TY - JOUR
T1 - The 3p21.31 genetic locus promotes progression to type 1 diabetes through the CCR2/CCL2 pathway
AU - Tran, Paul MH
AU - Purohit, Sharad
AU - Kim, Eileen
AU - bin Satter, Khaled
AU - Hopkins, Diane
AU - Waugh, Kathleen
AU - Dong, Fran
AU - Onengut-Gumuscu, Suna
AU - Rich, Stephen S.
AU - Rewers, Marian
AU - She, Jin-Xiong
N1 - Funding Information:
Support for this work to JXS was provided by the National Institutes of Health ( R21HD050196 , R33HD050196 , and 2RO1HD37800 ). SP was supported by Postdoctoral Fellowship ( 10-2006-792 and 3-2004-195 ) and Career Development Award ( 2-2011-153 ) from JDRF. PMHT was supported by NIH/NIDDK fellowship ( F30DK121461 ). Diabetes Autoimmunity Study in the Young (MR, KW, and FD) is supported by the National Institutes of Health ( R01 DK032493 and P30 DK116073 ) and Helmsley Charitable Trust ( G-1901-03687 ). This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) , National Institute of Allergy and Infectious Diseases (NIAID) , National Human Genome Research Institute (NHGRI) , National Institute of Child Health and Human Development (NICHD) , and JDRF and supported by U01 DK062418 .
Publisher Copyright:
© 2021 The Authors
PY - 2021/1
Y1 - 2021/1
N2 - Multiple cross-sectional and longitudinal studies have shown that serum levels of the chemokine ligand 2 (CCL-2) are associated with type 1 diabetes (T1D), although the direction of effect differs. We assessed CCL-2 serum levels in a longitudinal cohort to clarify this association, combined with genetic data to elucidate the regulatory role of CCL-2 in T1D pathogenesis. The Diabetes Autoimmunity Study in the Young (DAISY) followed 310 subjects with high risk of developing T1D. Of these, 42 became persistently seropositive for islet autoantibodies but did not develop T1D (non-progressors); 48 did develop T1D (progressors). CCL-2 serum levels among the three study groups were compared using linear mixed models adjusting for age, sex, HLA genotype, and family history of T1D. Summary statistics were obtained from the CCL-2 protein quantitative trait loci (pQTL) and CCR2 expression QTL (eQTL) studies. The T1D fine mapping association data were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). Serum CCL-2 levels were significantly lower in both progressors (p = 0.004) and non-progressors (p = 0.005), compared to controls. Two SNPs (rs1799988 and rs746492) in the 3p21.31 genetic locus, which includes the CCL-2 receptor, CCR2, were associated with increased CCR2 expression (p = 8.2e-5 and 5.2e-5, respectively), decreased CCL-2 serum level (p = 2.41e-9 and 6.21e-9, respectively), and increased risk of T1D (p = 7.9e-5 and 7.9e-5, respectively). The 3p21.31 genetic region is associated with developing T1D through regulatory control of the CCR2/CCL2 immune pathway.
AB - Multiple cross-sectional and longitudinal studies have shown that serum levels of the chemokine ligand 2 (CCL-2) are associated with type 1 diabetes (T1D), although the direction of effect differs. We assessed CCL-2 serum levels in a longitudinal cohort to clarify this association, combined with genetic data to elucidate the regulatory role of CCL-2 in T1D pathogenesis. The Diabetes Autoimmunity Study in the Young (DAISY) followed 310 subjects with high risk of developing T1D. Of these, 42 became persistently seropositive for islet autoantibodies but did not develop T1D (non-progressors); 48 did develop T1D (progressors). CCL-2 serum levels among the three study groups were compared using linear mixed models adjusting for age, sex, HLA genotype, and family history of T1D. Summary statistics were obtained from the CCL-2 protein quantitative trait loci (pQTL) and CCR2 expression QTL (eQTL) studies. The T1D fine mapping association data were provided by the Type 1 Diabetes Genetics Consortium (T1DGC). Serum CCL-2 levels were significantly lower in both progressors (p = 0.004) and non-progressors (p = 0.005), compared to controls. Two SNPs (rs1799988 and rs746492) in the 3p21.31 genetic locus, which includes the CCL-2 receptor, CCR2, were associated with increased CCR2 expression (p = 8.2e-5 and 5.2e-5, respectively), decreased CCL-2 serum level (p = 2.41e-9 and 6.21e-9, respectively), and increased risk of T1D (p = 7.9e-5 and 7.9e-5, respectively). The 3p21.31 genetic region is associated with developing T1D through regulatory control of the CCR2/CCL2 immune pathway.
KW - Autoimmune
KW - CCL2
KW - CCR2
KW - DAISY
KW - Fine mapping
KW - MCP1
KW - T1D
UR - http://www.scopus.com/inward/record.url?scp=85122821418&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85122821418&partnerID=8YFLogxK
U2 - 10.1016/j.jtauto.2021.100127
DO - 10.1016/j.jtauto.2021.100127
M3 - Article
AN - SCOPUS:85122821418
VL - 4
JO - Journal of Translational Autoimmunity
JF - Journal of Translational Autoimmunity
SN - 2589-9090
M1 - 100127
ER -