypes using an existing genotype dataset
- 2023
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Ingår i: Transfusion. - 0041-1132. ; 63:12, s. 2297-2310
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Tidskriftsartikel (refereegranskat)abstract
- Background: Accurate blood type data are essential for blood bank management, but due to costs, few of 43 blood group systems are routinely determined in Danish blood banks. However, a more comprehensive dataset of blood types is useful in scenarios such as rare blood type allocation. We aimed to investigate the viability and accuracy of predicting blood types by leveraging an existing dataset of imputed genotypes for two cohorts of approximately 90,000 each (Danish Blood Donor Study and Copenhagen Biobank) and present a more comprehensive overview of blood types for our Danish donor cohort. Study Design and Methods: Blood types were predicted from genome array data using known variant determinants. Prediction accuracy was confirmed by comparing with preexisting serological blood types. The Vel blood group was used to test the viability of using genetic prediction to narrow down the list of candidate donors with rare blood types. Results: Predicted phenotypes showed a high balanced accuracy >99.5% in most cases: A, B, C/c, Coa/Cob, Doa/Dob, E/e, Jka/Jkb, Kna/Knb, Kpa/Kpb, M/N, S/s, Sda, Se, and Yta/Ytb, while some performed slightly worse: Fya/Fyb, K/k, Lua/Lub, and Vel ~99%–98% and CW and P1 ~96%. Genetic prediction identified 70 potential Vel negatives in our cohort, 64 of whom were confirmed correct using polymerase chain reaction (negative predictive value: 91.5%). Discussion: High genetic prediction accuracy in most blood groups demonstrated the viability of generating blood types using preexisting genotype data at no cost and successfully narrowed the pool of potential individuals with the rare Vel-negative phenotype from 180,000 to 70.
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| 6. |
- Skotte, Line, et al.
(författare)
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Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes
- 2022
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 145:2, s. 555-568
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Tidskriftsartikel (refereegranskat)abstract
- Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.
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| 7. |
- Ullum, Henrik, et al.
(författare)
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Blood donation and blood donor mortality after adjustment for a healthy donor effect
- 2015
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Ingår i: Transfusion. - : Wiley. - 0041-1132 .- 1537-2995. ; 55:10, s. 2479-2485
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Studies have repeatedly demonstrated that blood donors experience lower mortality than the general population. While this may suggest a beneficial effect of blood donation, it may also reflect the selection of healthy persons into the donor population. To overcome this bias, we investigated the relation between blood donation frequency and mortality within a large cohort of blood donors. In addition, our analyses also took into consideration the effects of presumed health differences linked to donation behavior.STUDY DESIGN AND METHODS Using the Scandinavian Donation and Transfusion database (SCANDAT), we assessed the association between annual number of donations in 5-year windows and donor mortality by means of Poisson regression analysis. The analyses included adjustment for demographic characteristics and for an internal healthy donor effect, estimated among elderly donors exempted from continued donation because of age criteria.RESULTS Statistical analyses included 1,182,495 donors of whom 15,401 died during 9,526,627 person-years of follow-up. Analyses adjusted only for demographic characteristics showed a 18.6% reduction in mortality per additional annual donation (95% confidence interval [CI], 16.8%-20.4%). After additional adjustment for the internal healthy donor effect, each additional annual donation was associated with a 7.5% decreased mortality risk 7.5% (95% CI, 5.7%-9.4%).CONCLUSION We observed an inverse relationship between donation frequency and mortality. The magnitude of the association was reduced after adjustment for an estimate of self-selection in the donor population. Our observations indicate that repeated blood donation is not associated with premature death, but cannot be interpreted as conclusive evidence of a beneficial health effect.
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| 8. |
- Beaumont, Robin N, et al.
(författare)
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Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth.
- 2023
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Ingår i: Nature genetics. - 1546-1718 .- 1061-4036. ; 55:11, s. 1807-19
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Tidskriftsartikel (refereegranskat)abstract
- A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n=65,405), maternal (n=61,228) and paternal (n=52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.
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| 9. |
- Fadista, João, et al.
(författare)
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Comprehensive genome-wide association study of different forms of hernia identifies more than 80 associated loci
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Hernias are characterized by protrusion of an organ or tissue through its surrounding cavity and often require surgical repair. In this study we identify 65,492 cases for five hernia types in the UK Biobank and perform genome-wide association study scans for these five types and two combined groups. Our results show associated variants in all scans. Inguinal hernia has the most associations and we conduct a follow-up study with 23,803 additional cases from four study groups giving 84 independently associated variants. Identified variants from all scans are collapsed into 81 independent loci. Further testing shows that 26 loci are associated with more than one hernia type, suggesting substantial overlap between the underlying genetic mechanisms. Pathway analyses identify several genes with a strong link to collagen and/or elastin (ADAMTS6, ADAMTS16, ADAMTSL3, LOX, ELN) in the vicinity of associated loci for inguinal hernia, which substantiates an essential role of connective tissue morphology.
