• GWAS have greatly increased the knowledge about obesity genetics. • Common forms of obesity are polygenic with small effects sizes of each variant. • The largest genetic effects size on obesity are ...reported for FTO variants. • We expect large advances over the coming years regarding knowledge on gene function.
Until just a few years ago, the genetic determinants of obesity and metabolic syndrome were largely unknown, with the exception of a few forms of monogenic extreme obesity. Since genome-wide association studies (GWAS) became available, large advances have been made. The first single nucleotide polymorphism robustly associated with increased body mass index (BMI) was in 2007 mapped to a gene with for the time unknown function. This gene, now known as fat mass and obesity associated (FTO) has been repeatedly replicated in several ethnicities and is affecting obesity by regulating appetite. Since the first report from a GWAS of obesity, an increasing number of markers have been shown to be associated with BMI, other measures of obesity or fat distribution and metabolic syndrome. This systematic review of obesity GWAS will summarize genome-wide significant findings for obesity and metabolic syndrome and briefly give a few suggestions of what is to be expected in the next few years.
Attributes and predictors of long COVID Sudre, Carole H; Murray, Benjamin; Varsavsky, Thomas ...
Nature medicine,
04/2021, Letnik:
27, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called 'long COVID', are rising but little is known about prevalence, risk factors or whether it is possible to predict a ...protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app
. A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76-4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services.
The genetic background of general obesity and fat distribution is different, pointing to separate underlying physiology. Here, we searched for metabolites and lipoprotein particles associated with ...fat distribution, measured as waist/hip ratio adjusted for fat mass (WHRadjfatmass), and general adiposity measured as percentage fat mass.
The sex-stratified association of 791 metabolites detected by liquid chromatography-mass spectrometry (LC-MS) and 91 lipoprotein particles measured by nuclear magnetic spectroscopy (NMR) with WHRadjfatmass and fat mass were assessed using three population-based cohorts: EpiHealth (n = 2350) as discovery cohort, with PIVUS (n = 603) and POEM (n = 502) as replication cohorts.
Of the 193 LC-MS-metabolites being associated with WHRadjfatmass in EpiHealth (false discovery rate (FDR) <5%), 52 were replicated in a meta-analysis of PIVUS and POEM. Nine metabolites, including ceramides, sphingomyelins or glycerophosphatidylcholines, were inversely associated with WHRadjfatmass in both sexes. Two of the sphingomyelins (d18:2/24:1, d18:1/24:2 and d18:2/24:2) were not associated with fat mass (p>0.50). Out of 91, 82 lipoprotein particles were associated with WHRadjfatmass in EpiHealth and 42 were replicated. Fourteen of those were associated in both sexes and belonged to very-large or large HDL particles, all being inversely associated with both WHRadjfatmass and fat mass.
Two sphingomyelins were inversely linked to body fat distribution in both men and women without being associated with fat mass, while very-large and large HDL particles were inversely associated with both fat distribution and fat mass. If these metabolites represent a link between an impaired fat distribution and cardiometabolic diseases remains to be established.
The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies ...are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations.
We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index SDS-BMI). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study.
This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.
Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be ...established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor β1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.
Insulin resistance (IR) is a precursor of type 2 diabetes (T2D), and improved risk prediction and understanding of the pathogenesis are needed. We used a novel high-throughput 92-protein assay to ...identify circulating biomarkers for HOMA of IR in two cohorts of community residents without diabetes (n = 1,367) (mean age 73 ± 3.6 years). Adjusted linear regression identified cathepsin D and confirmed six proteins (leptin, renin, interleukin-1 receptor antagonist IL-1ra, hepatocyte growth factor, fatty acid-binding protein 4, and tissue plasminogen activator t-PA) as IR biomarkers. Mendelian randomization analysis indicated a positive causal effect of IR on t-PA concentrations. Two biomarkers, IL-1ra (hazard ratio HR 1.28, 95% CI 1.03-1.59) and t-PA (HR 1.30, 1.02-1.65) were associated with incident T2D, and t-PA predicted 5-year transition to hyperglycemia (odds ratio 1.30, 95% CI 1.02-1.65). Additional adjustment for fasting glucose rendered both coefficients insignificant and revealed an association between renin and T2D (HR 0.79, 0.62-0.99). LASSO regression suggested a risk model including IL-1ra, t-PA, and the Framingham Offspring Study T2D score, but prediction improvement was nonsignificant (difference in C-index 0.02, 95% CI -0.08 to 0.12) over the T2D score only. In conclusion, proteomic blood profiling indicated cathepsin D as a new IR biomarker and suggested a causal effect of IR on t-PA.
