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1.  Genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease 
Scott, Robert A. | Freitag, Daniel F. | Li, Li | Chu, Audrey Y. | Surendran, Praveen | Young, Robin | Grarup, Niels | Stancáková, Alena | Chen, Yuning | V.Varga, Tibor | Yaghootkar, Hanieh | Luan, Jian'an | Zhao, Jing Hua | Willems, Sara M. | Wessel, Jennifer | Wang, Shuai | Maruthur, Nisa | Michailidou, Kyriaki | Pirie, Ailith | van der Lee, Sven J. | Gillson, Christopher | Olama, Ali Amin Al | Amouyel, Philippe | Arriola, Larraitz | Arveiler, Dominique | Aviles-Olmos, Iciar | Balkau, Beverley | Barricarte, Aurelio | Barroso, Inês | Garcia, Sara Benlloch | Bis, Joshua C. | Blankenberg, Stefan | Boehnke, Michael | Boeing, Heiner | Boerwinkle, Eric | Borecki, Ingrid B. | Bork-Jensen, Jette | Bowden, Sarah | Caldas, Carlos | Caslake, Muriel | Cupples, L. Adrienne | Cruchaga, Carlos | Czajkowski, Jacek | den Hoed, Marcel | Dunn, Janet A. | Earl, Helena M. | Ehret, Georg B. | Ferrannini, Ele | Ferrieres, Jean | Foltynie, Thomas | Ford, Ian | Forouhi, Nita G. | Gianfagna, Francesco | Gonzalez, Carlos | Grioni, Sara | Hiller, Louise | Jansson, Jan-Håkan | Jørgensen, Marit E. | Jukema, J. Wouter | Kaaks, Rudolf | Kee, Frank | Kerrison, Nicola D. | Key, Timothy J. | Kontto, Jukka | Kote-Jarai, Zsofia | Kraja, Aldi T. | Kuulasmaa, Kari | Kuusisto, Johanna | Linneberg, Allan | Liu, Chunyu | Marenne, Gaëlle | Mohlke, Karen L. | Morris, Andrew P. | Muir, Kenneth | Müller-Nurasyid, Martina | Munroe, Patricia B. | Navarro, Carmen | Nielsen, Sune F. | Nilsson, Peter M. | Nordestgaard, Børge G. | Packard, Chris J. | Palli, Domenico | Panico, Salvatore | Peloso, Gina M. | Perola, Markus | Peters, Annette | Poole, Christopher J. | Quirós, J. Ramón | Rolandsson, Olov | Sacerdote, Carlotta | Salomaa, Veikko | Sánchez, María-José | Sattar, Naveed | Sharp, Stephen J. | Sims, Rebecca | Slimani, Nadia | Smith, Jennifer A. | Thompson, Deborah J. | Trompet, Stella | Tumino, Rosario | van der A, Daphne L. | van der Schouw, Yvonne T. | Virtamo, Jarmo | Walker, Mark | Walter, Klaudia | Abraham, Jean E. | Amundadottir, Laufey T. | Aponte, Jennifer L. | Butterworth, Adam S. | Dupuis, Josée | Easton, Douglas F. | Eeles, Rosalind A. | Erdmann, Jeanette | Franks, Paul W. | Frayling, Timothy M. | Hansen, Torben | Howson, Joanna M. M. | Jørgensen, Torben | Kooner, Jaspal | Laakso, Markku | Langenberg, Claudia | McCarthy, Mark I. | Pankow, James S. | Pedersen, Oluf | Riboli, Elio | Rotter, Jerome I. | Saleheen, Danish | Samani, Nilesh J. | Schunkert, Heribert | Vollenweider, Peter | O'Rahilly, Stephen | Deloukas, Panos | Danesh, John | Goodarzi, Mark O. | Kathiresan, Sekar | Meigs, James B. | Ehm, Margaret G. | Wareham, Nicholas J. | Waterworth, Dawn M.
Science translational medicine  2016;8(341):341ra76.
Regulatory authorities have indicated that new drugs to treat type 2 diabetes (T2D) should not be associated with an unacceptable increase in cardiovascular risk. Human genetics may be able to inform development of antidiabetic therapies by predicting cardiovascular and other health endpoints. We therefore investigated the association of variants in 6 genes that encode drug targets for obesity or T2D with a range of metabolic traits in up to 11,806 individuals by targeted exome sequencing, and follow-up in 39,979 individuals by targeted genotyping, with additional in silico follow up in consortia. We used these data to first compare associations of variants in genes encoding drug targets with the effects of pharmacological manipulation of those targets in clinical trials. We then tested the association those variants with disease outcomes, including coronary heart disease, to predict cardiovascular safety of these agents. A low-frequency missense variant (Ala316Thr;rs10305492) in the gene encoding glucagon-like peptide-1 receptor (GLP1R), the target of GLP1R agonists, was associated with lower fasting glucose and lower T2D risk, consistent with GLP1R agonist therapies. The minor allele was also associated with protection against heart disease, thus providing evidence that GLP1R agonists are not likely to be associated with an unacceptable increase in cardiovascular risk. Our results provide an encouraging signal that these agents may be associated with benefit, a question currently being addressed in randomised controlled trials. Genetic variants associated with metabolic traits and multiple disease outcomes can be used to validate therapeutic targets at an early stage in the drug development process.
doi:10.1126/scitranslmed.aad3744
PMCID: PMC5219001  PMID: 27252175
2.  Elevated levels of circulating CDH5 and FABP1 in association with human drug‐induced liver injury 
Liver International  2016;37(1):132-140.
Abstract
Background & Aims
The occurrence of drug‐induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls.
Methods
An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins.
Results
We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid‐binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated.
Conclusions
These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.
doi:10.1111/liv.13174
PMCID: PMC5215406  PMID: 27224670
drug‐induced liver injury; biomarker discovery; affinity proteomics; plasma profiling; suspension bead arrays
3.  CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer's disease 
Proteomics. Clinical Applications  2016;10(12):1242-1253.
Purpose
This study is part of a larger effort aiming to expand the knowledge of brain‐enriched proteins in human cerebrospinal fluid (CSF) and to provide novel insight into the relation between such proteins and different neurodegenerative diseases.
Experimental design
Here 280 brain‐enriched proteins in CSF from patients with Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are profiled. In total, 441 human samples of ventricular CSF collected post mortem and lumbar CSF collected ante mortem are analyzed using 376 antibodies in a suspension bead array setup, utilizing a direct labelling approach.
Results
Among several proteins displaying differentiated profiles between sample groups, we focus here on two synaptic proteins, neuromodulin (GAP43) and neurogranin (NRGN). They are both found at elevated levels in CSF from AD patients in two independent cohorts, providing disease‐associated profiles in addition to verifying and strengthening previously observed patterns. Increased levels are also observed for patients for whom the AD diagnosis was not established at the time of sampling.
