Patterns of reproductive health in inflammatory rheumatic diseases and other immune-mediated diseases: a nationwide registry study.

OBJECTIVES: Rheumatic diseases may impair reproductive success and pregnancy outcomes, but systematic evaluations across diseases are lacking. We conducted a nationwide cohort study to examine the impact of rheumatic diseases on reproductive health measures, comparing the impacts with those of other immune-mediated diseases (IMDs). METHODS: Out of all of the 5 339 804 Finnish citizens, individuals born 1964-1984 and diagnosed with any of the 19 IMDs before age 30 (women) or 35 (men) were matched with 20 controls by birth year, sex, and education. We used data from nationwide health registers to study the impact of IMDs on reproductive health measures, such as reproductive success and, for women, ever having experienced adverse maternal and perinatal outcomes. RESULTS: Several of the rheumatic diseases, particularly SLE, JIA, and seropositive RA, were associated with higher rates of childlessness and fewer children. The risks for pre-eclampsia, newborns being small for gestational age, preterm delivery, non-elective Caesarean sections, and need of neonatal intensive care were increased in many IMDs. Particularly, SLE, SS, type 1 diabetes, and Addison's disease showed >2-fold risks for some of these outcomes. In most rheumatic diseases, moderate (1.1-1.5-fold) risk increases were observed for diverse adverse pregnancy outcomes, with similar effects in IBD, celiac disease, asthma, ITP, and psoriasis. CONCLUSION: Rheumatic diseases have a broad impact on reproductive health, with effects comparable with that of several other IMDs. Of the rheumatic diseases, SLE and SS conferred the largest risk increases on perinatal adverse event outcomes.

Changes in the fine-scale genetic structure of Finland through the 20th century.

Information about individual-level genetic ancestry is central to population genetics, forensics and genomic medicine. So far, studies have typically considered genetic ancestry on a broad continental level, and there is much less understanding of how more detailed genetic ancestry profiles can be generated and how accurate and reliable they are. Here, we assess these questions by developing a framework for individual-level ancestry estimation within a single European country, Finland, and we apply the framework to track changes in the fine-scale genetic structure throughout the 20th century. We estimate the genetic ancestry for 18,463 individuals from the National FINRISK Study with respect to up to 10 genetically and geographically motivated Finnish reference groups and illustrate the annual changes in the fine-scale genetic structure over the decades from 1920s to 1980s for 12 geographic regions of Finland. We detected major changes after a sudden, internal migration related to World War II from the region of ceded Karelia to the other parts of the country as well as the effect of urbanization starting from the 1950s. We also show that while the level of genetic heterogeneity in general increases towards the present day, its rate of change has considerable differences between the regions. To our knowledge, this is the first study that estimates annual changes in the fine-scale ancestry profiles within a relatively homogeneous European country and demonstrates how such information captures a detailed spatial and temporal history of a population. We provide an interactive website for the general public to examine our results.

Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.

Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and MPHOSPH6 loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.

Longitudinal metabolomics of increasing body-mass index and waist-hip ratio reveals two dynamic patterns of obesity pandemic.