Dogs may be beneficial in reducing cardiovascular risk in their owners by providing social support and motivation for physical activity. We aimed to investigate the association of dog ownership with ...incident cardiovascular disease (CVD) and death in a register-based prospective nation-wide cohort (n = 3,432,153) with up to 12 years of follow-up. Self-reported health and lifestyle habits were available for 34,202 participants in the Swedish Twin Register. Time-to-event analyses with time-updated covariates were used to calculate hazard ratios (HR) with 95% confidence intervals (CI). In single- and multiple-person households, dog ownership (13.1%) was associated with lower risk of death, HR 0.67 (95% CI, 0.65-0.69) and 0.89 (0.87-0.91), respectively; and CVD death, HR 0.64 (0.59-0.70), and 0.85 (0.81-0.90), respectively. In single-person households, dog ownership was inversely associated with cardiovascular outcomes (HR composite CVD 0.92, 95% CI, 0.89-0.94). Ownership of hunting breed dogs was associated with lowest risk of CVD. Further analysis in the Twin Register could not replicate the reduced risk of CVD or death but also gave no indication of confounding by disability, comorbidities or lifestyle factors. In conclusion, dog ownership appears to be associated with lower risk of CVD in single-person households and lower mortality in the general population.
We tested whether pregnant and non-pregnant women differ in COVID-19 symptom profile and severity, and we extended previous investigations on hospitalized pregnant women to those who did not require ...hospitalization. Two female community-based cohorts (18-44 years) provided longitudinal (smartphone application, N = 1,170,315, n = 79 pregnant tested positive) and cross-sectional (web-based survey, N = 1,344,966, n = 134 pregnant tested positive) data, prospectively collected through self-participatory citizen surveillance in UK, Sweden and USA. Pregnant and non-pregnant were compared for frequencies of events, including SARS-CoV-2 testing, symptoms and hospitalization rates. Multivariable regression was used to investigate symptoms severity and comorbidity effects. Pregnant and non-pregnant women positive for SARS-CoV-2 infection were not different in syndromic severity, except for gastrointestinal symptoms. Pregnant were more likely to have received testing, despite reporting fewer symptoms. Pre-existing lung disease was most closely associated with syndromic severity in pregnant hospitalized. Heart and kidney diseases and diabetes increased risk. The most frequent symptoms among non-hospitalized women were anosmia 63% pregnant, 92% non-pregnant and headache 72%, 62%. Cardiopulmonary symptoms, including persistent cough 80% and chest pain 73%, were more frequent among pregnant who were hospitalized. Consistent with observations in non-pregnant populations, lung disease and diabetes were associated with increased risk of more severe SARS-CoV-2 infection during pregnancy.
Currently studies aiming for the comprehensive metabolomics profiling of measured total fat (%) as well as fat distribution in both sexes are lacking. In this work, bioimpedance analysis was applied ...to measure total fat (%) and fat distribution (trunk to leg ratio). Liquid chromatography-mass spectrometry-based untargeted metabolomics was employed to profile the metabolic signatures of total fat (%) and fat distribution in 3447 participants from three Swedish cohorts (EpiHealth, POEM and PIVUS) using a discovery-replication cross-sectional study design. Total fat (%) and fat distribution were associated with 387 and 120 metabolites in the replication cohort, respectively. Enriched metabolic pathways for both total fat (%) and fat distribution included protein synthesis, branched-chain amino acids biosynthesis and metabolism, glycerophospholipid metabolism and sphingolipid metabolism. Four metabolites were mainly related to fat distribution: glutarylcarnitine (C5-DC), 6-bromotryptophan, 1-stearoyl-2-oleoyl-GPI (18:0/18:1) and pseudouridine. Five metabolites showed different associations with fat distribution in men and women: quinolinate, (12Z)-9,10-dihydroxyoctadec-12-enoate (9,10-DiHOME), two sphingomyelins and metabolonic lactone sulfate. To conclude, total fat (%) and fat distribution were associated with a large number of metabolites, but only a few were exclusively associated with fat distribution and of those metabolites some were associated with sex*fat distribution. Whether these metabolites mediate the undesirable effects of obesity on health outcomes remains to be further investigated.
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