title: Genetic polymorphisms of innate immunity-related inflammatory pathways and their association with factors related to type 2 diabetes.
abstract: BACKGROUND
  Type 2 diabetes mellitus (T2DM) has been linked to a state of pre-clinical chronic inflammation resulting from abnormalities in the innate immune pathway. Serum levels of pro-inflammatory cytokines and acute-phase proteins, collectively known as 'inflammatory network', are elevated in the pre-, or early, stages of T2DM and increase with disease progression. Genetic variation can affect the innate immune response to certain environmental factors, and may, therefore, determine an individual's lifetime risk of disease.
  
  
  METHODS
  We conducted a cross-sectional study in 6,720 subjects from the Twins UK Registry to evaluate the association between 18 single nucleotide polymorphisms (SNPs) in five genes (TLR4, IL1A, IL6, TNFA, and CRP) along the innate immunity-related inflammatory pathway and biomarkers of predisposition to T2DM [fasting insulin and glucose, HDL- and LDL- cholesterols, triglycerides (TGs), amyloid-A, sensitive C-reactive protein (sCRP) and vitamin D binding protein (VDBP) and body mass index (BMI)].
  
  
  RESULTS
  Of 18 the SNPs examined for their association with nine metabolic phenotypes of interest, six were significantly associated with five metabolic phenotypes (Bonferroni correction, P ≤ 0.0027). Fasting insulin was associated with SNPs in IL6 and TNFA, serum HDL-C with variants of TNFA and CRP and serum sCRP level with SNPs in CRP. Cross-correlation analysis among the different metabolic factors related to risk of T2DM showed several significant associations. For example, BMI was directly correlated with glucose (r = 0.11), insulin (r = 0.15), sCRP (r = 0.23), LDL-C (r = 0.067) and TGs (r = 0.18) but inversely with HDL-C (r = -0.14). sCRP was also positively correlated (P < 0.0001) with insulin (r = 0.17), amyloid-A (r = 0.39), TGs (r = 0.26), and VDBP (r = 0.36) but inversely with HDL-C (r = -0.12).
  
  
  CONCLUSIONS
  Genetic variants in the innate immunity pathway and its related inflammatory cascade is associated with some metabolic risk factors for T2DM; an observation that may provide a rationale for further studying their role as biomarkers for disease early risk prediction.
authors.affiliation: Office for Biotechnology, Genomics and Population Health, Public Health Agency of Canada, 180 Queen Street West, Toronto, M5V 3L7, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Arora
authors.forename: Bibiana
authors.initials: B
authors.lastname: Garcia-Bailo
authors.forename: Zari
authors.initials: Z
authors.lastname: Dastani
authors.forename: Darren
authors.initials: D
authors.lastname: Brenner
authors.forename: Andre
authors.initials: A
authors.lastname: Villegas
authors.forename: Suneil
authors.initials: S
authors.lastname: Malik
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Spector
authors.forename: Brent
authors.initials: B
authors.lastname: Richards
authors.forename: Ahmed
authors.initials: A
authors.lastname: El-Sohemy
authors.forename: Mohamed
authors.initials: M
authors.lastname: Karmali
authors.forename: Alaa
authors.initials: A
authors.lastname: Badawi
mesh_terms: D000209:Acute-Phase Proteins / Q000378:metabolism; D001786:Blood Glucose; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D007328:Insulin / Q000097:blood; D053582:Interleukin-1alpha / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016014:Linear Models; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics; D000685:Serum Amyloid A Protein / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014280:Triglycerides / Q000097:blood; D006113:United Kingdom; D014809:Vitamin D-Binding Protein / Q000097:blood
chemical_list: D000209:Acute-Phase Proteins; D001786:Blood Glucose; C071581:CRP protein, human; D016207:Cytokines; C508584:IL1A protein, human; C508600:IL6 protein, human; D007328:Insulin; D053582:Interleukin-1alpha; D015850:Interleukin-6; D011971:Receptors, Immunologic; D000685:Serum Amyloid A Protein; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D014809:Vitamin D-Binding Protein; D002097:C-Reactive Protein; D002784:Cholesterol