A variation in 3' UTR of hPTP1B increases specific gene expression and associates with insulin resistance.
Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling and, when overexpressed, plays a role in insulin resistance (Ahmad et al. 1997). We identified, in the 3' untranslated region of the PTP1B gene, a 1484insG variation that, in two different populations, is associated with several features of insulin resistance: among male individuals, higher values of the insulin resistance HOMA(IR) index (P=.006), serum triglycerides (P=.0002), and total/HDL cholesterol ratio (P=.025) and, among female individuals, higher blood pressure (P=.01). Similar data were also obtained in a family-based association study by use of sib pairs discordant for genotype (Gu et al. 2000). Subjects carrying the 1484insG variant showed also PTP1B mRNA overexpression in skeletal muscle (6,166 plus minus 1,879 copies/40 ng RNA vs. 2,983 plus minus 1,620; P<.01). Finally, PTP1B mRNA stability was significantly higher (P<.01) in human embryo kidney 293 cells transfected with 1484insG PTP1B, as compared with those transfected with wild-type PTP1B. Our data indicate that the 1484insG allele causes PTP1B overexpression and plays a role in insulin resistance. Therefore, individuals carrying the 1484insG variant might particularly benefit from PTP1B inhibitors, a promising new tool for treatment of insulin resistance (Kennedy and Ramachandran 2000).
Di Paola
Rosa
R
Unit of Endocrinology, Scientific Institute CSS, San Giovanni Rotondo (FG), Italy.
Frittitta
Lucia
L
Miscio
Giuseppe
G
Bozzali
Maura
M
Baratta
Roberto
R
Centra
Marta
M
Spampinato
Daniela
D
Santagati
Maria Grazia
MG
Ercolino
Tonino
T
Cisternino
Carmela
C
Soccio
Teresa
T
Mastroianno
Sandra
S
Tassi
Vittorio
V
Almgren
Peter
P
Pizzuti
Antonio
A
Vigneri
Riccardo
R
Trischitta
Vincenzo
V
D020413:3' Untranslated Regions / Q000235:genetics*; D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000097:blood; D003609:Dactinomycin / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D005215:Fasting / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D007438:Introns / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D020413:3' Untranslated Regions; D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D014280:Triglycerides; D003609:Dactinomycin; D002784:Cholesterol; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases