Ceramides are molecular lipids implicated in apoptosis, inflammation, obesity, and insulin resistance. An earlier study reported that ceramides were associated with fatal outcome among patients with ...coronary heart disease. Here, we examined whether ceramides are associated with major adverse cardiovascular events (MACEs) among apparently healthy individuals.
FINRISK 2002 is a population-based risk factor survey, which recruited men and women aged 25 to 74 years. The cohort was followed up until the end of 2014. We quantified 4 circulating ceramides, Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1), in 8101 serum samples by a targeted liquid chromatography-tandem mass spectrometry assay. Primary outcome of interest was incident MACE (n=813). Secondary analyses were performed for MACE death (n=116) without previous nonfatal MACE and for recurrent MACE (n=226) among survivors of a previous incident MACE. We used Cox proportional hazard models adjusted for the Framingham covariates to determine the association of ceramides with the outcomes. Of the ceramide species, Cer(d18:1/18:0) had the strongest association with incident MACE and the highest unadjusted hazard ratio of 1.31 (95% confidence interval, 1.21-1.41), which remained significant at 1.21 (95% confidence interval, 1.11-1.33) after Framingham risk factor adjustments. The hazard ratios were generally stronger for recurrent and fatal events than for first events. Clinical net reclassification improvement was 7.5% (P=6.9×10
) for Cer(d18:1/18:0).
Distinct serum ceramides are associated with the risk of incident MACE in apparently healthy individuals. These results should encourage more detailed analyses of ceramides in cardiovascular pathobiology and suggest new biomarkers of MACE risk.
During the past few years, various novel statistical methods have been developed for fine-mapping with the use of summary statistics from genome-wide association studies (GWASs). Although these ...approaches require information about the linkage disequilibrium (LD) between variants, there has not been a comprehensive evaluation of how estimation of the LD structure from reference genotype panels performs in comparison with that from the original individual-level GWAS data. Using population genotype data from Finland and the UK Biobank, we show here that a reference panel of 1,000 individuals from the target population is adequate for a GWAS cohort of up to 10,000 individuals, whereas smaller panels, such as those from the 1000 Genomes Project, should be avoided. We also show, both theoretically and empirically, that the size of the reference panel needs to scale with the GWAS sample size; this has important consequences for the application of these methods in ongoing GWAS meta-analyses and large biobank studies. We conclude by providing software tools and by recommending practices for sharing LD information to more efficiently exploit summary statistics in genetics research.
The goal of fine-mapping in genomic regions associated with complex diseases and traits is to identify causal variants that point to molecular mechanisms behind the associations. Recent fine-mapping ...methods using summary data from genome-wide association studies rely on exhaustive search through all possible causal configurations, which is computationally expensive.
We introduce FINEMAP, a software package to efficiently explore a set of the most important causal configurations of the region via a shotgun stochastic search algorithm. We show that FINEMAP produces accurate results in a fraction of processing time of existing approaches and is therefore a promising tool for analyzing growing amounts of data produced in genome-wide association studies and emerging sequencing projects.
FINEMAP v1.0 is freely available for Mac OS X and Linux at http://www.christianbenner.com
: christian.benner@helsinki.fi or matti.pirinen@helsinki.fi.
The collection of fecal material and developments in sequencing technologies have enabled standardised and non-invasive gut microbiome profiling. Microbiome composition from several large cohorts ...have been cross-sectionally linked to various lifestyle factors and diseases. In spite of these advances, prospective associations between microbiome composition and health have remained uncharacterised due to the lack of sufficiently large and representative population cohorts with comprehensive follow-up data. Here, we analyse the long-term association between gut microbiome variation and mortality in a well-phenotyped and representative population cohort from Finland (n = 7211). We report robust taxonomic and functional microbiome signatures related to the Enterobacteriaceae family that are associated with mortality risk during a 15-year follow-up. Our results extend previous cross-sectional studies, and help to establish the basis for examining long-term associations between human gut microbiome composition, incident outcomes, and general health status.
