fc75aa4a-caba-4f68-a13a-325f9117cdec
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.
c5abebc1-28c4-4b1b-b1b8-6addad3944d4
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.