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SH2B3 (lnk) Regulates Type 1 Diabetes Immune Phenotypes

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Background: The type 1 diabetes (T1D)-associated risk gene SH2B Adaptor Protein 3 (SH2B3) encodes a phosphatase with specificity for Janus Kinase 2 (JAK2). We hypothesized that variations in SH2B3 would… Click to show full abstract

Background: The type 1 diabetes (T1D)-associated risk gene SH2B Adaptor Protein 3 (SH2B3) encodes a phosphatase with specificity for Janus Kinase 2 (JAK2). We hypothesized that variations in SH2B3 would affect immune signaling pathways relevant to T1D autoimmunity. Here we report: 1) Occurrence of the SH2B3 risk variant among T1D patients, unaffected first-degree relatives and controls; 2) Prevalence of SH2B3 risk genotype in African Americans in the Southeastern U.S.; and 3) Alterations to immune composition associated with the SH2B3 risk variant. Approach and Results: 1) The University of Florida Diabetes Institute (UFDI) cohort (n=1946) was analyzed for genetic risk of T1D using a Taqman single nucleotide polymorphism (SNP) genotyping array with coverage of 32 SNPs. Two SNPs (rs3184504 and rs653178) corresponding to SH2B3 were in perfect linkage disequilibrium and will be described here as minor (T1D risk) or common variant. Among Caucasian subjects, the odds ratio (OR) for the minor variant among T1D subjects was 1.30 (1.06-1.59, p=1.42x10-2), similar to previous reports. Among African American subjects, the minor variant OR was elevated (2.93, 1.22-7.03, p=1.30x10-2), representing the most highly-associated non-HLA gene. Complete blood count (CBC, n=954) and flow cytometric human immunophenotyping (HIP, n=252) were performed on a subset of subjects. Individuals carrying the risk variant of SH2B3 had significantly more blood monocytes and neutrophils but similar numbers of lymphocytes compared to non-carriers. HIP revealed a significantly higher frequency of type 1 (CXCR3+) CD8+ T cells in subjects with the risk variant of SH2B3. Conclusions: The risk variant of SH2B3 is associated with both increased risk for T1D and seroconversion in Caucasian and African American subjects. Phenotypically, this element of T1D genetic risk presents as increased frequency of some myeloid cell populations and either expansion or polarization of CD8+ T cells bearing the canonical Th1 chemokine receptor CXCR3. Disclosure A. Camargo: None. D.J. Perry: None. T.M. Brusko: Stock/Shareholder; Self; OneVax, LLC. Advisory Panel; Self; Caladrius Biosciences, Inc.. Consultant; Self; Merck & Co., Inc., Sanofi-Aventis. M.A. Wallet: None.

Keywords: risk variant; t1d; risk; variant; type diabetes; sh2b3

Journal Title: Diabetes
Year Published: 2018

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