Although genetic risk scores have been used to predict hypertension, their utility in the clinical setting remains uncertain. Our study comprised N=218 792 FinnGen participants (mean age 58 years, ...56% women) and N=22 624 well-phenotyped FINRISK participants (mean age 50 years, 53% women). We used public genome-wide association data to compute polygenic risk scores (PRSs) for systolic and diastolic blood pressure (BP). Using time-to-event analysis, we then assessed (1) the association of BP PRSs with hypertension and cardiovascular disease (CVD) in FinnGen and (2) the improvement in model discrimination when combining BP PRSs with the validated 4- and 10-year clinical risk scores for hypertension and CVD in FINRISK. In FinnGen, compared with having a 20 to 80 percentile range PRS, a PRS in the highest 2.5% conferred 2.3-fold (95% CI, 2.2–2.4) risk of hypertension and 10.6 years (95% CI, 9.9–11.4) earlier hypertension onset. In subgroup analyses, this risk was only 1.6-fold (95% CI, 1.5–1.7) for late-onset hypertension (age ≥55 years) but 2.8-fold (95% CI, 2.6–2.9) for early-onset hypertension (age <55 years). Elevated systolic BP PRS also conferred 1.3-fold (95% CI, 1.2–1.4) risk of CVD and 2.3 years (95% CI, 1.6–3.1) earlier onset. In FINRISK, systolic and diastolic BP PRSs improved clinical risk prediction of hypertension (but not CVD), increasing the C statistics by 0.7% (95% CI, 0.3–1.1). We demonstrate that genetic information improves hypertension risk prediction. BP PRSs together with traditional risk factors could improve prediction of hypertension and particularly early-onset hypertension, which confers substantial CVD risk.
Background and Aims
The effects of alcohol use in nonalcoholic fatty liver disease are unclear. We investigated the impact of alcohol use in fatty liver disease on incident liver, cardiovascular, and ...malignant disease, as well as death.
Approach and Results
Our study comprised 8,345 persons with hepatic steatosis (fatty liver index >60) who participated in health‐examination surveys (FINRISK 1992‐2012 or Health 2000), with available data on baseline alcohol intake. Main exclusions were baseline clinical liver disease, viral hepatitis, ethanol intake >50 g/day, and current abstainers. Data were linked with national registers for hospital admissions, malignancies, and death regarding liver, cardiovascular, and malignant disease, as well as all‐cause death. Adjustment were for multiple confounders. Alcohol consumption showed a dose‐dependent risk increase for incident advanced liver disease and malignancies. Consuming 10‐19 g/day of alcohol in general or 0‐9 g/day as nonwine beverages doubled the risk for advanced liver disease compared to lifetime abstainers. In contrast, alcohol intake up to 49 g/day was associated with a 22%‐40% reduction of incident cardiovascular disease (CVD). We observed a J‐shaped association between alcohol intake and all‐cause death with a maximal risk reduction of 21% (95% confidence interval, 5%‐34%) at alcohol intake of 0‐9 g/day compared to lifetime abstainers. However, these benefits on CVD and mortality were only observed in never smokers. Alcohol intake >30 g/day yielded increased risk estimates for mortality compared to lifetime abstainers. In a subpopulation with longitudinal data, alcohol intake remained stable over time in >80% of subjects.
Conclusions
Even low alcohol intake in fatty liver disease is associated with increased risks for advanced liver disease and cancer. Low to moderate alcohol use is associated with reduced mortality and CVD risk but only among never smokers.
Blood lipids and metabolites are markers of current health and future disease risk. Here, we describe plasma nuclear magnetic resonance (NMR) biomarker data for 118,461 participants in the UK ...Biobank. The biomarkers cover 249 measures of lipoprotein lipids, fatty acids, and small molecules such as amino acids, ketones, and glycolysis metabolites. We provide an atlas of associations of these biomarkers to prevalence, incidence, and mortality of over 700 common diseases ( nightingalehealth.com/atlas ). The results reveal a plethora of biomarker associations, including susceptibility to infectious diseases and risk of various cancers, joint disorders, and mental health outcomes, indicating that abundant circulating lipids and metabolites are risk markers beyond cardiometabolic diseases. Clustering analyses indicate similar biomarker association patterns across different disease types, suggesting latent systemic connectivity in the susceptibility to a diverse set of diseases. This work highlights the value of NMR based metabolic biomarker profiling in large biobanks for public health research and translation.
