Differential White Blood Cell Count and Type 2 Diabetes: Systematic Review and Meta-Analysis of Cross-Sectional and Prospective Studies

Objective: Biological evidence suggests that inflammation might induce type 2 diabetes (T2D), and epidemiological studies have shown an association between higher white blood cell count (WBC) and T2D. However, the association has not been systematically investigated.Research Design and Methods: Studies were identified through computer-based and manual searches. Previously unreported studies were sought through correspondence. 20 studies were identified (8,647 T2D cases and 85,040 non-cases). Estimates of the association of WBC with T2D were combined using random effects meta-analysis; sources of heterogeneity as well as presence of publication bias were explored.Results: The combined relative risk (RR) comparing the top to bottom tertile of the WBC count was 1.61 (95% CI: 1.45; 1.79, p = 1.5*10(-18)). Substantial heterogeneity was present (I-2 = 83%). For granulocytes the RR was 1.38 (95% CI: 1.17; 1.64, p = 1.5*10(-4)), for lymphocytes 1.26 (95% CI: 1.02; 1.56, p = 0.029), and for monocytes 0.93 (95% CI: 0.68; 1.28, p = 0.67) comparing top to bottom tertile. In cross-sectional studies, RR was 1.74 (95% CI: 1.49; 2.02, p = 7.7*10(-13)), while in cohort studies it was 1.48 (95% CI: 1.22; 1.79, p = 7.7*10(-5)). We assessed the impact of confounding in EPIC-Norfolk study and found that the age and sex adjusted HR of 2.19 (95% CI: 1.74; 2.75) was attenuated to 1.82 (95% CI: 1.45; 2.29) after further accounting for smoking, T2D family history, physical activity, education, BMI and waist circumference.Conclusions: A raised WBC is associated with higher risk of T2D. The presence of publication bias and failure to control for all potential confounders in all studies means the observed association is likely an overestimate

Multiethnic Meta-Analysis of Genome-Wide Association Studies in > 100 000 Subjects Identifies 23 FibrinogenAssociated Loci but No Strong Evidence of a Causal Association Between Circulating Fibrinogen and Cardiovascular Disease