Conclusions and clinical relevance
These findings indicate that analyzing the brain‐enriched proteins in CSF is of particular interest to increase the understanding of the CSF proteome and its relation to neurodegenerative disorders. In addition, this study lends support to the notion that measurements of these synaptic proteins could potentially be of great relevance in future diagnostic tests for AD.
doi:10.1002/prca.201500150
PMCID: PMC5157753  PMID: 27604409
Alzheimer's disease; Cerebrospinal fluid; Neurogranin; Neuromodulin; Neuroproteomics
4.  Serum Autoantibody Profiling of Patients with Paraneoplastic and Non-Paraneoplastic Autoimmune Retinopathy 
PLoS ONE  2016;11(12):e0167909.
Purpose
Although multiple serum antiretinal autoantibodies (ARAs) have been reported in patients with paraneoplastic and non-paraneoplastic autoimmune retinopathy ((n)pAIR), not all retinal antigens involved in (n)pAIR are specified. This study aims to serologically identify patients with presumed (n)pAIR through determination of both known and unknown ARAs by autoantibody profiling.
Methods
An antigen suspension bead array using 188 different antigens representing 97 ocular proteins was performed to detect ARAs in serum samples of patients with presumed (n)pAIR (n = 24), uveitis (n = 151) and cataract (n = 21). Logistic regressions were used to estimate the associations between ocular antigens and diagnosis. Validation of interphotoreceptor matrix proteoglycan 2 (IMPG2) and recoverin antigens was performed by immunohistochemistry and immunoblot, respectively.
Results
Samples of patients with presumed (n)pAIR exhibited a broad spectrum of ARAs. We identified retinal antigens that have already been described previously (e.g. recoverin), but also identified novel ARA targets. Most ARAs were not specific for (n)pAIR since their presence was also observed in patients with cataract or uveitis. High titers of autoantibodies directed against photoreceptor-specific nuclear receptor and retinol-binding protein 3 were more common in patients with presumed (n)pAIR compared to uveitis (p = 0.015 and p = 0.018, respectively). The presence of all other ARAs did not significantly differ between groups. In patients with presumed (n)pAIR, anti-recoverin autoantibodies were the most prevalent ARAs. Validation of bead array results by immunohistochemistry (anti-IMPG2) and immunoblot (anti-recoverin) showed concordant results in (n)pAIR patients.
Conclusions
Patients with (n)pAIR are characterized by the presence of a broad spectrum of ARAs. The diagnosis of (n)pAIR cannot be based on the mere presence of serum ARAs, as these are also commonly present in uveitis as well as in age-related cataract patients.
doi:10.1371/journal.pone.0167909
PMCID: PMC5145218  PMID: 27930731
5.  Multiplexed protein profiling by sequential affinity capture 
Proteomics  2016;16(8):1251-1256.
Antibody microarrays enable parallelized and miniaturized analysis of clinical samples, and have proven to provide novel insights for the analysis of different proteomes. However, there are concerns that the performance of such direct labeling and single antibody assays are prone to off‐target binding due to the sample context. To improve selectivity and sensitivity while maintaining the possibility to conduct multiplexed protein profiling, we developed a multiplexed and semi‐automated sequential capture assay. This novel bead‐based procedure encompasses a first antigen capture, labeling of captured protein targets on magnetic particles, combinatorial target elution and a read‐out by a secondary capture bead array. We demonstrate in a proof‐of‐concept setting that target detection via two sequential affinity interactions reduced off‐target contribution, while lowered background and noise levels, improved correlation to clinical values compared to single binder assays. We also compared sensitivity levels with single binder and classical sandwich assays, explored the possibility for DNA‐based signal amplification, and demonstrate the applicability of the dual capture bead‐based antibody microarray for biomarker analysis. Hence, the described concept enhances the possibilities for antibody array assays to be utilized for protein profiling in body fluids and beyond.
doi:10.1002/pmic.201500398
PMCID: PMC5071697  PMID: 26935855
Affinity proteomics; Antibody arrays; Plasma profiling; Suspension bead arrays
6.  The Association of Multiple Biomarkers of Iron Metabolism and Type 2 Diabetes - the EPIC-InterAct Study 
Diabetes care  2016;39(4):572-581.
Objective
Observational studies show an association between ferritin and type 2 diabetes (T2D), suggesting a role of high iron stores for T2D development. However, ferritin is influenced by factors other than iron stores, which is less the case for other biomarkers of iron metabolism. We investigate associations of ferritin, transferrin saturation (TSAT), serum iron and transferrin with T2D incidence, to clarify the role of iron in the pathogenesis of T2D.
Research and Design Methods
The EPIC-InterAct study includes 12,403 incident T2D cases and a representative sub-cohort of 16,154 individuals from a European cohort with 3.99 million person-years of follow-up. We studied the prospective association of ferritin, TSAT, serum iron and transferrin with incident T2D in 11,052 cases and a random sub-cohort of 15,182 individuals and assessed whether these associations differed by subgroups of the population.
Results
Higher levels of ferritin and transferrin were associated with a higher risk of T2D [HR in men and women, respectively: 1.07 (95% CI: 1.01; 1.12) and 1.12 (1.05; 1.19) per 100 μg/L higher ferritin level; 1.11 (1.00; 1.24) and 1.22 (1.12; 1.33) per 0.5 g/L higher transferrin level] after adjustment for age, centre, BMI, physical activity, smoking status, education, hsCRP, ALT and GGT. Elevated TSAT (≥45% versus <45%) was associated with a lower risk of T2D in women [0.68 (0.54; 0.86)] but was not statistically significantly associated in men [0.90 (0.75; 1.08)]. Serum iron was not associated with T2D. The association of ferritin with T2D was stronger among leaner individuals (pinteraction<0.01).
Conclusions
The pattern of association of TSAT and transferrin with T2D suggests that the underlying relationship between iron stores and T2D is more complex than the simple link suggested by the association of ferritin with T2D.
doi:10.2337/dc15-0257
PMCID: PMC5058436  PMID: 26861925
7.  Affinity proteomics discovers decreased levels of AMFR in plasma from Osteoporosis patients 
Proteomics. Clinical Applications  2015;10(6):681-690.
Purpose
Affinity proteomic approaches by antibody bead arrays enable multiplexed analysis of proteins in body fluids. In the presented study, we investigated blood plasma within osteoporosis to discovery differential protein profiles and to propose novel biomarkers candidates for subsequent studies.
Experimental design
Starting with 4608 antibodies and plasma samples from 22 women for an untargeted screening, a set of 72 proteins were suggested for further analysis. Complementing these with targets from literature and other studies, a targeted bead array of 180 antibodies was built to profile for 92 proteins in plasma samples of 180 women from two independent population‐based studies.
Results
Differential profiles between osteoporosis patients and matched controls were discovered for 12 proteins in at least one of the two study sets. Among these targets, the levels of autocrine motility factor receptor (AMFR) were concordantly lower in plasma of female osteoporosis patients. Subsequently, verification of anti‐AMFR antibody selectivity was conducted using high‐density peptide and protein arrays, and Western blotting.