Women are at higher risk for subarachnoid hemorrhage (SAH) than men for unknown reasons. Also cumulative effects of smoking have been neglected among prospective studies. We studied associations ...between smoking habits and SAH and interactions between known SAH risk factors in a prospective population-based study.
The population-based FINRISK study cohort of 65 521 individuals was followed up for 1.38 million person-years. We used the Cox proportional hazards model to calculate hazard ratios and evaluated additive and multiplicative interactions between study variables, with all analyses adjusted for known SAH risk factors.
During follow-up, we identified 492 SAHs (266 women). Smoking had a linear dose-dependent and cumulative association with risk for SAH in both sexes. Women smoking >20 cigarettes per day had a hazard ratio of 8.35 (95% confidence interval, 3.86-18.06) compared with a hazard ratio of 2.76 (95% confidence interval, 1.68-4.52) in men in the same cigarettes per day group. Hazard ratios differed by sex in all cigarettes per day and pack-year categories; this association was stronger in women in all categories (P=0.01). When an adjusted model included interaction terms between sex and cigarettes per day or pack-years, female sex was no longer an independent SAH risk factor. Former smokers had a markedly decreased risk for SAH in both sexes when compared with current smokers.
Smoking has a dose-dependent and cumulative association with SAH risk, and this risk is highest in female heavy smokers. Vulnerability to smoking seems to explain in part the increased SAH risk in women.
Individuals with a later chronotype (evening types) tend to have unhealthier behaviors and increased morbidity and mortality as compared with those with an earlier chronotype (morning types). ...However, the role of genetics in explaining evening types’ adverse health and health behavior is unclear. Our aim was to study genetic associations of chronotype among 8433 Finns from the cross-sectional National FINRISK 2007 and 2012 studies. First, we studied associations between chronotype and 20 key clock genes with a candidate-gene approach and then performed a full genome-wide association study (GWAS) of chronotype. We also developed a genetic risk score (GRS) for chronotype based on 313 single nucleotide polymorphisms (SNPs) that have previously been associated with chronotype. Chronotype was assessed with a shortened version of Horne and Östberg’s Morningness-Eveningness Questionnaire (sMEQ), and for comparison, we also used the single self-evaluation question on chronotype from the questionnaire. Linear and logistic regression was used for statistical analysis assuming additive effects. The clock gene analysis revealed 1 independent association signal within NR1D2 (lead SNP rs4131403) that was associated with chronotype (p < 0.05; as based on both chronotype assessment methods). The GWAS analysis did not yield any genome-wide significant associations (p > 5 × 10−8). However, higher GRS was associated with evening chronotype (p < 0.001; as based on both chronotype assessment methods). In conclusion, our findings indicated novel genetic associations between chronotype and the NR1D2 clock gene, which has previously been associated with carbohydrate and lipid metabolism. Furthermore, the GRS was able to capture the genetic aspect of chronotype in our study population. These findings expand our knowledge of the genetic basis of chronotype.
Circulating cytokines and growth factors are regulators of inflammation and have been implicated in autoimmune and metabolic diseases. In this genome-wide association study (GWAS) of up to 8,293 ...Finns we identified 27 genome-widely significant loci (p < 1.2 × 10−9) for one or more cytokines. Fifteen of the associated variants had expression quantitative trait loci in whole blood. We provide genetic instruments to clarify the causal roles of cytokine signaling and upstream inflammation in immune-related and other chronic diseases. We further link inflammatory markers with variants previously associated with autoimmune diseases such as Crohn disease, multiple sclerosis, and ulcerative colitis and hereby elucidate the molecular mechanisms underpinning these diseases and suggest potential drug targets.
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