Abdominal obesity and circulating metabolites : A twin study approach

Objective. To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors. Subjects and methods. Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (r(g)) and environmental (re) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs (intrapair BMI difference >= 3 kg/m(2)). Results. Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (r(g) = 0.40), glycoprotein (r(g) = 0.37), serum triglycerides (r(g) = 0.36), BCAAs (r(g) = 0.30-0.40), HDL particle diameter (r(g) = -0.33) and HDL cholesterol (r(g) = -0.30). The effect of acquired obesity within the discordant MZ pairs was particularly strong for atherogenic lipoproteins. Conclusions. A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability. (C) 2015 Elsevier Inc. All rights reserved.Peer reviewe

GeV Gamma-Ray Attenuation and the High-Redshift UV Background

We present new calculations of the evolving UV background out to the epoch of cosmological reionization and make predictions for the amount of GeV gamma-ray attenuation by electron-positron pair production. Our results are based on recent semi-analytic models of galaxy formation, which provide predictions of the dust-extinguished UV radiation field due to starlight, and empirical estimates of the contribution due to quasars. We account for the reprocessing of ionizing photons by the intergalactic medium. We test whether our models can reproduce estimates of the ionizing background at high redshift from flux decrement analysis and proximity effect measurements from quasar spectra, and identify a range of models that can satisfy these constraints. Pair-production against soft diffuse photons leads to a spectral cutoff feature for gamma rays observed between 10 and 100 GeV. This cutoff varies with redshift and the assumed star formation and quasar evolution models. We find only negligible amounts of absorption for gamma rays observed below 10 GeV for any emission redshift. With observations of high-redshift sources in sufficient numbers by the Fermi Gamma-ray Space Telescope and new ground-based instruments it should be possible to constrain the extragalactic background light in the UV and optical portion of the spectrum.Comment: 19 pages, 12 figures, Accepted for publication in MNRAS, this version includes minor correction

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