Conclusions and clinical relevance
Further validation in additional study sets will be needed to determine the clinical value of the observed decrease in AMFR plasma levels in osteoporosis patients, but AMFR may aid our understanding of disease mechanisms and could support existing tools for diagnosis and monitoring of patient mobility within osteoporosis.
doi:10.1002/prca.201400167
PMCID: PMC5029581  PMID: 25689831
Antibody bead arrays; Biomarker discovery; Osteoporosis; Plasma
8.  Acute-phase proteins and incidence of diabetes: a population-based cohort study 
Acta Diabetologica  2016;53(6):981-989.
Aims
To examine the relationship between plasma levels of the acute-phase proteins ceruloplasmin, alpha-1-antitrypsin, orosomucoid, haptoglobin and C-reactive protein (CRP), and incidence of diabetes in the population-based Malmö Diet and Cancer Study—Cardiovascular Cohort (MDCS-CC).
Methods
The study population consists of 4246 participants (aged 46–67 years, 60.8 % women) with no previous history of diabetes. Participants were followed, and incidence of diabetes was assessed by linkage with national registers and a clinical re-examination of the cohort. Cox proportional hazard regression analysis was used to compare incidence of diabetes in relation to sex-specific quartiles of the acute-phase proteins.
Results
During a mean follow-up period of 15.6 ± 3.4 years, a total of 390 participants were diagnosed with diabetes. Orosomucoid, haptoglobin, and CRP showed a significant increased risk of diabetes after adjustment for potential confounders. However, further adjustments for fasting glucose at baseline resulted in significant association only for CRP. The multivariable-adjusted hazard ratios (HR: 4th vs. 1st quartile) were 1.18 (95 % CI: 0.83–1.67; p = 0.51), 1.19 (CI: 0.85–1.62; p = 0.10), and 1.40 (CI: 1.01–1.95; p = 0.046) for orosomucoid, haptoglobin, and CRP respectively.
Conclusion
The study demonstrated that there are associations between orosomucoid, haptoglobin and CRP and the risk of incidence of diabetes. However, after additional adjustment for fasting glucose levels at baseline, the association stayed significant only for CRP.
doi:10.1007/s00592-016-0903-8
PMCID: PMC5114318  PMID: 27581604
Acute-phase proteins; Diabetes; Incidence; Ceruloplasmin; Alpha-1-antitrypsin; Orosomucoid; Haptoglobin; CRP
9.  Dimethylglycine Deficiency and the Development of Diabetes 
Diabetes  2015;64(8):3010-3016.
Experimental studies have suggested possible protective effects of dimethylglycine (DMG) on glucose metabolism. DMG is degraded to glycine through a DMG-dehydrogenase (DMGDH)-catalyzed reaction, and this is the only known pathway for the breakdown of DMG in mammals. In this study, we aimed to identify the strongest genetic determinant of circulating DMG concentration and to investigate its associations with metabolic traits and incident diabetes. In the cohort with full metabolomics data (n = 709), low plasma levels of DMG were significantly associated with higher blood glucose levels (P = 3.9E–4). In the genome-wide association study (GWAS) of the discovery cohort (n = 5,205), the strongest genetic signal of plasma DMG was conferred by rs2431332 at the DMGDH locus, where the major allele was associated with lower DMG levels (P = 2.5E–15). The same genetic variant (major allele of rs2431332) was also significantly associated with higher plasma insulin (P = 0.019), increased HOMA insulin resistance (P = 0.019), and an increased risk of incident diabetes (P = 0.001) in the pooled analysis of the discovery cohort together with the two replication cohorts (n = 20,698 and n = 7,995). These data are consistent with a possible causal role of DMG deficiency in diabetes development and encourage future studies examining if inhibition of DMGDH, or alternatively, supplementation of DMG, might prove useful for the treatment/prevention of diabetes.
doi:10.2337/db14-1863
PMCID: PMC4512219  PMID: 25795213
10.  Evaluation of the BD Max Enteric Parasite Panel for Clinical Diagnostics 
Journal of Clinical Microbiology  2016;54(2):443-444.
We compared the performance of the BD Max enteric parasite panel to routine microscopy and an in-house PCR for the detection of Giardia intestinalis, Entamoeba histolytica, and Cryptosporidium spp. The enteric parasite panel showed good specificity for all targets and good sensitivity for E. histolytica and Cryptosporidium spp. Sensitivity for G. intestinalis with the BD Max enteric parasite panel was equivalent to that with microscopy.
doi:10.1128/JCM.02100-15
PMCID: PMC4733193  PMID: 26582832
11.  Association of Plasma Phospholipid n-3 and n-6 Polyunsaturated Fatty Acids with Type 2 Diabetes: The EPIC-InterAct Case-Cohort Study 
PLoS Medicine  2016;13(7):e1002094.
Background
Whether and how n-3 and n-6 polyunsaturated fatty acids (PUFAs) are related to type 2 diabetes (T2D) is debated. Objectively measured plasma PUFAs can help to clarify these associations.
Methods and Findings
Plasma phospholipid PUFAs were measured by gas chromatography among 12,132 incident T2D cases and 15,919 subcohort participants in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct study across eight European countries. Country-specific hazard ratios (HRs) were estimated using Prentice-weighted Cox regression and pooled by random-effects meta-analysis. We also systematically reviewed published prospective studies on circulating PUFAs and T2D risk and pooled the quantitative evidence for comparison with results from EPIC-InterAct. In EPIC-InterAct, among long-chain n-3 PUFAs, α-linolenic acid (ALA) was inversely associated with T2D (HR per standard deviation [SD] 0.93; 95% CI 0.88–0.98), but eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not significantly associated. Among n-6 PUFAs, linoleic acid (LA) (0.80; 95% CI 0.77–0.83) and eicosadienoic acid (EDA) (0.89; 95% CI 0.85–0.94) were inversely related, and arachidonic acid (AA) was not significantly associated, while significant positive associations were observed with γ-linolenic acid (GLA), dihomo-GLA, docosatetraenoic acid (DTA), and docosapentaenoic acid (n6-DPA), with HRs between 1.13 to 1.46 per SD. These findings from EPIC-InterAct were broadly similar to comparative findings from summary estimates from up to nine studies including between 71 to 2,499 T2D cases. Limitations included potential residual confounding and the inability to distinguish between dietary and metabolic influences on plasma phospholipid PUFAs.
Conclusions
These large-scale findings suggest an important inverse association of circulating plant-origin n-3 PUFA (ALA) but no convincing association of marine-derived n3 PUFAs (EPA and DHA) with T2D. Moreover, they highlight that the most abundant n6-PUFA (LA) is inversely associated with T2D. The detection of associations with previously less well-investigated PUFAs points to the importance of considering individual fatty acids rather than focusing on fatty acid class.
Using a large European cohort, Nita Forouhi and colleagues investigate the association between the concentration of polyunsaturated fatty acids measured in plasma and risk of developing type 2 diabetes.
Author Summary
Why Was This Study Done?
Most dietary guidelines recommend the consumption of polyunsaturated fatty acids for cardiovascular health, but it is unclear whether or how n-3 and n-6 types of polyunsaturated fatty acids are related to type 2 diabetes.
Health concerns have been raised previously about a diet high in linoleic acid (n-6 fatty acid), but its association with type 2 diabetes is unclear.