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| 10. |
- Gelpi, Marco, et al.
(författare)
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The central role of the glutamate metabolism in long-term antiretroviral treated HIV-infected individuals with metabolic syndrome
- 2021
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Ingår i: Aging. - : Impact Journals, LLC. - 1945-4589. ; 13:19, s. 22732-22751
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic syndrome (MetS) is a significant factor for cardiometabolic comorbidities in people living with HIV (PLWH) and a barrier to healthy aging. The long-term consequences of HIV-infection and combination antiretroviral therapy (cART) in metabolic reprogramming are unknown. In this study, we investigated metabolic alterations in well-treated PLWH with MetS to identify potential mechanisms behind the MetS phenotype using advanced statistical and machine learning algorithms. We included 200 PLWH from the Copenhagen Comorbidity in HIV-infection (COCOMO) study. PLWH were grouped into PLWH with MetS (n = 100) defined according to the International Diabetes Federation (IDF) consensus worldwide definition of the MetS or without MetS (n = 100). The untargeted plasma metabolomics was performed using ultra-high-performance liquid chromatography/mass spectrometry (UHPLC/MS/MS) and immune-phenotyping of Glut1 (glucose transporter), xCT (glutamate/cysteine transporter) and MCT1 (pyruvate/lactate transporter) by flow cytometry. We applied several conventional approaches, machine learning algorithms, and linear classification models to identify the biologically relevant metabolites associated with MetS in PLWH. Of the 877 identified biochemicals, 9% (76/877) differed significantly between PLWH with and without MetS (false discovery rate < 0.05). The majority belonged to amino acid metabolism (43%). A consensus identification by combining supervised and unsupervised methods indicated 11 biomarkers of MetS phenotype in PLWH. A weighted co-expression network identified seven communities of positively intercorrelated metabolites. A single community contained six of the potential biomarkers mainly related to glutamate metabolism. Transporter expression identified altered xCT and MCT in both lymphocytic and monocytic cells. Combining metabolomics and immune-phenotyping indicated altered glutamate metabolism associated with MetS in PLWH, which has clinical significance.
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| 11. |
- Ghouse, Jonas, et al.
(författare)
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Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors
- 2021
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 78:7, s. 696-709
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensinconverting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. OBJECTIVES The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. METHODS A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors #180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. RESULTS The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 x 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 x 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 x 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI:-0.83 to-0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI:-0.46 to-0.05; P = 0.013) blood pressure. CONCLUSIONS In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.
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| 12. |
- Hedström, Anna Karin, et al.
(författare)
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The interaction between smoking and HLA genes in multiple sclerosis : replication and refinement
- 2017
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Ingår i: European Journal of Epidemiology. - : Springer Science and Business Media LLC. - 0393-2990 .- 1573-7284. ; 23:1, s. 37-37
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Tidskriftsartikel (refereegranskat)abstract
- Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.
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| 13. |
- Hindy, George, et al.
(författare)
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Increased soluble urokinase plasminogen activator levels modulate monocyte function to promote atherosclerosis
- 2022
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 132:24, s. 1-14
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Tidskriftsartikel (refereegranskat)abstract
- People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin–9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.
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| 14. |
- Nethander, Maria, 1980, et al.
(författare)
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An atlas of genetic determinants of forearm fracture.
- 2023
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Ingår i: Nature genetics. - : Springer Nature. - 1546-1718 .- 1061-4036. ; 55:11, s. 1820-1830
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Tidskriftsartikel (refereegranskat)abstract
- Osteoporotic fracture is among the most common and costly of diseases. While reasonably heritable, its genetic determinants have remained elusive. Forearm fractures are the most common clinically recognized osteoporotic fractures with a relatively high heritability. To establish an atlas of the genetic determinants of forearm fractures, we performed genome-wide association analyses including 100,026 forearm fracture cases. We identified 43 loci, including 26 new fracture loci. Although most fracture loci associated with bone mineral density, we also identified loci that primarily regulate bone quality parameters. Functional studies of one such locus, at TAC4, revealed that Tac4-/- mice have reduced mechanical bone strength. The strongest forearm fracture signal, at WNT16, displayed remarkable bone-site-specificity with no association with hip fractures. Tall stature and low body mass index were identified as new causal risk factors for fractures. The insights from this atlas may improve fracture prediction and enable therapeutic development to prevent fractures.