BACKGROUND/OBJECTIVE: This observational study dissects the complex temporal associations between body-mass index (BMI), waist-hip ratio (WHR) and circulating metabolomics using a combination of longitudinal and cross-sectional population-based datasets and new systems epidemiology tools. SUBJECTS/METHODS: Firstly, a data-driven subgrouping algorithm was employed to simplify high-dimensional metabolic profiling data into a single categorical variable: a self-organizing map (SOM) was created from 174 metabolic measures from cross-sectional surveys (FINRISK, n = 9708, ages 25-74) and a birth cohort (NFBC1966, n = 3117, age 31 at baseline, age 46 at follow-up) and an expert committee defined four subgroups of individuals based on visual inspection of the SOM. Secondly, the subgroups were compared regarding BMI and WHR trajectories in an independent longitudinal dataset: participants of the Young Finns Study (YFS, n = 1286, ages 24-39 at baseline, 10 years follow-up, three visits) were categorized into the four subgroups and subgroup-specific age-dependent trajectories of BMI, WHR and metabolic measures were modelled by linear regression. RESULTS: The four subgroups were characterised at age 39 by high BMI, WHR and dyslipidemia (designated TG-rich); low BMI, WHR and favourable lipids (TG-poor); low lipids in general (Low lipid) and high low-density-lipoprotein cholesterol (High LDL-C). Trajectory modelling of the YFS dataset revealed a dynamic BMI divergence pattern: despite overlapping starting points at age 24, the subgroups diverged in BMI, fasting insulin (three-fold difference at age 49 between TG-rich and TG-poor) and insulin-associated measures such as triglyceride-cholesterol ratio. Trajectories also revealed a WHR progression pattern: despite different starting points at the age of 24 in WHR, LDL-C and cholesterol-associated measures, all subgroups exhibited similar rates of change in these measures, i.e. WHR progression was uniform regardless of the cross-sectional metabolic profile. CONCLUSIONS: Age-associated weight variation in adults between 24 and 49 manifests as temporal divergence in BMI and uniform progression of WHR across metabolic health strata.

Correction: Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

[This corrects the article DOI: 10.1371/journal.pbio.3000572.].

Abdominal obesity and alcohol use modify the impact of genetic risk for incident advanced liver disease in the general population.

BACKGROUND & AIMS: Genetic variants, abdominal obesity and alcohol use are risk factors for incident liver disease (ILD). We aimed to study whether variants either alone or when aggregated into genetic risk scores (GRSs) associate with ILD, and whether waist-hip ratio (WHR) or alcohol use interacts with this risk. METHODS: Our study included 33 770 persons (mean age 50 years, 47% men) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000) with data on alcohol use, WHR and 63 genotypes associated with liver disease. Data were linked with national health registers for liver-related outcomes (hospitalizations, malignancies and death). Exclusions were baseline clinical liver disease. Mean follow-up time was 12.2 years. Cox regression analyses between variants and ILD were adjusted for age, sex and BMI. RESULTS: Variants in PNPLA3, IFNL4, TM6SF2, FDFT1, PPP1R3B, SERPINA1 and HSD17B13 were associated with ILD. GRSs calculated from these variants were not associated with WHR or alcohol use, but were exponentially associated with ILD (up to 25-fold higher risk in high versus low score). The risk of ILD in individuals with high GRS and high WHR or alcohol use compared with those with none of these risk factors was increased by up to 90-fold. GRSs provided new prognostic information particularly in individuals with high WHR. CONCLUSIONS: The effect of multiple genetic variants on the risk of ILD is potentiated by abdominal obesity and alcohol use. Simple GRSs may help to identify individuals with adverse lifestyle who are at a particularly high risk of ILD.

Persistent organic pollutants associate with liver disease in a Finnish general population sample.

BACKGROUND AND AIMS: Persistent organic pollutants (POPs) have multiple adverse effects on human health. Recent studies show a possible association with liver disease, but population-based data are scarce. In this population-based study, we studied the associations between POPs and biomarkers of liver disease and incident liver disease. METHODS: This study consisted of 2789 adults that participated in the environmental toxin subset of the Finnish health-examination survey, FINRISK 2007. Toxins were measured from serum samples, and standard liver tests and dynamic aspartate aminotransferase-alanine aminotransferase ratio (dAAR) were measured as biomarkers of liver function. Associations between POPs and the biomarkers were then analysed using linear regression. Associations between POPs and incident liver disease (n = 36) were analysed by Cox regression. RESULTS: Organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs) and several perfluorinated alkyl substances exhibited statistically significant positive associations with several biomarkers of liver injury (betacoefficient per SD 0.04-0.14, p < 0.05). These associations were stronger in subgroups of individuals with obesity or non-alcoholic fatty liver disease. OCPs, PCBs and perfluoro-octanoic acid also had significant positive associations with dAAR, which can be used to predict risk of incident severe liver outcomes (beta coefficient per SD 0.05-0.08, p < 0.05). OCPs and PCBs were also significantly and positively associated with incident liver disease (hazard ratio per SD 1.82 95% CI 1.21-2.73, p < 0.01 and hazard ratio per SD 1.69, 95% CI 1.07-2.68, p < 0.05 respectively). CONCLUSIONS: Several POPs show positive associations with markers of liver injury and incident liver disease, suggesting that environmental toxins are important risk factors for chronic liver disease.

Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study.

OBJECTIVE: The objective of the study was to investigate the role of genetic variants in complement proteins in pre-eclampsia. DESIGN: In a case-control study involving 609 cases and 2092 controls, five rare variants in complement factor H (CFH) were identified in women with severe and complicated pre-eclampsia. No variants were identified in controls. SETTING: Pre-eclampsia is a leading cause of maternal and fetal morbidity and mortality. Immune maladaptation, in particular, complement activation that disrupts maternal-fetal tolerance leading to placental dysfunction and endothelial injury, has been proposed as a pathogenetic mechanism, but this remains unproven. POPULATION: We genotyped 609 pre-eclampsia cases and 2092 controls from FINNPEC and the national FINRISK cohorts. METHODS: Complement-based functional and structural assays were conducted in vitro to define the significance of these five missense variants and each compared with wild type. MAIN OUTCOME MEASURES: Secretion, expression and ability to regulate complement activation were assessed for factor H proteins harbouring the mutations. RESULTS: We identified five heterozygous rare variants in complement factor H (L3V, R127H, R166Q, C1077S and N1176K) in seven women with severe pre-eclampsia. These variants were not identified in controls. Variants C1077S and N1176K were novel. Antigenic, functional and structural analyses established that four (R127H, R166Q, C1077S and N1176K) were deleterious. Variants R127H and C1077S were synthesised, but not secreted. Variants R166Q and N1176K were secreted normally but showed reduced binding to C3b and consequently defective complement regulatory activity. No defect was identified for L3V. CONCLUSIONS: These results suggest that complement dysregulation due to mutations in complement factor H is among the pathophysiological mechanisms underlying severe pre-eclampsia.

Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma.

Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (ß = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes, P = 5.96 x 10-9 and 1.07 x 10-13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29% lower glaucoma risk (P = 1.9 x 10-12 for all glaucoma types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma.

Development and validation of a model to predict incident chronic liver disease in the general population: The CLivD score.

BACKGROUND & AIMS: Current screening strategies for chronic liver disease focus on detection of subclinical advanced liver fibrosis but cannot identify those at high future risk of severe liver disease. Our aim was to develop and validate a risk prediction model for incident chronic liver disease in the general population based on widely available factors. METHODS: Multivariable Cox regression analyses were used to develop prediction models for liver-related outcomes with and without laboratory measures (Modellab and Modelnon-lab) in 25,760 individuals aged 40-70 years. Their data were sourced from the Finnish population-based health examination surveys FINRISK 1992-2012 and Health 2000 (derivation cohort). The models were externally validated in the Whitehall II (n = 5,058) and Copenhagen City Heart Study (CCHS) (n = 3,049) cohorts. RESULTS: The absolute rate of incident liver outcomes per 100,000 person-years ranged from 53 to 144. The final prediction model included age, sex, alcohol use (drinks/week), waist-hip ratio, diabetes, and smoking, and Modellab also included gamma-glutamyltransferase values. Internally validated Wolbers' C-statistics were 0.77 for Modellab and 0.75 for Modelnon-lab, while apparent 15-year AUCs were 0.84 (95% CI 0.75-0.93) and 0.82 (95% CI 0.74-0.91). The models identified a small proportion (<2%) of the population with >10% absolute 15-year risk for liver events. Of all liver events, only 10% occurred in participants in the lowest risk category. In the validation cohorts, 15-year AUCs were 0.78 (Modellab) and 0.65 (Modelnon-lab) in the CCHS cohort, and 0.78 (Modelnon-lab) in the Whitehall II cohort. CONCLUSIONS: Based on widely available risk factors, the Chronic Liver Disease (CLivD) score can be used to predict risk of future advanced liver disease in the general population. LAY SUMMARY: Liver disease often progresses silently without symptoms and thus the diagnosis is often delayed until severe complications occur and prognosis becomes poor. In order to identify individuals in the general population who have a high risk of developing severe liver disease in the future, we developed and validated a Chronic Liver Disease (CLivD) risk prediction score, based on age, sex, alcohol use, waist-hip ratio, diabetes, and smoking, with or without measurement of the liver enzyme gamma-glutamyltransferase. The CLivD score can be used as part of health counseling, and for planning further liver investigations and follow-up.

