title: The allelic variant of LAR gene promoter -127 bp T-->A is associated with reduced risk of obesity and other features related to insulin resistance.
abstract: Insulin resistance, which is pathogenic for type 2 diabetes (T2D), is under the control of largely unknown genetic determinants. LAR, a protein-tyrosine phosphatase which inhibits insulin signalling, is overexpressed in animal and human models of insulin resistance. We studied the entire sequence of the LAR gene by SSCP analysis and automatic DNA sequencing, with the aim of verifying whether its sequence variants might be associated with insulin resistance. In the 276 bp sequence upstream of the transcriptional start site (i.e. a region we have identified as having basal promoter activity) a -127 bp T-->A SNP (5% frequency) was associated with lower body mass index (BMI) ( P=0.03), waist circumference ( P=0.01), blood pressure ( P=0.01) and urinary albumin/creatinine ratio ( P=0.04) in 589 non-diabetic unrelated individuals from the Gargano region (central east coast of Italy). To quantify the risk for a high body weight conferred by the -127 T-->A SNP, the whole cohort was divided into tertiles according to the individual BMI. The risk of belonging to the heavier tertile, as compared to the leaner one, was reduced by approximately 60%. In a population from East Sicily ( n=307), T/A genotype carriers ( n=13) showed lower triglyceride levels ( P=0.04) and higher insulin sensitivity as indicated by lower plasma glucose ( P=0.03) and serum insulin ( P=0.006) during oral glucose tolerance testing (OGTT). Promoter activity, studied by cDNA transfection experiments, was similar for the A and T alleles. In conclusion, a genetic variant of the LAR gene promoter is consistently associated with features of insulin resistance in two different Caucasian populations. Although the biological relevance of this variant has yet to be determined, this finding underlines the potential importance of the LAR gene in dysregulation of insulin sensitivity and related disorders.
authors.affiliation: Unit of Endocrinology, Scientific Institute CSS, Viale Cappuccini 1, 71013 San Giovanni Rotondo (FG), Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Miscio
authors.forename: Vittorio
authors.initials: V
authors.lastname: Tassi
authors.forename: Angelo
authors.initials: A
authors.lastname: Coco
authors.forename: Teresa
authors.initials: T
authors.lastname: Soccio
authors.forename: Rosa
authors.initials: R
authors.lastname: Di Paola
authors.forename: Sabrina
authors.initials: S
authors.lastname: Prudente
authors.forename: Roberto
authors.initials: R
authors.lastname: Baratta
authors.forename: Lucia
authors.initials: L
authors.lastname: Frittitta
authors.forename: Ornella
authors.initials: O
authors.lastname: Ludovico
authors.forename: Libera
authors.initials: L
authors.lastname: Padovano
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.forename: Umberto
authors.initials: U
authors.lastname: Di Mario
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Cosmo
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Trischitta
mesh_terms: D000328:Adult; D000483:Alleles; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2; D011956:Receptors, Cell Surface / Q000235:genetics*
chemical_list: D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; C516772:PTPRF protein, human; D017027:Protein Tyrosine Phosphatases; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2