Circulating metabolites and the risk of type 2 diabetes : a prospective study of 11,896 young adults from four Finnish cohorts

Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk.Peer reviewe

Polygenic and clinical risk scores and their impact on age at onset and prediction of cardiometabolic diseases and common cancers

Polygenic risk scores (PRSs) have shown promise in predicting susceptibility to common diseases1,2,3. We estimated their added value in clinical risk prediction of five common diseases, using large-scale biobank data (FinnGen; n = 135,300) and the FINRISK study with clinical risk factors to test genome-wide PRSs for coronary heart disease, type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer. We evaluated the lifetime risk at different PRS levels, and the impact on disease onset and on prediction together with clinical risk scores. Compared to having an average PRS, having a high PRS contributed 21% to 38% higher lifetime risk, and 4 to 9 years earlier disease onset. PRSs improved model discrimination over age and sex in type 2 diabetes, atrial fibrillation, breast cancer and prostate cancer, and over clinical risk in type 2 diabetes, breast cancer and prostate cancer. In all diseases, PRSs improved reclassification over clinical thresholds, with the largest net reclassification improvements for early-onset coronary heart disease, atrial fibrillation and prostate cancer. This study provides evidence for the additional value of PRSs in clinical disease prediction. The practical applications of polygenic risk information for stratified screening or for guiding lifestyle and medical interventions in the clinical setting remain to be defined in further studies.Peer reviewe

Circulating metabolites and the risk of type 2 diabetes: a prospective study of 11,896 young adults from four Finnish cohorts

Aims/hypothesis Metabolomics technologies have identified numerous blood biomarkers for type 2 diabetes risk in case-control studies of middle-aged and older individuals. We aimed to validate existing and identify novel metabolic biomarkers predictive of future diabetes in large cohorts of young adults. Methods NMR metabolomics was used to quantify 229 circulating metabolic measures in 11,896 individuals from four Finnish observational cohorts (baseline age 24-45 years). Associations between baseline metabolites and risk of developing diabetes during 8-15 years of follow-up (392 incident cases) were adjusted for sex, age, BMI and fasting glucose. Prospective metabolite associations were also tested with fasting glucose, 2 h glucose and HOMA-IR at follow-up. Results Out of 229 metabolic measures, 113 were associated with incident type 2 diabetes in meta-analysis of the four cohorts (ORs per 1 SD: 0.59-1.50; p< 0.0009). Among the strongest biomarkers of diabetes risk were branched-chain and aromatic amino acids (OR 1.31-1.33) and triacylglycerol within VLDL particles (OR 1.33-1.50), as well as linoleic n-6 fatty acid (OR 0.75) and non-esterified cholesterol in large HDL particles (OR 0.59). The metabolic biomarkers were more strongly associated with deterioration in post-load glucose and insulin resistance than with future fasting hyperglycaemia. A multi-metabolite score comprised of phenylalanine, non-esterified cholesterol in large HDL and the ratio of cholesteryl ester to total lipid in large VLDL was associated with future diabetes risk (OR 10.1 comparing individuals in upper vs lower fifth of the multi-metabolite score) in one of the cohorts (mean age 31 years). Conclusions/interpretation Metabolic biomarkers across multiple molecular pathways are already predictive of the long-term risk of diabetes in young adults. Comprehensive metabolic profiling may help to target preventive interventions for young asymptomatic individuals at increased risk

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.Peer reviewe

The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease

Objective This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.Methods BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases. Results Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases.Conclusions Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.</p

Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.</p

Author Correction:Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article

The Role of Inflammatory Cytokines as Intermediates in the Pathway from Increased Adiposity to Disease

Objective This study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease. Methods BMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI-driven cytokines on risk of obesity-related diseases. Results Observationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08-1.19), 1.08 (95% CI: 1.04-1.14), and 1.13 (95% CI: 1.04-1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00-1.06). There was inconsistent evidence for a protective role of MCP-1 against inflammatory bowel diseases. Conclusions Observational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI-driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.Peer reviewe

Functional characterization of six SLCO1B1 (OATP1B1) variants observed in Finnish individuals with a psychotic disorder

Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide variants (SNVs) occurring in Finnish individuals with a psychotic disorder on expression and functionality of the OATP1B1 protein. The SUPER-Finland study has performed exome sequencing on 9381 individuals with at least one psychotic episode during their lifetime. SLCO1B1 SNVs were annotated with PHRED-scaled combined annotation-dependent (CADD) scores and the Ensembl variant effect predictor. In vitro functionality studies were conducted for the SNVs with a PHRED-scaled CADD score of &gt;10 and predicted to be missense. To estimate possible changes in transport activity caused by the variants, transport of 2′,7′-dichlorofluorescein (DCF) in OATP1B1-expressing HEK293 cells was measured. According to the findings, additional tests with rosuvastatin and estrone sulfate were conducted. The amount of OATP1B1 in crude membrane fractions was quantified using a liquid chromatography tandem mass spectrometry-based quantitative targeted absolute proteomics analysis. Six rare missense variants of SLCO1B1 were identified in the study population, located in transmembrane helix 3: c.317T&gt;C (p.106I&gt;T), intracellular loop 2: c.629G&gt;T (p.210G&gt;V), c.633A&gt;G (p.211I&gt;M), c.639T&gt;A (p.213N&gt;L), transmembrane helix 6: 820A&gt;G (p.274I&gt;V), and the C-terminal end: 2005A&gt;C (p.669N&gt;H). Of these variants, SLCO1B1 c.629G&gt;T (p.210G&gt;V) resulted in the loss of in vitro function, abolishing the uptake of DCF, estrone sulfate, and rosuvastatin and reducing the membrane protein expression to 31% of reference OATP1B1. Of the six rare missense variants, SLCO1B1 c.629G&gt;T (p.210G&gt;V) causes a loss of function of OATP1B1 transport in vitro and severely decreases membrane protein abundance. Carriers of SLCO1B1 c.629G&gt;T might be susceptible to altered pharmacokinetics of OATP1B1 substrate drugs and might have increased likelihood of adverse drug effects such as statin-associated musculoskeletal symptoms