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Elucidating the Role of SNPs in AKT1 Gene Expression
Author(s) -
Yeh Joannie T,
Harmon Brennan T,
Hoffman Eric P,
Goldspink Paul H
Publication year - 2007
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.21.6.a1152-b
Subject(s) - haplotype , single nucleotide polymorphism , biology , akt1 , enhancer , genetics , gene , transfection , repressor , allele , protein kinase b , transcription factor , signal transduction , genotype
AKT1 is part of the AKT family of intracellular kinases that regulates cell growth, proliferation, survival, and metabolism. In data pending publication, we identified a haplotype upstream of AKT1 that drives human variation in risk for metabolic syndrome and insulin resistance. Two SNPs in this haplotype, ‐C11898A and ‐C8166T, alter evolutionarily conserved nucleotides, and have been shown to alter enhancer and repressor activity in muscle, bone, and fat cells. Given the importance of AKT1 in the heart, we investigated the functional consequences of these upstream regulatory SNPs in heart cells. We transfected H9C2 cells with luciferase vectors, with (Pro) and without (Basic) the SV40 promoter, containing haplotype 1 (ancestral) or haplotype 2 (protects from metabolic syndrome) sequences derived from human subjects. In C8166T Pro vectors, haplotype 2 showed more relative light units (RLU) than haplotype 1, while C11898A Pro vectors did not show a difference in RLU between the two haplotypes. The C8116T region, consistent with haplotype 2 sequences that are protective against metabolic syndrome, shows greater enhancer activity in heart cells. This work is supported by funds from the Craig Summer Research Fellowship, UIC (JTY), by grant RO1 NS40606 and the Parsons Family Foundation (EPH), and by funds from the CCVR, UIC (PHG).