Geographic Variation and Bias in the Polygenic Scores of Complex Diseases and Traits in Finland.

Polygenic scores (PSs) are becoming a useful tool to identify individuals with high genetic risk for complex diseases, and several projects are currently testing their utility for translational applications. It is also tempting to use PSs to assess whether genetic variation can explain a part of the geographic distribution of a phenotype. However, it is not well known how the population genetic properties of the training and target samples affect the geographic distribution of PSs. Here, we evaluate geographic differences, and related biases, of PSs in Finland in a geographically well-defined sample of 2,376 individuals from the National FINRISK study. First, we detect geographic differences in PSs for coronary artery disease (CAD), rheumatoid arthritis, schizophrenia, waist-hip ratio (WHR), body-mass index (BMI), and height, but not for Crohn disease or ulcerative colitis. Second, we use height as a model trait to thoroughly assess the possible population genetic biases in PSs and apply similar approaches to the other phenotypes. Most importantly, we detect suspiciously large accumulations of geographic differences for CAD, WHR, BMI, and height, suggesting bias arising from the population's genetic structure rather than from a direct genotype-phenotype association. This work demonstrates how sensitive the geographic patterns of current PSs are for small biases even within relatively homogeneous populations and provides simple tools to identify such biases. A thorough understanding of the effects of population genetic structure on PSs is essential for translational applications of PSs.

Multivariate Genome-wide Association Analysis of a Cytokine Network Reveals Variants with Widespread Immune, Haematological, and Cardiometabolic Pleiotropy.

Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes.

BMI is positively associated with accelerated epigenetic aging in twin pairs discordant for body mass index.

BACKGROUND: Obesity is a heritable complex phenotype that can increase the risk of age-related outcomes. Biological age can be estimated from DNA methylation (DNAm) using various "epigenetic clocks." Previous work suggests individuals with elevated weight also display accelerated aging, but results vary by epigenetic clock and population. Here, we utilize the new epigenetic clock GrimAge, which closely correlates with mortality. OBJECTIVES: We aimed to assess the cross-sectional association of body mass index (BMI) with age acceleration in twins to limit confounding by genetics and shared environment. METHODS AND RESULTS: Participants were from the Finnish Twin Cohort (FTC; n = 1424), including monozygotic (MZ) and dizygotic (DZ) twin pairs, and DNAm was measured using the Illumina 450K array. Multivariate linear mixed effects models including MZ and DZ twins showed an accelerated epigenetic age of 1.02 months (p-value = 6.1 × 10-12 ) per one-unit BMI increase. Additionally, heavier twins in a BMI-discordant MZ twin pair (ΔBMI >3 kg/m2 ) had an epigenetic age 5.2 months older than their lighter cotwin (p-value = 0.0074). We also found a positive association between log (homeostatic model assessment of insulin resistance) and age acceleration, confirmed by a meta-analysis of the FTC and two other Finnish cohorts (overall effect = 0.45 years, p-value = 4.1 × 10-25 ) from adjusted models. CONCLUSION: We identified significant associations of BMI and insulin resistance with age acceleration based on GrimAge, which were not due to genetic effects on BMI and aging. Overall, these results support a role of BMI in aging, potentially in part due to the effects of insulin resistance.

