A Cluster of Three Single Nucleotide Polymorphisms in the 3′-Untranslated Region of Human Glycoprotein PC-1 Gene Stabilizes PC-1 mRNA and Is Associated With Increased PC-1 Protein Content and Insulin Resistance–Related Abnormalities
- Lucia Frittitta1,
- Tonino Ercolino2,
- Maura Bozzali34,
- Alessandra Argiolas2,
- Salvo Graci1,
- Maria G. Santagati12,
- Daniela Spampinato1,
- Rosa Di Paola2,
- Carmela Cisternino2,
- Vittorio Tassi2,
- Riccardo Vigneri1,
- Antonio Pizzuti45 and
- Vincenzo Trischitta2
- 1Institute of Internal Medicine, Endocrine and Metabolic Diseases, University of Catania, Ospedale Garibaldi, Catania
- 2Clinical and Research Unit of Endocrinology, Scientific Institute, Casa Sollievo della Sofferenza, San Giovanni Rotondo
- 3Institute of Neurological Diseases, University of Milan, Ospedale Policlinico, Milan
- 4Casa Sollievo della Sofferenza-Mendel Scientific Institute
- 5Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy
Abstract
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 risk 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 oral glucose tolerance test and higher levels of cholesterol, HDL cholesterol, and systolic blood pressure. They also had higher (P < 0.05–0.01) PC-1 protein content in both skeletal muscle and cultured skin fibroblasts. In CHO cells transfected with either P or wild-type cDNA, specific PC-1 mRNA half-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 healthy control subjects (7.8 vs. 1.5%, P < 0.01), thus replicating the association between the P allele and the insulin resistance–related abnormalities observed among Sicilians. In conclusion, we have identified a possible molecular mechanism for PC-1 overexpression that confers an increased risk for insulin resistance–related abnormalities.
Footnotes
-
Address correspondence and reprint requests to V. Trischitta, MD, Clinical and Research Unit of Endocrinology, Scientific Institute, Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo (FG), Italy. E-mail: enzotris{at}tin.it.
Received for publication 12 June 2000 and accepted in revised form 23 April 2001.
AF, allele frequency; ANOVA, analysis of variance; ELISA, enzyme-linked immunosorbent assay; OGTT, oral glucose tolerance test; PCR, polymerase chain reaction; SBP, systolic blood pressure; SNP, single nucleotide polymorphism; SSC, sodium chloride–sodium citrate; SSCP, single-strand conformation polymorphism; UTR, untranslated region.