Major limitations in previous studies have included the error-prone subjective assessment of the habitual consumption of polyunsaturated fatty acids when dietary intakes were evaluated and a small number of type 2 diabetes cases (n = 71 to 673) when objective biomarkers of polyunsaturated fatty acids were measured.
What Did the Researchers Do and Find?
We measured circulating individual polyunsaturated fatty acids in the blood samples of individuals within a large study from across eight countries of Europe among a reference sample of 15,919 individuals as well as 12,132 individuals who subsequently developed diabetes. Individuals were followed up for an average of approximately 10 y.
We investigated the association between individual polyunsaturated fatty acids and the risk of future type 2 diabetes using statistical analyses that accounted for factors that could be potential alternative explanations for any observed associations.
We found that higher levels of blood alpha-linolenic acid, a plant-origin n-3 fatty acid, and n-6 linoleic acid, the most abundant type of polyunsaturated fatty acid, were associated with a lower risk of future type 2 diabetes. In contrast, higher levels of four other minor individual n-6 fatty acids were associated with higher type 2 diabetes risk, while the blood marine-origin n-3 fatty acids were not associated with future diabetes.
What Do These Findings Mean?
Our findings show that it is important to consider individual circulating polyunsaturated fatty acids for association with type 2 diabetes risk, rather than placing emphasis on the class of circulating polyunsaturated fatty acids.
We found that blood n-6 linoleic acid, the most abundant polyunsaturated fatty acid, is inversely associated with type 2 diabetes.
We found no evidence that blood total n-6 polyunsaturated fatty acids may elevate the risk of type 2 diabetes, but several individual minor blood n-6 polyunsaturated fatty acids were associated with increased type 2 diabetes risk, highlighting the importance of polyunsaturated fatty acid metabolism in the development of type 2 diabetes.
doi:10.1371/journal.pmed.1002094
PMCID: PMC4951144  PMID: 27434045
12.  Non-hemodynamic predictors of arterial stiffness after 17 years of follow-up: the Malmö Diet and Cancer study 
Journal of Hypertension  2015;33(5):957-965.
Background:
Arterial stiffness plays a fundamental role in the development of hypertension and is a risk factor for both cardiovascular disease and mortality. The stiffening that occurs with increasing age has, in numerous cross-sectional studies, been shown to be associated with several cardiovascular risk factors. This observational study aims to characterize the predictive and cross-sectional markers focusing on the non-hemodynamic component of arterial stiffness.
Method:
In all, 2679 men and women from Malmö, Sweden, were examined at baseline during 1991–1994, and again at follow-up during 2007–2012 (mean age 72 years, 38% men). Follow-up examination included measurement of arterial stiffness by carotid–femoral pulse wave velocity (c-fPWV), after a mean period of 17 years. The associations between c-fPWV and risk markers were calculated with multiple linear regression.
Results:
The results indicated that for both sexes, waist circumference (β = 0.17, P < 0.001), fasting glucose (β = 0.13, P < 0.001), Homeostatic Model Assessment – Insulin Resistance (β = 0.10, P < 0.001), triglycerides (β = 0.10, P < 0.001), and high-density lipoprotein cholesterol (β = −0.08, P < 0.001) were all predictors of cfPWV adjusted for mean arterial pressure and heart rate, as well as for classical cardiovascular risk factors and drug treatment. There were no associations between baseline or follow-up low-density lipoprotein cholesterol, smoking, or eGFR and c-fPWV.
Conclusion:
The non-hemodynamic cluster of risk markers and predictors of arterial stiffness in a middle-aged population includes abdominal obesity, hyperglycemia, and dyslipidemia, but not smoking and low-density lipoprotein cholesterol. This pattern existed in both sexes.
doi:10.1097/HJH.0000000000000520
PMCID: PMC4947539  PMID: 25634451
ageing; arterial stiffness; diabetes mellitus; epidemiology; follow-up; glucose; hypertension; pulse wave velocity
13.  N-Terminal Prosomatostatin as a Risk Marker for Cardiovascular Disease and Diabetes in a General Population 
Context:
Somatostatin inhibits a range of hormones, including GH, insulin, and glucagon, but little is known about its role in the development of cardiometabolic disease.
Objective:
The objective of the study was to investigate whether fasting plasma concentration of N-terminal prosomatostatin (NT-proSST) is associated with the development of diabetes, coronary artery disease (CAD), and mortality.
Design, Setting, and Participants:
NT-proSST was measured in plasma from 5389 fasting participants of the population-based study Malmö Preventive Project, with a mean baseline age of 69.4 ± 6.2 years. Cox proportional hazards models adjusted for traditional cardiovascular risk factors were used to investigate the relationships between baseline NT-proSST and end points, with a mean follow-up of 5.6 ± 1.4 years.
Main Outcome Measures:
CAD, diabetes, and mortality were measured.
Results:
Overall, NT-proSST (hazard ratio [HR] per SD increment of log transformed NT-proSST) was unrelated to the risk of incident diabetes (220 events; HR 1.05; 95% confidence interval [CI] 0.91–1.20; P = .531) but was related to the risk of incident CAD (370 events; HR 1.17; 95% CI 1.06–1.30; P = .003), all-cause mortality (756 events; HR 1.24; 95% CI 1.15–1.33; P < .001), and cardiovascular mortality (283 events; HR 1.33; 95% CI 1.19–1.43; P < .001). The relationships were not linear, with most of the excess risk observed in subjects with high values of NT-proSST. Subjects in the top vs bottom decile had a severely increased risk of incident CAD (HR 2.41; 95% CI 1.45–4.01; P < .001), all-cause mortality (HR 1.84; 95% CI 1.33–2.53; P < .001), and cardiovascular mortality (HR 2.44; 95% CI 1.39–4.27; P < .001).
Conclusion:
NT-proSST was significantly and independently associated with the development of CAD, all-cause mortality, and cardiovascular mortality.
In a general population, NT-proSST was measured at baseline and subjects were followed for a 5.6 years. An association between NT-proSST and incident coronary artery disease and death was found.
doi:10.1210/jc.2016-1736
PMCID: PMC5010564  PMID: 27399347
14.  Elevated levels of FN1 and CCL2 in bronchoalveolar lavage fluid from sarcoidosis patients 
Respiratory Research  2016;17:69.
Background
Sarcoidosis is a granulomatous systemic inflammatory disease in which more than 90 % of all patients develop pulmonary manifestations. Several gene associations have previously been described, but established and clinically useful biomarkers are still absent. This study aimed to find proteins in bronchoalveolar lavage (BAL) fluid that can be associated with the disease.
Methods
We developed and performed profiling of 94 selected proteins in BAL fluid and serum samples obtained from newly diagnosed and non-treated patients with sarcoidosis. Using multiplexed immunoassays, a total of 317 BAL and 217 serum samples were analyzed, including asthmatic patients and healthy individuals as controls.
Results
Our analyses revealed increased levels of eight proteins in sarcoidosis patients compared to controls. Out of these, fibronectin (FN1) and C-C motif chemokine 2 (CCL2) revealed the strongest associations. In addition, cadherin 5 (CDH5) was found to correlate positively with lymphocyte cell numbers in BAL fluid.