Genetic and observational evidence: No independent role for cholesterol efflux over static high-density lipoprotein concentration measures in coronary heart disease risk assessment.

BACKGROUND: Observational findings for high-density lipoprotein (HDL)-mediated cholesterol efflux capacity (HDL-CEC) and coronary heart disease (CHD) appear inconsistent, and knowledge of the genetic architecture of HDL-CEC is limited. OBJECTIVES: A large-scale observational study on the associations of HDL-CEC and other HDL-related measures with CHD and the largest genome-wide association study (GWAS) of HDL-CEC. PARTICIPANTS/METHODS: Six independent cohorts were included with follow-up data for 14,438 participants to investigate the associations of HDL-related measures with incident CHD (1,570 events). The GWAS of HDL-CEC was carried out in 20,372 participants. RESULTS: HDL-CEC did not associate with CHD when adjusted for traditional risk factors and HDL cholesterol (HDL-C). In contradiction, almost all HDL-related concentration measures associated consistently with CHD after corresponding adjustments. There were no genetic loci associated with HDL-CEC independent of HDL-C and triglycerides. CONCLUSION: HDL-CEC is not unequivocally associated with CHD in contrast to HDL-C, apolipoprotein A-I, and most of the HDL subclass particle concentrations.

Mitochondrial bioenergetic pathways in blood leukocyte transcriptome decrease after intensive weight loss but are rescued following weight regain in female physique athletes.

Prolonged periods of energy deficit leading to weight loss induce metabolic adaptations resulting in reduced energy expenditure, but the mechanisms for energy conservation are incompletely understood. We examined 42 healthy athletic females (age 27.5 ± 4.0 years, body mass index 23.4 ± 1.7 kg/m2 ) who volunteered into either a group dieting for physique competition (n = 25) or a control group (n = 17). The diet group substantially reduced their energy intake and moderately increased exercise levels to induce loss of fat mass that was regained during a voluntary weight regain period. The control group maintained their typical lifestyle habits and body mass as instructed. From the diet group, fasting blood samples were drawn at baseline (PRE), after 4- to 5-month weight loss (PRE-MID), and after 4- to 5-month weight regain (MID-POST) as well as from the control group at similar intervals. Blood was analyzed to determine leukocyte transcriptome by RNA-Sequencing and serum metabolome by nuclear magnetic resonance (NMR) platform. The intensive weight loss period induced several metabolic adaptations, including a prominent suppression of transcriptomic signature for mitochondrial OXPHOS and ribosome biogenesis. The upstream regulator analysis suggested that this reprogramming of cellular energy metabolism may be mediated via AMPK/PGC1-α signaling and mTOR/eIF2 signaling-dependent pathways. Our findings show for the first time that prolonged energy deprivation induced modulation of mitochondrial metabolism can be observed through minimally invasive measures of leukocyte transcriptome and serum metabolome at systemic level, suggesting that adaptation to energy deficit is broader in humans than previously thought.

Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants.

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66-0.89]) and lower household income (OR = 0.77 [0.66-0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38-0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32-0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26-0.37]), lower-income (OR = 0.66 [0.57-0.77]), lower subjective health (OR = 0.72 [0.61-0.83]), and increased mortality (Cox's HR = 1.55 [1.21-1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.

Lipoprotein signatures of cholesteryl ester transfer protein and HMG-CoA reductase inhibition.

