Common variation in a putative regulatory region of STAM2 is associated with skeletal muscle expression of STAM2 and increased risk for type 2 diabetes in American Indians

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NIDDK	GEN-10

* FARE Award Winner

Authors

• AK Nair
• RL Hanson
• P Piaggi
• N Mclean
• YL Muller
• K Huang
• S Kobes
• WC Knowler
• C Bogardus
• LJ Baier

Abstract

A recent genome-wide association study in Pima Indians identified a nominal association for rs10930939 in STAM2 with Type 2 Diabetes (T2D) in full heritage Pima Indians. The focus of the current study was to further investigate this signal. Whole genome sequence data from 234 Pima Indians identified rs10930939 to be in high LD (r2=1) with rs4368329 that maps to ENCODE transcription factor binding site (TFBS) in the promoter of STAM2. Based on the LD pattern, tag SNPs (r2>0.8) and ENCODE TFBS SNPs in STAM2 were genotyped in 3604 full heritage Pima Indians and significant associations were replicated in 4063 mixed heritage American Indians. Three ENCODE TFBS variants (rs6740224, rs4368329, rs60252671) and an intronic variant (rs7603232) associated with T2D; the strongest evidence for association was for rs7603232 (P=1.1×10-5, OR=1.23[1.12-1.35]). The T2D risk alleles of these variants increased the expression of STAM2 mRNA in skeletal muscles biopsies from 208 Pima Indians (P=2.5×10-3 – 6.3×10-4, β= 0.29-0.34 SD units) and luciferase assay further identified rs4368329 as a functional variant in C2C12 cells(P=0.001). STAM2 is involved in the sorting and cell surface expression of ubiquitinated receptors including receptor tyrosine kinases and may play a role in determining the cell surface availability of insulin receptor.

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