Conclusions
Applying a high throughput proteomics screening technique, we found proteins of potential clinical relevance in the context of sarcoidosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-016-0381-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s12931-016-0381-0
PMCID: PMC4893268  PMID: 27259755
Sarcoidosis; Bronchoalveolar lavage; Protein profiling; Löfgren’s syndrome
15.  Cystatin C and Risk of Diabetes and the Metabolic Syndrome – Biomarker and Genotype Association Analyses 
PLoS ONE  2016;11(5):e0155735.
Background
We recently reported a relationship between plasma levels of cystatin C and incidence of the metabolic syndrome (MetS) among the first 2,369 subjects who participated in the re-examination study of the population-based Malmö and Diet Cancer Cardiovascular cohort (MDC-CC-re-exam). In this study we aimed to replicate these results and also investigate if cystatin C was causally associated with MetS and diabetes.
Methods
We estimated the effect size of the strongest GWAS derived cystatin C SNP (major allele of rs13038305) on plasma cystatin C in the now completed MDC-CC-re-exam (n = 3,734) and thereafter examined the association between plasma cystatin C (403 cases of diabetes and 2665 controls) as well as rs13038305 (235 cases and 2425 controls) with incident diabetes. The association of rs13038305 and incident MetS (511 cases of MetS and 1980 controls) was similarly investigated in the whole MDC-CC-re-exam. We also attempted to replicate our previously shown association of cystatin C with incident MetS in subjects from the MDC-CC-re-exam (147 cases and 711 controls) that were not included in our previous report.
Results
In the entire MDC-CC-re-exam, each copy of the major allele of rs13038305 was associated with approximately 0.30 standard deviation (SD) higher plasma concentration of cystatin C (β = 0.33, p = 4.2E-28) in age and sex adjusted analysis. Cystatin C in plasma was not associated with incident diabetes after adjustment for known diabetes risk factors (OR per 1 SD increment 0.99 (0.86–1.13), p = 0.842). In the replication cohort of MDC-CC-re-exam, the OR (95% CI) for incident MetS in subjects belonging to quartiles 1, 2, 3 and 4 of plasma cystatin C levels was 1.00 (reference), 1.21 (0.70–2.07), 1.62 (0.95–2.78) and 1.72 (1.01–2.93) (ptrend = 0.026) in age and sex adjusted analysis. In the entire MDC-CC-re-exam the odds ratio for incident MetS and diabetes per copy of the major rs13038305 allele was 1.13, (0.95–1.34), p = 0.160 and 1.07, 95% CI 0.89–1.30, p = 0.478, respectively.
Conclusion
We were able to replicate our previously shown association between high levels of cystatin C and increased risk of future development of MetS. However, a causal involvement of cystatin C in the etiology of MetS or diabetes seems unlikely since genetic elevation of plasma cystatin C was not significantly related to incidence of these diseases.
doi:10.1371/journal.pone.0155735
PMCID: PMC4878806  PMID: 27218257
16.  Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci 
Gaulton, Kyle J | Ferreira, Teresa | Lee, Yeji | Raimondo, Anne | Mägi, Reedik | Reschen, Michael E | Mahajan, Anubha | Locke, Adam | Rayner, N William | Robertson, Neil | Scott, Robert A | Prokopenko, Inga | Scott, Laura J | Green, Todd | Sparso, Thomas | Thuillier, Dorothee | Yengo, Loic | Grallert, Harald | Wahl, Simone | Frånberg, Mattias | Strawbridge, Rona J | Kestler, Hans | Chheda, Himanshu | Eisele, Lewin | Gustafsson, Stefan | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Qi, Lu | Karssen, Lennart C | van Leeuwen, Elisabeth M | Willems, Sara M | Li, Man | Chen, Han | Fuchsberger, Christian | Kwan, Phoenix | Ma, Clement | Linderman, Michael | Lu, Yingchang | Thomsen, Soren K | Rundle, Jana K | Beer, Nicola L | van de Bunt, Martijn | Chalisey, Anil | Kang, Hyun Min | Voight, Benjamin F | Abecasis, Goncalo R | Almgren, Peter | Baldassarre, Damiano | Balkau, Beverley | Benediktsson, Rafn | Blüher, Matthias | Boeing, Heiner | Bonnycastle, Lori L | Borringer, Erwin P | Burtt, Noël P | Carey, Jason | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn C | Couper, David J | Crenshaw, Andrew T | van Dam, Rob M | Doney, Alex SF | Dorkhan, Mozhgan | Edkins, Sarah | Eriksson, Johan G | Esko, Tonu | Eury, Elodie | Fadista, João | Flannick, Jason | Fontanillas, Pierre | Fox, Caroline | Franks, Paul W | Gertow, Karl | Gieger, Christian | Gigante, Bruna | Gottesman, Omri | Grant, George B | Grarup, Niels | Groves, Christopher J | Hassinen, Maija | Have, Christian T | Herder, Christian | Holmen, Oddgeir L | Hreidarsson, Astradur B | Humphries, Steve E | Hunter, David J | Jackson, Anne U | Jonsson, Anna | Jørgensen, Marit E | Jørgensen, Torben | Kao, Wen-Hong L | Kerrison, Nicola D | Kinnunen, Leena | Klopp, Norman | Kong, Augustine | Kovacs, Peter | Kraft, Peter | Kravic, Jasmina | Langford, Cordelia | Leander, Karin | Liang, Liming | Lichtner, Peter | Lindgren, Cecilia M | Lindholm, Eero | Linneberg, Allan | Liu, Ching-Ti | Lobbens, Stéphane | Luan, Jian’an | Lyssenko, Valeriya | Mӓnnistö, Satu | McLeod, Olga | Meyer, Julia | Mihailov, Evelin | Mirza, Ghazala | Mühleisen, Thomas W | Müller-Nurasyid, Martina | Navarro, Carmen | Nöthen, Markus M | Oskolkov, Nikolay N | Owen, Katharine R | Palli, Domenico | Pechlivanis, Sonali | Peltonen, Leena | Perry, John RB | Platou, Carl GP | Roden, Michael | Ruderfer, Douglas | Rybin, Denis | van der Schouw, Yvonne T | Sennblad, Bengt | Sigurđsson, Gunnar | Stančáková, Alena | Steinbach, Gerald | Storm, Petter | Strauch, Konstantin | Stringham, Heather M | Sun, Qi | Thorand, Barbara | Tikkanen, Emmi | Tonjes, Anke | Trakalo, Joseph | Tremoli, Elena | Tuomi, Tiinamaija | Wennauer, Roman | Wiltshire, Steven | Wood, Andrew R | Zeggini, Eleftheria | Dunham, Ian | Birney, Ewan | Pasquali, Lorenzo | Ferrer, Jorge | Loos, Ruth JF | Dupuis, Josée | Florez, Jose C | Boerwinkle, Eric | Pankow, James S | van Duijn, Cornelia | Sijbrands, Eric | Meigs, James B | Hu, Frank B | Thorsteinsdottir, Unnur | Stefansson, Kari | Lakka, Timo A | Rauramaa, Rainer | Stumvoll, Michael | Pedersen, Nancy L | Lind, Lars | Keinanen-Kiukaanniemi, Sirkka M | Korpi-Hyövӓlti, Eeva | Saaristo, Timo E | Saltevo, Juha | Kuusisto, Johanna | Laakso, Markku | Metspalu, Andres | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Ripatti, Samuli | Salomaa, Veikko | Ingelsson, Erik | Boehm, Bernhard O | Bergman, Richard N | Collins, Francis S | Mohlke, Karen L | Koistinen, Heikki | Tuomilehto, Jaakko | Hveem, Kristian | Njølstad, Inger | Deloukas, Panagiotis | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | de Faire, Ulf | Hamsten, Anders | Illig, Thomas | Peters, Annette | Cauchi, Stephane | Sladek, Rob | Froguel, Philippe | Hansen, Torben | Pedersen, Oluf | Morris, Andrew D | Palmer, Collin NA | Kathiresan, Sekar | Melander, Olle | Nilsson, Peter M | Groop, Leif C | Barroso, Inês | Langenberg, Claudia | Wareham, Nicholas J | O’Callaghan, Christopher A | Gloyn, Anna L | Altshuler, David | Boehnke, Michael | Teslovich, Tanya M | McCarthy, Mark I | Morris, Andrew P
Nature genetics  2015;47(12):1415-1425.
