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GWAS nominated gene SH2B3 increases cardiac remodeling and inflammation associated with type 1 diabetes (T1D)
Author(s) -
Flister Michael,
Jia Shuang,
Tsaih Shirng-Wern,
Sarkis Allison,
Zheng Sasha,
Geurts Aron,
Moreno-Quinn Carol,
Lazar Jozef,
Hessner Martin J,
Jacob Howard
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1057.25
Subject(s) - inflammation , medicine , endocrinology , chemistry , immunology
SH2B3 functions largely as a negative regulator of inflammation. The rs3184504 [T] allele of SH2B3 causes an R262W substitution that is associated with multiple inflammatory diseases, yet the effect of R262W on SH2B3 function and downstream target pathways is completely unknown. We found the homozygous SH2B3 rs3184504 [T] allele (referred to as TT) to be significantly associated with T1D [( P = 0.04; OR = 1.49 (95% CI: 1.02–2.19)] compared with rs3184504 [C] alleles (CC/CT). We tested the role of rs3184504 [T] by performing microarray analysis of peripheral blood mononuclear cells (PBMCs) to detect inflammatory factors in serum of SH2B3‐genotyped T1D patients (n=48) and controls (n=44). Compared with CC/CT, T1D patients with TT had 377 elevated genes, including many that are associated with T1D and cardiac remodeling (e.g., CCL2, IL1R2, CD36, and CCR5). RNAseq of PBMCs from SS Sh2b3mut rats showed 534 elevated genes compared to WT, of which 84 corresponded to TT associated genes in T1D. SH2B3 associated genes were significantly enriched in multiple inflammatory pathways (e.g., NF‐κB, IL1β, IL6, TGFβ, and TNFα). Following aortic banding, SS Sh2b3mut rats had higher interstitial fibrosis (7.0% vs 4.2%), 40% thicker LV walls, and 21% decrease in capillary density compared to WT. Collectively, we show that rs3184504 [T] alters SH2B3 function and elevates T1D associated inflammation. Support: NHLBI5R01HL089930 to HJJ.