Valence-state mixing and separation in SmBaFe2O5+w

A mixed-valence state, formally denoted as Fe2.5+, is observed in the 300 K Mössbauer spectra of the most reduced samples of SmBaFe2O5+w. Upon cooling below the Verwey-type transition temperature (TV≈200K), the component assigned to Fe2.5+ separates into a high-spin Fe3+ state and an Fe2+ state with an unusually low internal field. The separation of the mixed-valence state at TV is also confirmed by magnetic susceptibility measurements and differential scanning calorimetry. A model is proposed which accounts for the variation of the amount of the mixed-valence state with the oxygen content parameter w.Peer reviewe

Valence-state mixing and separation in SmBaFe2O5+w

A mixed-valence state, formally denoted as Fe2.5+, is observed in the 300 K Mössbauer spectra of the most reduced samples of SmBaFe2O5+w. Upon cooling below the Verwey-type transition temperature (TV≈200K), the component assigned to Fe2.5+ separates into a high-spin Fe3+ state and an Fe2+ state with an unusually low internal field. The separation of the mixed-valence state at TV is also confirmed by magnetic susceptibility measurements and differential scanning calorimetry. A model is proposed which accounts for the variation of the amount of the mixed-valence state with the oxygen content parameter w.Peer reviewe

Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1,2,3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.Peer reviewe

The Contribution of GWAS Loci in Familial Dyslipidemias

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.Peer reviewe

Coronary Artery Disease Risk and Lipidomic Profiles Are Similar in Hyperlipidemias With Family History and Population-Ascertained Hyperlipidemias

Background-We asked whether, after excluding familial hypercholesterolemia, individuals with high low-density lipoprotein cholesterol (LDL-C) or triacylglyceride levels and a family history of the same hyperlipidemia have greater coronary artery disease risk or different lipidomic profiles compared with population-based hyperlipidemias. Methods and Results-We determined incident coronary artery disease risk for 755 members of 66 hyperlipidemic families (>2 first-degree relatives with similar hyperlipidemia) and 19 644 Finnish FINRISK population study participants. We quantified 151 circulating lipid species from 550 members of 73 hyperlipidemic families and 897 FINRISK participants using mass spectrometric shotgun lipidomics. Familial hypercholesterolemia was excluded using functional LDL receptor testing and genotyping. Hyperlipidemias (LDL-C or triacylglycerides >90th population percentile) associated with increased coronary artery disease risk in meta-analysis of the hyperlipidemic families and the population cohort (high LDL-C: hazard ratio, 1.74 [95% CI, 1.48-2.04]; high triacylglycerides: hazard ratio, 1.38 [95% CI 1.09-1.74]). Risk estimates were similar in the family and population cohorts also after adjusting for lipid-lowering medication. In lipidomic profiling, high LDL-C associated with 108 lipid species, and high triacylglycerides associated with 131 lipid species in either cohort (at 5% false discovery rate; P-value range 0.038-2.3x 10(-56)). Lipidomic profiles were highly similar for hyperlipidemic individuals in the families and the population (LDL-C: r=0.80; triacylglycerides: r=0.96; no lipid species deviated between the cohorts). Conclusions-Hyperlipidemias with family history conferred similar coronary artery disease risk as population-based hyperlipidemias. We identified distinct lipidomic profiles associated with high LDL-C and triacylglycerides. Lipidomic profiles were similar between hyperlipidemias with family history and population-ascertained hyperlipidemias, providing evidence of similar and overlapping underlying mechanisms.Peer reviewe

Evidence for valence fluctuation of Fe in Sr_(2)FeMoO_(6-w) double perovskite

In this letter evidence for the formation of a valence-fluctuation state of iron, formally denoted as Fe2.5+, is presented. The system under study is the Sr2FeMoO6−w double perovskite, known for exhibiting a very large magnetoresistance. Samples of Sr2FeMoO6−w were synthesized by means of an encapsulation technique utilizing an Fe getter technique and characterized by 57Fe Mössbauer spectroscopy. From 5 K to room temperature the Mössbauer spectrum is dominated by a component with hyperfine parameter values between those expected for high-spin Fe3+ and high-spin Fe2+.Peer reviewe

Polygenic Hyperlipidemias and Coronary Artery Disease Risk

Background: Hyperlipidemia is a highly heritable risk factor for coronary artery disease (CAD). While monogenic familial hypercholesterolemia associates with severely increased CAD risk, it remains less clear to what extent a high polygenic load of a large number of LDL (low-density lipoprotein) cholesterol (LDL-C) or triglyceride (TG)-increasing variants associates with increased CAD risk. Methods: We derived polygenic risk scores (PRSs) with approximate to 6M variants separately for LDL-C and TG with weights from a UK Biobank-based genome-wide association study with approximate to 324K samples. We evaluated the impact of polygenic hypercholesterolemia and hypertriglyceridemia to lipid levels in 27 039 individuals from the National FINRISK Study (FINRISK) cohort and to CAD risk in 135 638 individuals (13 753 CAD cases) from the FinnGen project (FinnGen). Results: In FINRISK, median LDL-C was 3.39 (95% CI, 3.38-3.40) mmol/L, and it ranged from 2.87 (95% CI, 2.82-2.94) to 3.78 (95% CI, 3.71-3.83) mmol/L between the lowest and highest 5% of the LDL-C PRS distribution. Median TG was 1.19 (95% CI, 1.18-1.20) mmol/L, ranging from 0.97 (95% CI, 0.94-1.00) to 1.55 (95% CI, 1.48-1.61) mmol/L with the TG PRS. In FinnGen, comparing the highest 5% of the PRS to the lowest 95%, CAD odds ratio was 1.36 (95% CI, 1.24-1.49) for the LDL-C PRS and 1.31 (95% CI, 1.19-1.43) for the TG PRS. These estimates were only slightly attenuated when adjusting for a CAD PRS (odds ratio, 1.26 [95% CI, 1.16-1.38] for LDL-C and 1.24 [95% CI, 1.13-1.36] for TG PRS). Conclusions: The CAD risk associated with a high polygenic load for lipid-increasing variants was proportional to their impact on lipid levels and partially overlapping with a CAD PRS. In contrast with a PRS for CAD, the lipid PRSs point to known and directly modifiable risk factors providing additional guidance for clinical translation.Peer reviewe