We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
doi:10.1038/ng.3437
PMCID: PMC4666734  PMID: 26551672
17.  Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci 
Gaulton, Kyle J | Ferreira, Teresa | Lee, Yeji | Raimondo, Anne | Mägi, Reedik | Reschen, Michael E | Mahajan, Anubha | Locke, Adam | Rayner, N William | Robertson, Neil | Scott, Robert A | Prokopenko, Inga | Scott, Laura J | Green, Todd | Sparso, Thomas | Thuillier, Dorothee | Yengo, Loic | Grallert, Harald | Wahl, Simone | Frånberg, Mattias | Strawbridge, Rona J | Kestler, Hans | Chheda, Himanshu | Eisele, Lewin | Gustafsson, Stefan | Steinthorsdottir, Valgerdur | Thorleifsson, Gudmar | Qi, Lu | Karssen, Lennart C | van Leeuwen, Elisabeth M | Willems, Sara M | Li, Man | Chen, Han | Fuchsberger, Christian | Kwan, Phoenix | Ma, Clement | Linderman, Michael | Lu, Yingchang | Thomsen, Soren K | Rundle, Jana K | Beer, Nicola L | van de Bunt, Martijn | Chalisey, Anil | Kang, Hyun Min | Voight, Benjamin F | Abecasis, Goncalo R | Almgren, Peter | Baldassarre, Damiano | Balkau, Beverley | Benediktsson, Rafn | Blüher, Matthias | Boeing, Heiner | Bonnycastle, Lori L | Borringer, Erwin P | Burtt, Noël P | Carey, Jason | Charpentier, Guillaume | Chines, Peter S | Cornelis, Marilyn C | Couper, David J | Crenshaw, Andrew T | van Dam, Rob M | Doney, Alex SF | Dorkhan, Mozhgan | Edkins, Sarah | Eriksson, Johan G | Esko, Tonu | Eury, Elodie | Fadista, João | Flannick, Jason | Fontanillas, Pierre | Fox, Caroline | Franks, Paul W | Gertow, Karl | Gieger, Christian | Gigante, Bruna | Gottesman, Omri | Grant, George B | Grarup, Niels | Groves, Christopher J | Hassinen, Maija | Have, Christian T | Herder, Christian | Holmen, Oddgeir L | Hreidarsson, Astradur B | Humphries, Steve E | Hunter, David J | Jackson, Anne U | Jonsson, Anna | Jørgensen, Marit E | Jørgensen, Torben | Kao, Wen-Hong L | Kerrison, Nicola D | Kinnunen, Leena | Klopp, Norman | Kong, Augustine | Kovacs, Peter | Kraft, Peter | Kravic, Jasmina | Langford, Cordelia | Leander, Karin | Liang, Liming | Lichtner, Peter | Lindgren, Cecilia M | Lindholm, Eero | Linneberg, Allan | Liu, Ching-Ti | Lobbens, Stéphane | Luan, Jian’an | Lyssenko, Valeriya | Männistö, Satu | McLeod, Olga | Meyer, Julia | Mihailov, Evelin | Mirza, Ghazala | Mühleisen, Thomas W | Müller-Nurasyid, Martina | Navarro, Carmen | Nöthen, Markus M | Oskolkov, Nikolay N | Owen, Katharine R | Palli, Domenico | Pechlivanis, Sonali | Peltonen, Leena | Perry, John RB | Platou, Carl GP | Roden, Michael | Ruderfer, Douglas | Rybin, Denis | van der Schouw, Yvonne T | Sennblad, Bengt | Sigurðsson, Gunnar | Stančáková, Alena | Steinbach, Gerald | Storm, Petter | Strauch, Konstantin | Stringham, Heather M | Sun, Qi | Thorand, Barbara | Tikkanen, Emmi | Tonjes, Anke | Trakalo, Joseph | Tremoli, Elena | Tuomi, Tiinamaija | Wennauer, Roman | Wiltshire, Steven | Wood, Andrew R | Zeggini, Eleftheria | Dunham, Ian | Birney, Ewan | Pasquali, Lorenzo | Ferrer, Jorge | Loos, Ruth JF | Dupuis, Josée | Florez, Jose C | Boerwinkle, Eric | Pankow, James S | van Duijn, Cornelia | Sijbrands, Eric | Meigs, James B | Hu, Frank B | Thorsteinsdottir, Unnur | Stefansson, Kari | Lakka, Timo A | Rauramaa, Rainer | Stumvoll, Michael | Pedersen, Nancy L | Lind, Lars | Keinanen-Kiukaanniemi, Sirkka M | Korpi-Hyövälti, Eeva | Saaristo, Timo E | Saltevo, Juha | Kuusisto, Johanna | Laakso, Markku | Metspalu, Andres | Erbel, Raimund | Jöckel, Karl-Heinz | Moebus, Susanne | Ripatti, Samuli | Salomaa, Veikko | Ingelsson, Erik | Boehm, Bernhard O | Bergman, Richard N | Collins, Francis S | Mohlke, Karen L | Koistinen, Heikki | Tuomilehto, Jaakko | Hveem, Kristian | Njølstad, Inger | Deloukas, Panagiotis | Donnelly, Peter J | Frayling, Timothy M | Hattersley, Andrew T | de Faire, Ulf | Hamsten, Anders | Illig, Thomas | Peters, Annette | Cauchi, Stephane | Sladek, Rob | Froguel, Philippe | Hansen, Torben | Pedersen, Oluf | Morris, Andrew D | Palmer, Collin NA | Kathiresan, Sekar | Melander, Olle | Nilsson, Peter M | Groop, Leif C | Barroso, Inês | Langenberg, Claudia | Wareham, Nicholas J | O’Callaghan, Christopher A | Gloyn, Anna L | Altshuler, David | Boehnke, Michael | Teslovich, Tanya M | McCarthy, Mark I | Morris, Andrew P
Nature genetics  2015;47(12):1415-1425.