Cholesteryl ester transfer protein (CETP) inhibition reduces vascular event risk, but confusion surrounds its effects on low-density lipoprotein (LDL) cholesterol. Here, we clarify associations of genetic inhibition of CETP on detailed lipoprotein measures and compare those to genetic inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). We used an allele associated with lower CETP expression (rs247617) to mimic CETP inhibition and an allele associated with lower HMGCR expression (rs12916) to mimic the well-known effects of statins for comparison. The study consists of 65,427 participants of European ancestries with detailed lipoprotein subclass profiling from nuclear magnetic resonance spectroscopy. Genetic associations were scaled to 10% reduction in relative risk of coronary heart disease (CHD). We also examined observational associations of the lipoprotein subclass measures with risk of incident CHD in 3 population-based cohorts totalling 616 incident cases and 13,564 controls during 8-year follow-up. Genetic inhibition of CETP and HMGCR resulted in near-identical associations with LDL cholesterol concentration estimated by the Friedewald equation. Inhibition of HMGCR had relatively consistent associations on lower cholesterol concentrations across all apolipoprotein B-containing lipoproteins. In contrast, the associations of the inhibition of CETP were stronger on lower remnant and very-low-density lipoprotein (VLDL) cholesterol, but there were no associations on cholesterol concentrations in LDL defined by particle size (diameter 18-26 nm) (-0.02 SD LDL defined by particle size; 95% CI: -0.10 to 0.05 for CETP versus -0.24 SD, 95% CI -0.30 to -0.18 for HMGCR). Inhibition of CETP was strongly associated with lower proportion of triglycerides in all high-density lipoprotein (HDL) particles. In observational analyses, a higher triglyceride composition within HDL subclasses was associated with higher risk of CHD, independently of total cholesterol and triglycerides (strongest hazard ratio per 1 SD higher triglyceride composition in very large HDL 1.35; 95% CI: 1.18-1.54). In conclusion, CETP inhibition does not appear to affect size-specific LDL cholesterol but is likely to lower CHD risk by lowering concentrations of other atherogenic, apolipoprotein B-containing lipoproteins (such as remnant and VLDLs). Inhibition of CETP also lowers triglyceride composition in HDL particles, a phenomenon reflecting combined effects of circulating HDL, triglycerides, and apolipoprotein B-containing particles and is associated with a lower CHD risk in observational analyses. Our results reveal that conventional composite lipid assays may mask heterogeneous effects of emerging lipid-altering therapies.

Attribution of diabetes to the development of severe liver disease in the general population.

BACKGROUND AND AIMS: Diabetes is associated with advanced liver disease and predicts mortality regardless of the primary aetiology of the liver disease. Even a family history of diabetes has been linked to advanced liver fibrosis in non-alcoholic fatty liver disease (NAFLD). However, the fraction of liver-related outcomes in the general population that are attributable to diabetes remains unclear. METHODS: The population attributable fraction (PAF) of diabetes for liver disease as a time-dependent exposure was estimated in the Finnish FINRISK study (n = 28 787) and the British Whitehall II study (n = 7855). We also assessed the predictive ability of a family history of diabetes for liver-related outcomes. Incident diabetes data were from drug purchase/reimbursement and healthcare registries (FINRISK) or follow-up examinations (Whitehall II). Incident severe liver outcomes were identified through linkage with national healthcare registries. RESULTS: Diabetes was associated with a two-fold risk of liver-related outcomes in both the FINRISK (HR, 1.92; p < .001) and Whitehall II (HR, 2.37; p < .001) cohorts, and this remained significant after adjusting for multiple confounders. PAF analyses demonstrated that diabetes explained 12-14% of the risk for severe liver-related outcomes after 10 and 20 years of follow-up. Also, maternal diabetes increased the risk of liver-related outcomes in the FINRISK (HR, 1.43; p = .044) and Whitehall II (HR, 2.04; p = .051) cohorts. CONCLUSION: Approximately 12%-14% of severe liver-related outcomes are attributable to diabetes at the population level. The association between maternal diabetes and liver disease might suggest a mitochondrial genetic mechanism.

