title: Total and Differential Leukocyte Counts in Relation to Incidence of Diabetes Mellitus: A Prospective Population-Based Cohort Study.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
authors.forename: Yan
authors.initials: Y
authors.lastname: Borné
authors.affiliation: Department of Cardiology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.|Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.|Program of Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
authors.forename: J Gustav
authors.initials: JG
authors.lastname: Smith
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.|Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Nilsson
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.|Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Melander
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Hedblad
authors.affiliation: Department of Clinical Sciences, Malmö, Lund University, Malmö, Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Engström
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D015331:Cohort Studies; D003920:Diabetes Mellitus / Q000097:blood* / Q000453:epidemiology* / Q000235:genetics / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D015994:Incidence; D047908:Intracellular Signaling Peptides and Proteins; D007958:Leukocyte Count; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D011446:Prospective Studies; D011506:Proteins; D012307:Risk Factors; D013548:Sweden / Q000453:epidemiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C490778:SH2B3 protein, human