We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
doi:10.1038/ng.3437
PMCID: PMC4666734  PMID: 26551672
18.  The temporal relationship between poor lung function and the risk of diabetes 
Background
The association between impaired lung function and diabetes risk has been established in the past, however the temporal and causal relationships between the two remain unclear. We assessed the relationship between baseline FEV1 and FVC and risk of incident diabetes at different time intervals for participants in the Malmö Preventive Project cohort.
Methods
Baseline lung function was assessed in 20,295 men and 7416 women during 1974–1992; mean age 43.4 ± 6.6 and 47.6 ± 7.8, respectively. Sex-specific quartiles of FEV1%predicted and FVC%predicted were created (Q4 = highest; reference). Follow-up time was divided into 10-year time intervals from baseline examination. Cox proportional hazards regression was used to assess the incidence of diabetes according to quartiles of FEV1 and FVC%predicted, after adjustments for baseline glucose and potential confounding factors.
Results
Over 37-years’ follow-up there were 3753 and 993 incident diabetes events in men and women, respectively. When comparing FEV1%predicted in men (Q1 vs. Q4), the HR for diabetes was 1.64 (1.21–2.22) for events <10 years after baseline, 1.52 (1.27–1.81) for events 10–20 years after baseline, 1.39 (1.22–1.59) for events 20–30 years after baseline, and 1.46 (1.08–1.97) for events occurring >30 years after baseline. A broadly similar pattern was seen for FVC%predicted and for women.
Conclusions
Low FEV1 precedes and significantly predicts future diabetes. This risk is still significant many years after the baseline FEV1 measurement in middle-aged men. These results suggest that there is a relationship between impaired lung function and diabetes risk beyond the effects of hyperglycemia on lung function.
Electronic supplementary material
The online version of this article (doi:10.1186/s12890-016-0227-z) contains supplementary material, which is available to authorized users.
doi:10.1186/s12890-016-0227-z
PMCID: PMC4863358  PMID: 27165091
Diabetes; Incidence; Lung function
19.  Age- and Sex-Specific Causal Effects of Adiposity on Cardiovascular Risk Factors 
Fall, Tove | Hägg, Sara | Ploner, Alexander | Mägi, Reedik | Fischer, Krista | Draisma, Harmen H.M. | Sarin, Antti-Pekka | Benyamin, Beben | Ladenvall, Claes | Åkerlund, Mikael | Kals, Mart | Esko, Tõnu | Nelson, Christopher P. | Kaakinen, Marika | Huikari, Ville | Mangino, Massimo | Meirhaeghe, Aline | Kristiansson, Kati | Nuotio, Marja-Liisa | Kobl, Michael | Grallert, Harald | Dehghan, Abbas | Kuningas, Maris | de Vries, Paul S. | de Bruijn, Renée F.A.G. | Willems, Sara M. | Heikkilä, Kauko | Silventoinen, Karri | Pietiläinen, Kirsi H. | Legry, Vanessa | Giedraitis, Vilmantas | Goumidi, Louisa | Syvänen, Ann-Christine | Strauch, Konstantin | Koenig, Wolfgang | Lichtner, Peter | Herder, Christian | Palotie, Aarno | Menni, Cristina | Uitterlinden, André G. | Kuulasmaa, Kari | Havulinna, Aki S. | Moreno, Luis A. | Gonzalez-Gross, Marcela | Evans, Alun | Tregouet, David-Alexandre | Yarnell, John W.G. | Virtamo, Jarmo | Ferrières, Jean | Veronesi, Giovanni | Perola, Markus | Arveiler, Dominique | Brambilla, Paolo | Lind, Lars | Kaprio, Jaakko | Hofman, Albert | Stricker, Bruno H. | van Duijn, Cornelia M. | Ikram, M. Arfan | Franco, Oscar H. | Cottel, Dominique | Dallongeville, Jean | Hall, Alistair S. | Jula, Antti | Tobin, Martin D. | Penninx, Brenda W. | Peters, Annette | Gieger, Christian | Samani, Nilesh J. | Montgomery, Grant W. | Whitfield, John B. | Martin, Nicholas G. | Groop, Leif | Spector, Tim D. | Magnusson, Patrik K. | Amouyel, Philippe | Boomsma, Dorret I. | Nilsson, Peter M. | Järvelin, Marjo-Riitta | Lyssenko, Valeriya | Metspalu, Andres | Strachan, David P. | Salomaa, Veikko | Ripatti, Samuli | Pedersen, Nancy L. | Prokopenko, Inga | McCarthy, Mark I. | Ingelsson, Erik
Diabetes  2015;64(5):1841-1852.
Observational studies have reported different effects of adiposity on cardiovascular risk factors across age and sex. Since cardiovascular risk factors are enriched in obese individuals, it has not been easy to dissect the effects of adiposity from those of other risk factors. We used a Mendelian randomization approach, applying a set of 32 genetic markers to estimate the causal effect of adiposity on blood pressure, glycemic indices, circulating lipid levels, and markers of inflammation and liver disease in up to 67,553 individuals. All analyses were stratified by age (cutoff 55 years of age) and sex. The genetic score was associated with BMI in both nonstratified analysis (P = 2.8 × 10−107) and stratified analyses (all P < 3.3 × 10−30). We found evidence of a causal effect of adiposity on blood pressure, fasting levels of insulin, C-reactive protein, interleukin-6, HDL cholesterol, and triglycerides in a nonstratified analysis and in the <55-year stratum. Further, we found evidence of a smaller causal effect on total cholesterol (P for difference = 0.015) in the ≥55-year stratum than in the <55-year stratum, a finding that could be explained by biology, survival bias, or differential medication. In conclusion, this study extends previous knowledge of the effects of adiposity by providing sex- and age-specific causal estimates on cardiovascular risk factors.
doi:10.2337/db14-0988
PMCID: PMC4407863  PMID: 25712996
20.  THE METABOLIC SYNDROME ACROSS EUROPE – DIFFERENT CLUSTERS OF RISK FACTORS 
Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se’- were associated with accelerated arterial ageing and with CV events. To investigate whether the distribution of the “risky” clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and 1 from US participants in the MARE (Metabolic syndrome and Arteries REsearch) Consortium. In accordance with the ATP III criteria, MetS was defined as an alteration ≥3 of the following 5 components: elevated glucose (G): fasting glucose ≥110 mg/dl; low HDL cholesterol (H): <40 mg/dl for M or < 50 mg/dl for W; high triglycerides (T) ≥150 mg/dl; elevated BP (B): ≥130/≥85 mmHg; abdominal obesity (W): waist circumference > 102 cm for M or >88 cm for W.
MetS had a 24.3% prevalence (8468 subjects) (23.9% in men vs 24.6% in women, p<0.001) with an age-associated increase in its prevalence in all the cohorts.
