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- Gorski, Mathias, et al.
(författare)
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Meta-analysis uncovers genome-wide significant variants for rapid kidney function decline
- 2021
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Ingår i: Kidney International. - : Elsevier. - 0085-2538 .- 1523-1755. ; 99:4, s. 926-939
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Tidskriftsartikel (refereegranskat)abstract
- Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m2/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m2 at follow-up among those with eGFRcrea 60 mL/min/1.73m2 or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or LARP4B. Individuals at high compared to those at low genetic risk (8-14 vs 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
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- Drivelegka, Panagiota, et al.
(författare)
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Association between serum level of urate and subclinical atherosclerosis: results from the SCAPIS Pilot
- 2020
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Ingår i: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 22
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Tidskriftsartikel (refereegranskat)abstract
- Background Hyperuricemia is closely associated with cardiovascular disease (CVD). However, it has not been definitively established whether this association is independent of traditional cardiovascular risk factors (CVRFs) and whether it is gender-dependent. The aim of this study was to investigate in a population-based cohort (age range, 50-64 years) stratified by sex the association between the serum urate (SU) concentration and subclinical atherosclerosis, as reflected in the coronary artery calcification (CAC) score, common carotid intima-media thickness (CIMT), and carotid plaque score. Methods The study involved participants in the Swedish CArdioPulmonary bioImage Study (SCAPIS) Pilot cohort (N = 1040; 48.8% males). This pilot cohort is part of the large population-based SCAPIS with 30,000 participants in the age range of 50-64 years, aimed at improving risk prediction for CVD. Subjects with a self-reported previous history of CVD (N = 68) or gout (N = 3) were excluded. The CAC score was assessed with the Agatston method using computed tomography. CIMT and carotid plaques were quantified by ultrasound. The associations between the SU quartiles and different levels of CAC, CIMT, and carotid plaques were assessed by multivariable logistic regression. Results Age, BMI, education level, smoking, physical activity, hs-CRP, hypertension, and dyslipidemia showed no differences between males and females, while CAC (score > 0) and diabetes were both twice as common in men than in women (58% vs 26% and 8% vs 4%, respectively). Higher SU quartiles were in both sexes associated with BMI, hs-CRP, and the prevalence of hypertension, and in women, they were also associated with the prevalence of dyslipidemia. The three upper quartiles of SU (>308 mu mol/L) were linked to higher CAC scores in men, when adjusting for CVRFs, but not in women. CIMT and carotid plaques showed no correlation to SU in either sex. Conclusions Higher levels of SU are associated with the presence of CAC in men but not in women, whereas SU is not associated with CIMT or carotid plaques in either men or women. This implies that the biological effects of SU differ in men and women or that SU has varying effects on different vascular beds or during the different stages of the atherosclerotic process.
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- Escala-Garcia, Maria, et al.
(författare)
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A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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- Falcone, Guido J., et al.
(författare)
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Genetically Elevated LDL Associates with Lower Risk of Intracerebral Hemorrhage
- 2020
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 88:1, s. 56-66
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. Methods: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. Results: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85–0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81–0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65–0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42–0.82; p = 0.002), respectively. Interpretation: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020.
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- Johard, Helena, et al.
(författare)
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HCN Channel Activity Balances Quiescence and Proliferation in Neural Stem Cells and Is a Selective Target for Neuroprotection During Cancer Treatment
- 2020
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Ingår i: Molecular Cancer Research. - 1541-7786 .- 1557-3125. ; 18:10, s. 1522-1533
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Tidskriftsartikel (refereegranskat)abstract
- Children suffering from neurologic cancers undergoing chemotherapy and radiotherapy are at high risk of reduced neurocognitive abilities likely via damage to proliferating neural stem cells (NSC). Therefore, strategies to protect NSCs are needed. We argue that induced cell-cycle arrest/quiescence in NSCs during cancer treatment can represent such a strategy. Here, we show that hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels are dynamically expressed over the cell cycle in NSCs, depolarize the membrane potential, underlie spontaneous calcium oscillations and are required to maintain NSCs in the actively proliferating pool. Hyperpolarizing pharmacologic inhibition of HCN channels during exposure to ionizing radiation protects NSCs cells in neurogenic brain regions of young mice. In contrast, brain tumor-initiating cells, which also express HCN channels, remain proliferative during HCN inhibition.
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| 7. |
- Volgsten, Helena, 1959-, et al.
(författare)
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Motherhood through medically assisted reproduction - characteristics and motivations of Swedish single mothers by choice
- 2021
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Ingår i: Human Fertility. - : Taylor & Francis. - 1464-7273 .- 1742-8149. ; 24:3, s. 219-225
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Tidskriftsartikel (refereegranskat)abstract
- Characteristics and motivations of single mothers by choice were assessed in this pilot study, after new legislation in 2016 allowing access to medically assisted reproduction (MAR). Single women at a university clinic in Sweden were sent a postal questionnaire to their home address (n = 86) and 54 (62.8%) women filled it out and returned it. The women had a mean age of 35.1 years and were well-educated. Most of them worked full-time, were permanently employed, and had a stable income. They had previously had long-term relationships, although these had not been right for having children. More women (61%) could consider embryo donation rather than adoption (50%) (p < 0.05). The motivations most commonly cited for choosing motherhood by MAR was that because of their age, having a child was more important than waiting for the right partner. Nevertheless, they still had hope to find a partner in the future. In conclusion, Swedish single women accepted for MAR are no different from other single mothers by choice: they are financially and socially stable, and choose motherhood by MAR due to their advanced age and not wanting to wait too long in order to meet the right partner.
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