RAGE polymorphisms and the heritability of insulin resistance: the Leeds Family Study

Abstract

Activation of the receptor for advanced glycation end-products (RAGE) leads to a cascade of pro-inflammatory and pro-coagulant responses which are important in the pathogenesis of the vascular complications of diabetes mellitus. It is known that pro-inflammatory mechanisms underpin the development of type 2 diabetes. Our hypothesis is that RAGE may be involved in the evolution of insulin resistance in addition to mediating glucotoxic complications of diabetes mellitus.

Methods To investigate the relationship between RAGE allelic variation and insulin resistance, the Gly82Ser variant and three promoter variants (429, 374, 63 bp deletion) were studied in 480 subjects of known relationship from 89 families characterised for insulin resistance (using homeostasis model assessment [HOMA]) and for atherothrombotic risk. Carriage of the-429 C allele was weakly associated with increased insulin resistance (p=0.02) when pedigree analysis was performed using SOLAR software.

Results Insulin resistance was estimated to have a heritability of 25.8% before the addition of covariates. Analysis of the relationship between RAGE and insulin resistance indicated that the-429 polymorphism reduced the unexplained heritability of insulin resistance after adjusting for covariates (age, sex, body mass index) from 17.5% of the total variance to 15.6% of the total variance.

Conclusions These preliminary results indicate that the RAGE gene may affect the development of insulin resistance or be in linkage disequilibrium with a locus involved in this process.

Keywords

RAGE insulin resistance advanced glycation end-products polymorphism population studies

References

1. Stern MP. Diabetes and cardiovascular disease. The “common soil” hypothesis. Diabetes 1995;44:369–74.

2. Hofmann MA , Drury S , Fu C et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 1999;97:889–901.

3. Basta G , Lazzerini G , Massaro M et al. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation 2002;105:816–22.

4. Park L , Raman KG , Lee KJ et al. Suppression of accelerated diabetic atherosclerosis by the soluble receptor for advanced glycation end-products. Nat Med 1998;4:1025–31.

5. Pradhan AD , Manson JE , Rifai N , Buring JE , Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001;286:327–34.

6. Freeman MS , Mansfield MW , Barrett JH , Grant PJ. Genetic contribution to circulating levels of hemostatic factors in healthy families with effects of known genetic polymorphisms on heritability. Arterioscler Thromb Vasc Biol 2002;22:506–10.

7. Hudson BI , Stickland MH , Grant PJ. Identification of polymorphisms in the receptor for advanced glycation end products (RAGE) gene: prevalence in type 2 diabetes and ethnic groups. Diabetes 1998;47:1155–7.

8. Matthews DR , Hosker JP , Rudenski AS , Naylor BA , Treacher DF , Turner RC. Homeostasis model assessment: insulin resistance and (3-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412–19.

9. Mander AP. Analysis of quantitative traits using regression and log-linear modelling when phase is unknown. Stata J 2002;2:65–70.

10.

10. Almasy L , Blangero J. Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 1998;62:1198–211.

11.

11. Hudson BI , Stickland MH , Futers TS , Grant PJ. Effects of novel polymorphisms in the RAGE gene on transcriptional regulation and their association with diabetic retinopathy. Diabetes 2001;50:1505–11.

12.

12. Marx N , Walcher D , Ivanova N et al. Thiazolidinediones reduce endothelial expression of receptors for advanced glycation end products. Diabetes 2004;53:2662–8.

13.

13. Chen Y , Yan SS , Colgan J et al. Blockade of late stages of autoimmune diabetes by inhibition of the receptor for advanced glycation end products. J Immunol 2004;173:1399–405.