title: Large-Scale Discovery and Validation Studies Demonstrate Significant Reductions in Circulating Levels of IL8, IL-1Ra, MCP-1, and MIP-1β in Patients With Type 1 Diabetes.
abstract: BACKGROUND
  Previous studies have attempted to elucidate the potential role of various cytokines and chemokines in human type 1 diabetes (T1D); however, the precise role of these serum proteins in T1D is still controversial and undetermined primarily due to the small sample sizes of the previous studies. We profiled a panel of serum cytokines and chemokines using a large-scale, two-stage study design for the discovery and validation of the serum proteins associated with T1D.
  
  
  METHODS
  The participants were patients with T1D and islet autoantibody-negative control subjects from the Phenome and Genome of Diabetes Autoimmunity study.
  
  
  METHODS
  Thirteen cytokines and chemokines were measured in serum of 4424 subjects using multiplex immunoassays.
  
  
  RESULTS
  Using 1378 samples in Stage 1, we found that four of the 13 proteins are significantly lower in patients with T1D than controls (IL8: odds ratio [OR] = 0.40; P = 5.7 × 10(-19); IL-1Ra: OR = 0.42; P = 1.1 × 10(-13); MCP-1: OR = 0.60; P = 6.7 × 10(-9); and MIP-1β: OR = 0.63; P = 4.2 × 10(-7)). Our confirmation data with 3046 samples in Stage 2 further confirmed the significant negative associations of these four proteins with T1D (IL8: OR = 0.43; P = 8.9 × 10(-32); IL-1Ra: OR = 0.56, P = 3.7 × 10(-27); MCP-1: OR = 0.61, P = 4.3 × 10(-17); and MIP-1β: OR = 0.69, P = 2.4 × 10(-13)). Quartile analyses also suggested that significantly more T1D cases have protein levels in the bottom quartile than in the top quartile for all four proteins: IL8 (OR = 0.09), IL-1Ra (OR = 0.18), MCP-1 (OR = 0.38), and MIP-1β (OR = 0.44). Furthermore, the negative associations between T1D and serum levels of all four proteins are stronger in genetically high-risk groups compared with the moderate and low-risk groups.
  
  
  CONCLUSIONS
  IL8, IL-1Ra, MCP-1, and MIP-1β are significantly lower in patients with T1D than controls.
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: Sharad
authors.initials: S
authors.lastname: Purohit
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: Diane
authors.initials: D
authors.lastname: Hopkins
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: Leigh
authors.initials: L
authors.lastname: Steed
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: Bruce
authors.initials: B
authors.lastname: Bode
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Anderson
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: John Chip
authors.initials: JC
authors.lastname: Reed
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: R Dennis
authors.initials: RD
authors.lastname: Steed
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Center for Biotechnology and Genomic Medicine (S.P., A.S., D.H., L.S., J-X.S.), Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912; Atlanta Diabetes Associates (B.B.), Atlanta, Georgia 30318; Pediatric Endocrine Associates (S.W.A.), Atlanta, Georgia 30342; Southeastern Endocrine and Diabetes (J.C.R., R.D.S.), Atlanta, Georgia 30076; and Department of Endocrinology (T.Y.), First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China 210029.
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018932:Chemokine CCL2 / Q000097:blood*; D054407:Chemokine CCL4 / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000097:blood*; D005260:Female; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000097:blood*; D016209:Interleukin-8 / Q000097:blood*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054407:Chemokine CCL4; D053590:Interleukin 1 Receptor Antagonist Protein; D016209:Interleukin-8