A cluster of three single nucleotide polymorphisms in the 3 '-untranslatedregion of human glycoprotein PC-1 gene stabilizes PC-1 mRNA and is associated with increased PC-1 protein content and insulin resistance-related abnormalities

Glycoprotein PC-1 inhibits insulin signaling and, when overexpressed, plays a role in human insulin resistance. Mechanisms of PC-1 overexpression are unknown. We have identified a haplotype in the 3 ' -untranslated region of the PC-1 gene that may modulate PC-1 expression and confer an increased ris k for insulin resistance. Individuals from Sicily, Italy, carrying the "P" haplotype (i.e., a cluster of three single nucleotide polymorphisms: G2897A , G2906C, and C2948T) were at higher risk (P < 0.01) for insulin resistance and had higher (P < 0.05) levels of plasma glucose and insulin during an o ral glucose tolerance test and higher levels of cholesterol, HDL cholestero l, and systolic blood pressure. They also had higher (P < 0.05-0.01) PC-1 p rotein content in both skeletal muscle and cultured skin fibroblasts. In CH O cells transfected with either P or wild-type cDNA, specific PC-1 mRNA hal f-life was increased for those transfected with P (t/2 = 3.73 +/- 1.0 vs. 1 .57 +/- 0.2 h; P < 0.01). In a population of different ethnicity (Gargano, East Coast Italy), patients with type 2 diabetes (the most likely clinical outcome,of insulin resistance) had a higher P haplotype frequency than heal thy control subjects (7.8 vs. 1.5%, P < 0.01), thus replicating the associa tion between the P allele and the insulin resistance-related abnormalities observed among Sicilians. In conclusion, we have identified a possible mole cular mechanism for PC-1 overexpression that confers an increased risk for insulin resistance-related abnormalities.