sample sizes and a high resolution of clinical phenotypes and medication are required, while accounting for variables known to affect the gut microbiome. Finally, drug effects are often dose-dependent, yet dosage is rarely considered in microbiome studies.To overcome these limitations, we propose a general framework for separating disease from treatment associations in multi-omics cross-sectional studies and apply it to gut metagenomic, host clinical and metabolomic measurements of 2,173 European residents from the multicentre MetaCardis cohort. The MetaCardis cohort includes patients with metabolic syndrome, severe and morbid obesity, T2D, acute and chronic coronary artery disease and heart failure, and healthy control individuals. Considering cardiometabolic disease (CMD) and herein frequently prescribed medications, we investigated drug-hostmicrobiome associations for eight major indications (antidiabetic,
Background Lung cancer incidence and prevalence is increasing worldwide and there is a focus on prevention, early detection, and development of new treatments which will impact the epidemiological patterns of lung cancer. The clinical characteristics and the trends in incidence, mortality, and prevalence of lung cancer in Denmark from 2006 through 2015 are described and a model for predicting the future epidemiological profile of lung cancer through 2030 is introduced. Methods The study population comprised all cases of lung cancer, registered in the Danish Cancer Registry, who were alive on January 1, 2006 or had a first-time ever diagnosis of lung cancer during 2006 through 2015. Information on morphology, stage of the disease, comorbidity and survival was obtained from other Danish health registers. Based on NORDCAN data and estimated patient mortality rates as well as prevalence proportions for the period 2006 through 2015, future case numbers of annual incidence, deaths, and resulting prevalence were projected. Results A total of 44.291 patients were included in the study. A shift towards more patients diagnosed with lower stages and with adenocarcinoma was observed. The incidence increased and the patient mortality rate decreased significantly, with a doubling of the prevalence during the observation period. We project that the numbers of prevalent cases of lung cancer in Denmark most likely will increase from about 10,000 at the end of 2015 to about 23,000 at the end of 2030. Conclusions Our findings support that lung cancer is being diagnosed at an earlier stage, that incidence will stop increasing, that mortality will decrease further, and that the prevalence will continue to increase substantially. Projections of cancer incidence, mortality, and prevalence are important for planning health services and should be updated at regular intervals.
ObjectiveCandidate genes for non-alcoholic fatty liver disease (NAFLD) identified by a bioinformatics approach were examined for variant associations to quantitative traits of NAFLD-related phenotypes.Research Design and MethodsBy integrating public database text mining, trans-organism protein-protein interaction transferal, and information on liver protein expression a protein-protein interaction network was constructed and from this a smaller isolated interactome was identified. Five genes from this interactome were selected for genetic analysis. Twenty-one tag single-nucleotide polymorphisms (SNPs) which captured all common variation in these genes were genotyped in 10,196 Danes, and analyzed for association with NAFLD-related quantitative traits, type 2 diabetes (T2D), central obesity, and WHO-defined metabolic syndrome (MetS).Results273 genes were included in the protein-protein interaction analysis and EHHADH, ECHS1, HADHA, HADHB, and ACADL were selected for further examination. A total of 10 nominal statistical significant associations (P<0.05) to quantitative metabolic traits were identified. Also, the case-control study showed associations between variation in the five genes and T2D, central obesity, and MetS, respectively. Bonferroni adjustments for multiple testing negated all associations.ConclusionsUsing a bioinformatics approach we identified five candidate genes for NAFLD. However, we failed to provide evidence of associations with major effects between SNPs in these five genes and NAFLD-related quantitative traits, T2D, central obesity, and MetS.
BackgroundA genome-wide association study (GWAS) using metabolite concentrations as proxies for enzymatic activity, suggested that two variants: rs2014355 in the gene encoding short-chain acyl-coenzyme A dehydrogenase (ACADS) and rs11161510 in the gene encoding medium-chain acyl-coenzyme A dehydrogenase (ACADM) impair fatty acid β-oxidation. Chronic exposure to fatty acids due to an impaired β-oxidation may down-regulate the glucose-stimulated insulin release and result in an increased risk of type 2 diabetes (T2D). We aimed to investigate whether the two variants associate with altered insulin release following an oral glucose load or with T2D.MethodsThe variants were genotyped using KASPar® PCR SNP genotyping system and investigated for associations with estimates of insulin release and insulin sensitivity following an oral glucose tolerance test (OGTT) in a random sample of middle-aged Danish individuals (n ACADS = 4,324; n ACADM = 4,337). The T2D-case-control study involved a total of ~8,300 Danish individuals (n ACADS = 8,313; n ACADM = 8,344).ResultsIn glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS associated with reduced measures of serum insulin at 30 min following an oral glucose load (per allele effect (β) = -3.8% (-6.3%;-1.3%), P = 0.003), reduced incremental area under the insulin curve (β = -3.6% (-6.3%;-0.9%), P = 0.009), reduced acute insulin response (β = -2.2% (-4.2%;0.2%), P = 0.03), and with increased insulin sensitivity ISIMatsuda (β = 2.9% (0.5%;5.2%), P = 0.02). The C-allele did not associate with two other measures of insulin sensitivity or with a derived disposition index. The C-allele was not associated with T2D in the case-control analysis (OR 1.07, 95% CI 0.96-1.18, P = 0.21). rs11161510 of ACADM did not associate with any indices of glucose-stimulated insulin release or with T2D.ConclusionsIn glucose-tolerant individuals the minor C-allele of rs2014355 of ACADS was associated with reduced measures of glucose-stimulated insulin release during an OGTT, a finding which in part may be mediated through an impaired β-oxidation of fatty acids.
ObjectiveTo investigate the genetic influence of 48 type 2 diabetes susceptibility variants on disease progression measured as risk of early prescription redemption of glucose lowering drugs in screen-detected patients with type 2 diabetes.MethodsWe studied type 2 diabetes progression in 1,480 patients with screen-detected type 2 diabetes from the ADDITION-Denmark study using information of redeemed prescriptions from the Register of Medicinal Products Statistics from 2001–2009 in Denmark. Patients were cluster randomized by general practitioners, who were randomized to treat type 2 diabetes according to either a conventional or a multifactorial intensive treatment algorithm. We investigated the genetic influence on diabetes progression by constructing a genetic risk score (GRS) of all 48 validated type 2 diabetes susceptibility variants, a GRS of 11 variants linked to β-cell function and a GRS of 3 variants linked to insulin sensitivity and assessed the association between number of risk alleles and time from diagnosis until first redeemed prescription of either any glucose lowering drug or an insulin drug.ResultsThe GRS linked to insulin sensitivity only nominally increased the risk of an early prescription redemption with an insulin drug by 39% (HR [95% C.I.] = 1.39 [1.09–1.77], p = 0.009] in patients randomized to the intensive treatment group. Furthermore, the strongest univariate predictors of diabetes progression for the intensive treatment group (measured as time to first insulin) were younger age (HR [95% C.I.] = 0.96 [0.93–0.99]), increased BMI (1.05 [1.01–1.09]), increased HbA1c (1.50 [1.36–.66]), increased TG (1.24 [1.11–1.39]) and reduced fasting serum HDL (0.37 [0.17–0.80]) at baseline. Similar results were obtained for the conventional treatment group.ConclusionHigher levels of HbA1c, fasting circulating levels of triglyceride, lower HDL, larger BMI and younger age are significant determinants of early pharmacological intervention in type 2 diabetes. However, known common type 2 diabetes-associated gene variants do not appear to significantly affect disease progression.
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