The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p< 0.0001) and in men and women (gender effect p<0.0001). In details, the cluster T-B-W was observed in 12% of the subjects with MetS, but was far more common in the cohorts from UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and USA (2.5%). The cluster G-B-W accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal - with 31.4%, 18.4%, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania - with 7.6%, 9.4%, and 9.6% respectively).
The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries.
doi:10.1177/2047487314525529
PMCID: PMC4544872  PMID: 24647805
blood pressure; epidemiology; Europe; glucose; metabolic syndrome; triglycerides; HDL cholesterol; waist circumference
21.  Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium 
Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI).
Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis.
Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI:1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data.
Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.
doi:10.1093/ije/dyv075
PMCID: PMC4817600  PMID: 26050256
Mendelian randomization; BMI; periodontitis; casual inference; confounding
22.  Analysis of the Cerebrospinal Fluid Proteome in Alzheimer's Disease 
PLoS ONE  2016;11(3):e0150672.
Alzheimer’s disease is a neurodegenerative disorder accounting for more than 50% of cases of dementia. Diagnosis of Alzheimer’s disease relies on cognitive tests and analysis of amyloid beta, protein tau, and hyperphosphorylated tau in cerebrospinal fluid. Although these markers provide relatively high sensitivity and specificity for early disease detection, they are not suitable for monitor of disease progression. In the present study, we used label-free shotgun mass spectrometry to analyse the cerebrospinal fluid proteome of Alzheimer’s disease patients and non-demented controls to identify potential biomarkers for Alzheimer’s disease. We processed the data using five programs (DecyderMS, Maxquant, OpenMS, PEAKS, and Sieve) and compared their results by means of reproducibility and peptide identification, including three different normalization methods. After depletion of high abundant proteins we found that Alzheimer’s disease patients had lower fraction of low-abundance proteins in cerebrospinal fluid compared to healthy controls (p<0.05). Consequently, global normalization was found to be less accurate compared to using spiked-in chicken ovalbumin for normalization. In addition, we determined that Sieve and OpenMS resulted in the highest reproducibility and PEAKS was the programs with the highest identification performance. Finally, we successfully verified significantly lower levels (p<0.05) of eight proteins (A2GL, APOM, C1QB, C1QC, C1S, FBLN3, PTPRZ, and SEZ6) in Alzheimer’s disease compared to controls using an antibody-based detection method. These proteins are involved in different biological roles spanning from cell adhesion and migration, to regulation of the synapse and the immune system.
doi:10.1371/journal.pone.0150672
PMCID: PMC4780771  PMID: 26950848
23.  Total and Differential Leukocyte Counts in Relation to Incidence of Diabetes Mellitus: A Prospective Population-Based Cohort Study 
PLoS ONE  2016;11(2):e0148963.
Objective
High concentrations of leukocytes in blood have been associated with diabetes mellitus. This prospective study aimed to explore whether total and differential leukocyte counts are associated with incidence of diabetes. A missense variant R262W in the SH2B3 (SH2B adaptor protein 3) gene, coding for a protein that negatively regulates hematopoietic cell proliferation, was also studied in relation to incidence of diabetes.
Methods and Results
Leukocyte count and its subtypes (neutrophils, lymphocytes and mixed cells) were analyzed in 26,667 men and women, 45–73 years old, from the population-based Malmö Diet and Cancer study. Information about the R262W polymorphism (rs3184504) in SH2B3 was genotyped in 24,489 subjects. Incidence of diabetes was studied during a mean follow-up of 14 years. Cox proportional hazards regression was used to examine incidence of diabetes by total and differential leukocyte counts. Mendelian randomization analysis using R262W as an instrumental variable was performed with two-stage least squares regression. A total of 2,946 subjects developed diabetes during the follow-up period. After taking several possible confounders into account, concentrations of total leukocyte count, neutrophils and lymphocytes were all significantly associated with incidence of diabetes. The adjusted hazard ratios (95% confidence interval; quartile 4 vs quartile 1) were 1.37 (1.22–1.53) for total leukocytes, 1.33 (1.19–1.49) for neutrophils and 1.29 (1.15–1.44) for lymphocytes. The R262W polymorphism was strongly associated with leukocytes (0.11x109 cells/l per T allele, p = 1.14 x10-12), lymphocytes (p = 4.3 x10-16), neutrophils (p = 8.0 x10-6) and mixed cells (p = 3.0 x10-6). However, there was no significant association between R262W and fasting glucose, HbA1c or incidence of diabetes.
Conclusions
Concentrations of total leukocytes, neutrophils and lymphocytes are associated with incidence of diabetes. However, the lack of association with the R262W polymorphism suggests that the associations may not be causal, although limitations in statistical power and balancing pleiotropic effects cannot be excluded.
doi:10.1371/journal.pone.0148963
PMCID: PMC4758613  PMID: 26891449
24.  Immunocapture strategies in translational proteomics 
Expert Review of Proteomics  2015;13(1):83-98.
Aiming at clinical studies of human diseases, antibody-assisted assays have been applied to biomarker discovery and toward a streamlined translation from patient profiling to assays supporting personalized treatments. In recent years, integrated strategies to couple and combine antibodies with mass spectrometry-based proteomic efforts have emerged, allowing for novel possibilities in basic and clinical research. Described in this review are some of the field’s current and emerging immunocapture approaches from an affinity proteomics perspective. Discussed are some of their advantages, pitfalls and opportunities for the next phase in clinical and translational proteomics.
doi:10.1586/14789450.2016.1111141
PMCID: PMC4732419  PMID: 26558424
Antibodies; immunocapture; mass spectrometry; protein enrichment; sandwich assays; SRM
25.  Genetic vasopressin 1b receptor variance in overweight and diabetes mellitus 
Objective
Recently, imbalance in the vasopressin (AVP) system, measured as elevated levels of copeptin (the C-terminal part of the AVP pro-hormone) in plasma, was linked to the development of abdominal obesity and diabetes mellitus (DM). Here, we aim to investigate if the genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity and DM.
Design
Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991–1996.
Methods
Four tag single nucleotide polymorphisms (SNPs: rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC) and associated with measures of obesity and DM. Significant SNPs were replicated in another 24 344 MDC individuals (MDC replication cohort).
Results
In MDC-CC, the major allele of rs35810727 was associated with elevated BMI (β-coefficient±s.e.m.; 0.30±0.14, P=0.03) and waist (0.78±0.36, P=0.03) after age and gender adjustment. The association with BMI was replicated in the MDC replication cohort (0.21±0.07, P=0.003), whereas that with waist was not significant. In MDC-CC there was no association between the major allele of rs35810727 and DM, but in the complete MDC cohort (n=30 447) the major allele of rs35810727 was associated with DM (OR (95% CI); 1.10 (1.00–1.20), P=0.04).
Conclusions
Genetic variance of AVPR1B contributes to overweight. Furthermore, our data indicate a link between AVPR1B variance and DM development. Our data point at a relationship between the disturbance of the pharmacologically modifiable AVP system and the body weight regulation.
doi:10.1530/EJE-15-0781
PMCID: PMC4653349  PMID: 26503846

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