The SH2B Gene is Associated with Serum Leptin and Body Fat in Normal Female Twins

Abstract Src‐homology‐2 (SH2)‐B, a Janus tyrosine kinase 2‐interacting protein, has been identified recently as a key regulator of leptin and insulin sensitivity, glucose homeostasis, and body weight in mice. The aim of this study was to determine whether single‐nucleotide polymorphisms (SNPs) in the human SH2B gene are associated with these variables. A tagging SNP (tSNP), Ala484Thr (rs7498665), was selected to represent five common SNPs (minor allele frequency > 0.05) in perfect linkage disequilibrium in a 16‐kb region encompassing the SH2B gene. The tSNP was genotyped in 2455 white female twins (mean age, 47.4 ± 12.6 years) from the St. Thomas’ United Kingdom Adult Twin Registry (Twins United Kingdom). Ala484Thr (minor allele frequency, 0.38) was associated with serum leptin, total fat, waist circumference, and body weight ( P = 0.02 to 0.04). The coding SNP has no predicted effect on protein structure or function and is likely to be in linkage disequilibrium with an as‐yet unidentified functional variant in the SH2B gene. Our results support a role for SH2‐B in modulating the regulation of body weight and fat by leptin in this female population. If SH2‐B signaling is attenuated in diet‐induced obesity, it could become a target for drug‐induced leptin sensitization.