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.Estimates of the heritability of plasma fibrinogen concentration, an established predictor of cardiovascular disease, range from 34% to 50%. Genetic variants so far identified by genome-wide association studies explain only a small proportion (90 000 subjects of European ancestry, the first genome-wide association meta-analysis of fibrinogen levels in 7 studies in blacks totaling 8289 samples, and a genome-wide association study in Hispanics totaling 1366 samples. Evaluation for association of single-nucleotide polymorphisms with clinical outcomes included a total of 40 695 cases and 85 582 controls for coronary artery disease, 4752 cases and 24 030 controls for stroke, and 3208 cases and 46 167 controls for venous thromboembolism. Overall, we identified 24 genome-wide significant (P<5×10(-8)) independent signals in 23 loci, including 15 novel associations, together accounting for 3.7% of plasma fibrinogen variation. Gene-set enrichment analysis highlighted key roles in fibrinogen regulation for the 3 structural fibrinogen genes and pathways related to inflammation, adipocytokines, and thyrotrophin-releasing hormone signaling. Whereas lead single-nucleotide polymorphisms in a few loci were significantly associated with coronary artery disease, the combined effect of all 24 fibrinogen-associated lead single-nucleotide polymorphisms was not significant for coronary artery disease, stroke, or venous thromboembolism.We identify 23 robustly associated fibrinogen loci, 15 of which are new. Clinical outcome analysis of these loci does not support a causal relationship between circulating levels of fibrinogen and coronary artery disease, stroke, or venous thromboembolism.European Community LSHM-CT-2007-037273 AstraZeneca British Heart Foundation (BHF) Wellcome Trust075491/Z/04 Swedish Research Council Knut and Alice Wallenberg Foundation Swedish Heart-Lung Foundation Torsten and Ragnar Soderberg Foundation Karolinska Institutet Stockholm County Council Foundation for Strategic Research BHF Center of Research Excellence, Oxford Magnus Bergvall Foundation European Union PIEF-GA-2009-252361 National Heart, Lung, and Blood Institute's (NHLBI's) N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Diabetes and Digestive and Kidney Diseases K24 DK080140 DK063491 National Institute on Aging (NIA) National Institute for Neurological Disorders and Stroke R01 AG033193 NS017950 NHLBI HL043851 L080467 N01-HC-95095 N01-HC-48047 N01-HC-48048 N01-HC-48049 N01-HC-48050 01-HC-45134 N01-HC-05187 N01-HC-45205 N01-HC-45204 N01-HC-85239 N01-HC-85079 N01-HC-85080 N01-HC-85081 N01-HC-85082 N01-HC-85083 N01-HC-85084 National Cancer Institute CA047988 Donald W. Reynolds Foundation Fondation Leducq Amgen NIA NO1-AG-1-2109 AG-023629 AG-15928 AG-20098 AG-027058 National Institutes of Health (NIH), NIA Erasmus Medical Center Erasmus University Rotterdam Netherlands Organization for Scientific Research (NWO) Netherlands Organization for Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Netherlands Heart Foundation Ministry of Education, Culture and Science Ministry of Health Welfare and Sports European Commission Municipality of Rotterdam Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 RIDE2 Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) 050-060-810 NWO vici, 918-76-619 veni, 916.12.154 EUR Fellowship Netherlands Heart Foundation 2009B102 NHS 92345 Federal Ministry of Education and Research 01ZZ9603 1ZZ0103 01ZZ0403 03ZIK012 Ministry of Cultural Affairs Social Ministry of the Federal State of Mecklenburg, West Pomerania Siemens Healthcare, Erlangen, Germany Federal State of Mecklenburg, West Pomerania Leibniz Supercomputing Center of the Bavarian Academy of Sciences and Humanities (HLRB) h1231 Federal Ministry of Education and Research Ministry of Cultural Affairs of the Federal State of Mecklenburg, West Pomerania 03IS2061A National Human Genome Research Institute U01-HG-004729 U01-HG-004446 U01-HG-004424 European Union's 7th Framework Program HEALTH-F2-2009-223004 Netherlands Consortium of Healthy Aging (NGI) 05060810 Scottish Executive Chief Scientist Office, Health Services Research Committee CZG/4/306 National Institute of Neurological Disorders and Stroke National Center of Advancing Translational Technologies CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Diseases Zoll LifeCor Medtronic Biotechnology and Biological Sciences Research Council (BBSRC) BB/F019394/1 Research Into Ageing LBC1936 Help the Aged/Research Into Ageing (Disconnected Mind) BBSRC LBC1921 BBSRC Engineering and Physical Sciences Research Council (EPSRC) Economic and Social Research Council (ESRC) Medical Research Council (MRC), as part of the cross-council Lifelong Health and Wellbeing Initiative Program Hospitalier de la Recherche Clinique Fondation pour la Recherche Medicale La Region Ile de France Medical Research Council (UK) European Commission LSHG-CT-2006-018947 Republic of Croatia Ministry of Science, Education and Sports 108-1080315-0302 Medical Research Council G0000934 Wellcome Trust 068545/Z/02 UK National Blood Service controls Wellcome Trust BHF Center of Research Excellence, Oxford, UK Reynolds Foundation Boehringer Ingelheim Philips Medical Systems Government of Rheinland-Pfalz Johannes-Gutenberg University of Mainz MAIFOR Fondation de France French Ministry of Research Institut National de la Sante et de la Recherche Medica NIH NHLBI R01HL089650-02 N01-AG-12100 P01 HL098055 P01HL076491-06 R01DK080732 P01HL087018 1RO1HL103931-01 Deutsche Forschungsgemeinschaft German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network NGFN-2 EU LSHM-CT-2006-037593 LSHM-CT-2004-503485 HEALTH-F2-2008-201668 BMBF/ANR 01KU0908A Sanofi/Aventis Roche Dade Behring/Siemens US NIH NHLBI's STAMPEED genomics research program R01 HL087676 Canadian Institutes of Health Research Cardiovascular Institute of the University of Pennsylvania MedStar Research Institute Washington Hospital Center GlaxoSmithKline GlaxoSmithKline through an Alternate Drug Discovery Initiative Research Alliance Award University of Pennsylvania School of Medicine CIHR MOP-82810 MOP172605 MOP77682 CFI 11966 HSFO NA6001 BHF UK Medical Research Council NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association) Althingi (the Icelandic Parliament) German Migraine & Headache Society Berlin Chemie Boots Healthcare Glaxo-Smith-Kline McNeil Pharma MSD Sharp Dohme Pfizer Institute of Epidemiology and Social Medicine, University of Muenster Medical Research Council UK Cancer Research UK Canadian Institutes for Health Research Heart and Stroke Foundation of Ontario Sanofi-Aventis King Pharmaceuticals T.F.C. Frost charity Macular Disease Society Erasmus Medical Center and Erasmus University Rotterdam Netherlands Organization for Scientific Research Research Institute for Diseases in the Elderly European Commission (DG XII) Netherlands Organization for Scientific Research (NWO) 175.010.2005.011 911.03.012 NGI/NWO 050-060-810 NWO (Vici) 918-76-619 Swedish Heart & Lung Foundation Stockholm County Council (ALF) Netherlands Organisation for Scientific Research (NWO) Italian Ministry of University and Research Veneto Region Cariverona Foundation, Verona Helmholtz Zentrum Munchen-National Research Center for Environmental Health German Federal Ministry of Education, Science, Research and Technology State of Bavaria German National Genome Research Network Munich Center of Health Sciences (MC Health) as part of LMUinnovativ N.H.L.B.I HHSN268201200036C HL080295 HL087652 HL105756 R01-HL085251 HL087647 N01-HC-55015 N01-HC-55016 N01-HC-55018 N01-HC-55019 N01-HC-55020 N01-HC-85085 N01-HC-85086 N01-HC-35129 N01 HC-15103 N01 HC-55222 N01-HC-75150 N01-HC-45133 R01-HL-08409