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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

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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.

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Acknowledgements

This research was supported by Telethon Italia grant E1239 and by the Italian Ministry of Health (Ricerca Finalizzata 1999 and Ricerca Corrente 2000).

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Authors and Affiliations

  1. Unit of Endocrinology, Scientific Institute CSS, Viale Cappuccini 1, 71013, San Giovanni Rotondo (FG), Italy

    Giuseppe Miscio, Vittorio Tassi, Angelo Coco, Teresa Soccio, Rosa Di Paola, Sabrina Prudente, Ornella Ludovico, Libera Padovano, Salvatore De Cosmo & Vincenzo Trischitta

  2. Institute of Internal Medicine, Endocrinology and Metabolism Diseases, Hospital Garibaldi, University of Catania, 95100, Catania, Italy

    Roberto Baratta & Lucia Frittitta

  3. Scientific Institute CSS-Mendel, Rome, Italy

    Sabrina Prudente, Bruno Dallapiccola & Vincenzo Trischitta

  4. Department of Clinical Sciences, University La Sapienza, 00100, Rome, Italy

    Umberto Di Mario & Vincenzo Trischitta

  5. Department of Experimental Medicine and Pathology, University La Sapienza, 00100, Rome, Italy

    Bruno Dallapiccola

Authors
  1. Giuseppe Miscio
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  2. Vittorio Tassi
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  3. Angelo Coco
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  4. Teresa Soccio
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  5. Rosa Di Paola
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  6. Sabrina Prudente
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  7. Roberto Baratta
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  8. Lucia Frittitta
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  9. Ornella Ludovico
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  10. Libera Padovano
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  11. Bruno Dallapiccola
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  12. Umberto Di Mario
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  13. Salvatore De Cosmo
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  14. Vincenzo Trischitta
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Corresponding author

Correspondence to Vincenzo Trischitta.

Additional information

Giuseppe Miscio and Vittorio Tassi contributed equally to the work

Appendix

Appendix

Table 4 gives a list of the primers and PCR conditions for the detection of LAR polymorphisms

Table 4 Primers and PCR conditions
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Miscio, G., Tassi, V., Coco, A. et al. 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. J Mol Med 82, 459–466 (2004). https://doi.org/10.1007/s00109-004-0544-1

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  • DOI: https://doi.org/10.1007/s00109-004-0544-1

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