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| 15. |
- Olund Villumsen, Sofie, et al.
(författare)
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Integrative Lipidomics and Metabolomics for System-Level Understanding of the Metabolic Syndrome in Long-Term Treated HIV-Infected Individuals
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- People living with HIV (PLWH) require life-long anti-retroviral treatment and often present with comorbidities such as metabolic syndrome (MetS). Systematic lipidomic characterization and its association with the metabolism are currently missing. We included 100 PLWH with MetS and 100 without MetS from the Copenhagen Comorbidity in HIV Infection (COCOMO) cohort to examine whether and how lipidome profiles are associated with MetS in PLWH. We combined several standard biostatistical, machine learning, and network analysis techniques to investigate the lipidome systematically and comprehensively and its association with clinical parameters. Additionally, we generated weighted lipid-metabolite networks to understand the relationship between lipidomic profiles with those metabolites associated with MetS in PLWH. The lipidomic dataset consisted of 917 lipid species including 602 glycerolipids, 228 glycerophospholipids, 61 sphingolipids, and 26 steroids. With a consensus approach using four different statistical and machine learning methods, we observed 13 differentially abundant lipids between PLWH without MetS and PLWH with MetS, which mainly belongs to diacylglyceride (DAG, n = 2) and triacylglyceride (TAG, n = 11). The comprehensive network integration of the lipidomics and metabolomics data suggested interactions between specific glycerolipids' structural composition patterns and key metabolites involved in glutamate metabolism. Further integration of the clinical data with metabolomics and lipidomics resulted in the association of visceral adipose tissue (VAT) and exposure to earlier generations of antiretroviral therapy (ART). Our integrative omics data indicated disruption of glutamate and fatty acid metabolism, suggesting their involvement in the pathogenesis of PLWH with MetS. Alterations in the lipid homeostasis and glutaminolysis need clinical interventions to prevent accelerated aging in PLWH with MetS.
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| 16. |
- Solé Navais, Pol, et al.
(författare)
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Genetic effects on the timing of parturition and links to fetal birth weight.
- 2023
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Ingår i: Nature genetics. - 1546-1718. ; 55:4, s. 559-567
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Tidskriftsartikel (refereegranskat)abstract
- The timing of parturition is crucial for neonatal survival and infant health. Yet, its genetic basis remains largely unresolved. We present a maternal genome-wide meta-analysis of gestational duration (n=195,555), identifying 22 associated loci (24 independent variants) and an enrichment in genes differentially expressed during labor. A meta-analysis of preterm delivery (18,797 cases, 260,246 controls) revealed six associated loci and large genetic similarities with gestational duration. Analysis of the parental transmitted and nontransmitted alleles (n=136,833) shows that 15 of the gestational duration genetic variants act through the maternal genome, whereas 7 act both through the maternal and fetal genomes and 2 act only via the fetal genome. Finally, the maternal effects on gestational duration show signs of antagonistic pleiotropy with the fetal effects on birth weight: maternal alleles that increase gestational duration have negative fetal effects on birth weight. The present study provides insights into the genetic effects on the timing of parturition and the complex maternal-fetal relationship between gestational duration and birth weight.
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| 17. |
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| 18. |
- Stefanucci, Luca, et al.
(författare)
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SMIM1 absence is associated with reduced energy expenditure and excess weight
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Ingår i: Med (New York, N.Y.). - 2666-6340.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1 -/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan. FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure.CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.
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| 19. |
- Westergaard, David, et al.
(författare)
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Genome-wide association meta-analysis identifies five loci associated with postpartum hemorrhage.
- 2024
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Ingår i: Nature genetics. - 1546-1718.
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Tidskriftsartikel (refereegranskat)abstract
- Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severe impact on maternal-fetal health. We identified five genetic loci linked to PPH in a meta-analysis. Functional annotation analysis indicated candidate genes HAND2, TBX3 and RAP2C/FRMD7 at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors. There were strong genetic correlations with birth weight, gestational duration and uterine fibroids. Bleeding in early pregnancy yielded no genome-wide association signals but showed strong genetic correlation with various human traits, suggesting a potentially complex, polygenic etiology. Our results suggest that PPH is related to progesterone signaling dysregulation, whereas early bleeding is a complex trait associated with underlying health and possibly socioeconomic status and may include genetic factors that have not yet been identified.
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