Identification of healthspan-promoting genes in Caenorhabditis elegans based on a human GWAS study.

To find drivers of healthy ageing, a genome-wide association study (GWAS) was performed in healthy and unhealthy older individuals. Healthy individuals were defined as free from cardiovascular disease, stroke, heart failure, major adverse cardiovascular event, diabetes, dementia, cancer, chronic obstructive pulmonary disease (COPD), asthma, rheumatism, Crohn's disease, malabsorption or kidney disease. Six single nucleotide polymorphisms (SNPs) with unknown function associated with ten human genes were identified as candidate healthspan markers. Thirteen homologous or closely related genes were selected in the model organism C. elegans for evaluating healthspan after targeted RNAi-mediated knockdown using pathogen resistance, muscle integrity, chemotaxis index and the activity of known longevity and stress response pathways as healthspan reporters. In addition, lifespan was monitored in the RNAi-treated nematodes. RNAi knockdown of yap-1, wwp-1, paxt-1 and several acdh genes resulted in heterogeneous phenotypes regarding muscle integrity, pathogen resistance, chemotactic behaviour, and lifespan. Based on these observations, we hypothesize that their human homologues WWC2, CDKN2AIP and ACADS may play a role in health maintenance in the elderly.

Effects of dexmedetomidine, propofol, sevoflurane and S-ketamine on the human metabolome: A randomised trial using nuclear magnetic resonance spectroscopy.

BACKGROUND: Pharmacometabolomics uses large-scale data capturing methods to uncover drug-induced shifts in the metabolic profile. The specific effects of anaesthetics on the human metabolome are largely unknown. OBJECTIVE: We aimed to discover whether exposure to routinely used anaesthetics have an acute effect on the human metabolic profile. DESIGN: Randomised, open-label, controlled, parallel group, phase IV clinical drug trial. SETTING: The study was conducted at Turku PET Centre, University of Turku, Finland, 2016 to 2017. PARTICIPANTS: One hundred and sixty healthy male volunteers were recruited. The metabolomic data of 159 were evaluable. INTERVENTIONS: Volunteers were randomised to receive a 1-h exposure to equipotent doses (EC50 for verbal command) of dexmedetomidine (1.5 ng ml-1; n  = 40), propofol (1.7 µg ml-1; n  = 40), sevoflurane (0.9% end-tidal; n  = 39), S-ketamine (0.75 µg ml-1; n  = 20) or placebo (n = 20). MAIN OUTCOME MEASURES: Metabolite subgroups of apolipoproteins and lipoproteins, cholesterol, glycerides and phospholipids, fatty acids, glycolysis, amino acids, ketone bodies, creatinine and albumin and the inflammatory marker GlycA, were analysed with nuclear magnetic resonance spectroscopy from arterial blood samples collected at baseline, after anaesthetic administration and 70 min post-anaesthesia. RESULTS: All metabolite subgroups were affected. Statistically significant changes vs. placebo were observed in 11.0, 41.3, 0.65 and 3.9% of the 155 analytes in the dexmedetomidine, propofol, sevoflurane and S-ketamine groups, respectively. Dexmedetomidine increased glucose, decreased ketone bodies and affected lipoproteins and apolipoproteins. Propofol altered lipoproteins, fatty acids, glycerides and phospholipids and slightly increased inflammatory marker glycoprotein acetylation. Sevoflurane was relatively inert. S-ketamine increased glucose and lactate, whereasbranched chain amino acids and tyrosine decreased. CONCLUSION: A 1-h exposure to moderate doses of routinely used anaesthetics led to significant and characteristic alterations in the metabolic profile. Dexmedetomidine-induced alterations mirror a2-adrenoceptor agonism. Propofol emulsion altered the lipid profile. The inertness of sevoflurane might prove useful in vulnerable patients. S-ketamine induced amino acid alterations might be linked to its suggested antidepressive properties. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02624401.