In diabetes, the levels of advanced glycation end products (AGEs) increase as a result of chronic hyperglycemia (1). The best-characterized receptor for AGEs is RAGE. The AGE-RAGE interaction mediates activation and secretion of various cytokines via activation of factors such as the nuclear factor-κB, leading to a proinflammatory process (1). A guanine-to-adenine single nucleotide polymorphism at codon 82 (GGC→AGC) located in exon 3 of RAGE causes the amino acid change glycine to serine (Gly82Ser or G82S polymorphism) within the putative ligand-binding domain of the protein (2). The RAGE Ser82 isoform has been suggested to upregulate the inflammatory response upon engagement of S100/calgranulins, thereby contributing to the enhancement of proinflammatory mechanisms (3). The aim of this study was to investigate the association of the RAGE polymorphism Gly82Ser with type 1 and type 2 diabetes in a Brazilian population compared with a nondiabetic sample.

The ethnic composition of this unrelated sample was 65.4% Euro Brazilian, 33.8% African Brazilian, and 0.8% Asians. The American Diabetes Association criteria for diabetes diagnosis were used. Genotyping was performed by PCR–restriction fragment–length polymorphism using the AluI (AG↓CT) restriction enzyme; the DNA fragments were separated by 10% polyacrylamide (29:1) gel electrophoresis and stained with ethidium bromide. The DNA was then visualized under ultraviolet light and the images captured by a charge-coupled device camera (Biochemi System; UVP). Primers and PCR conditions were as described (2,4). Our university committee for ethics in human research approved this study. We analyzed 82 nondiabetic subjects (38 men and 44 women, aged 58.2 ± 10.1 years, and HbA1c [A1C] 5.2 ± 0.65%), 105 type 1 diabetic patients (41 men and 64 women, aged 24.3 ± 7.1 years, A1C 9.9 ± 2.4%), and 147 type 2 diabetic patients (50 men and 97 women, aged 55.1 ± 11.4 years, A1C 8.7 ± 2.1%).

Nonproliferative diabetic retinopathy was found in 15.4% of the diabetic patients and proliferative retinopathy in 12.4%. Furthermore, 0.9% of the diabetic patients had macrovascular disease, 19.6% had microalbuminuria, and 18.2% had either macroalbuminuria or overt renal insufficiency. We found two genotypes in the population studied: homogyzotes for the Gly82 isoform of RAGE (GG) and heterozygotes Gly82/Ser82 (GS). There were no differences (P > 0.05; two-tailed Fisher’s exact test) in the genotype frequencies (96.3% GG, 3.7% GS for nondiabetic subjects vs. 98.1% GG, 1.9% GS for type 1 diabetic subjects and 97.9% GG, 2.1% GS for type 2 diabetic subjects). No homozygote for the Ser82 isoform (SS) was detected. Of eight individuals with the GS genotype detected in all groups, seven (three nondiabetic, two type 2 diabetic, and two type 1 diabetic subjects) were found among the Euro Brazilians and one (type 2 diabetic) among Asians. The Gly82Ser polymorphism was not found in the African-Brazilian population. Further investigation of the frequency of this polymorphism in African Brazilians must be conducted to clarify the significance of this finding. The genotype frequency of the Gly82Ser polymorphism in this Brazilian population is similar (P > 0.05) to that found in Asian nondiabetic subjects (10%) (2), Caucasian-English type 2 diabetic subjects (7%) (2), Asian-Indian nondiabetic subjects (2%) and type 2 diabetic subjects with retinopathy (7%) (5), Finnish nondiabetic subjects (7%) (6), Caucasian- Czech nondiabetic subjects (0.7%) (4), American-Caucasian nondiabetic subjects (6.9%) and type 2 diabetic subjects (7.9%) (7), and Caucasian-Danish type 1 diabetic subjects with nephropathy (5.9%) (8). However, the frequencies found in this study were significantly lower (P < 0.05) when compared with Chinese nondiabetic (40.4%) and type 2 diabetic (32.3%) subjects (9), Japanese nondiabetic (34.6%) and type 2 diabetic (21.6%) subjects (10), Finnish subjects with coronary heart disease with or without type 2 diabetes (12 and 15%, respectively) (6), Asian-Indian type 2 diabetic subjects without retinopathy (18%) (5), the nondiabetic Caucasian-English population (12%) (2), and Caucasian-Danish type 1 diabetic subjects without nephropathy (9.4%) (8). We found no association of the GS genotype with diabetes complications. However, the lack of clear association of the RAGE polymorphism with diabetes complications may be due to the low frequencies observed in all groups studied.

In conclusion, our data indicate that the Gly82Ser polymorphism of the RAGE gene is not associated with either type 1 or type 2 diabetes in a Brazilian sample, suggesting that this single nucleotide polymorphism may not be associated with development of the disease in this population. Furthermore, our results suggest a very low frequency of the Gly82Ser polymorphism in the African-Brazilian population. This is the first frequency study of the Gly82Ser RAGE polymorphism in a Brazilian population.

Hudson BI, Hofmann MA, Bucciarelli L, Wendt T, Moser B, Lu Y, Qu W, Stern DM, D’Agati V, Yan SD, Yan SF, Grant PJ, Schmidt AM: Glycation and diabetes: the RAGE connection.
Curr Sci
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.
Hofmann MA, Drury S, Hudson BI, Gleason MR, Qu W, Lu Y, Lalla E, Chitnis S, Monteiro J, Stickland MH, Bucciarelli LG, Moser B, Moxley G, Itescu S, Grant PJ, Gregersen PK, Stern DM, Schmidt AM: RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response.
Genes Immun
Kanková K, Záhejský J, Márová I, Muzik J, Kuhrová V, Blazková M, Znojil V, Beránek M, Vácha J: Polymorphisms in the RAGE gene influence susceptibility to diabetes-associated microvascular dermatoses in NIDD.
J Diabetes Complications
Kumaramanickavel G, Ramprasad VL, Sripriya S, Upadyay NK, Paul PG, Sharma T: Association of Gly82Ser polymorphism in the RAGE gene with diabetic retinopathy in type II Asian Indian patients.
J Diabetes Complications
Pulkkinen A, Viitanen L, Kareinen A, Letho S, Laakso M: Gly82Ser polymorphism of the receptor of advanced glycation end product gene is not associated with coronary heart disease in Finnish nondiabetic subjects or in patients with type 2 diabetes (Letter).
Diabetes Care
Hofmann MA, Yang Q, Harja E, Kedia P, Gregersen PK, Cupples LA, Schmidt AM, Hudson BI: The RAGE Gly82Ser polymorphism is not associated with cardiovascular disease in the Framingham Offspring Study.
Poirier O, Nicaud V, Vionnet N, Raoux S, Tarnow L, Vlassara H, Parving H-H, Cambien F: Polymorphism screening of four genes encoding advanced glycation end-product putative receptors: association study with nephropathy in type 1 diabetic patients.
Liu L, Xiang K: RAGE Gly82Ser polymorphism in diabetic microangiopathy (Letter).
Diabetes Care
Yoshioka K, Yoshida T, Takakura Y, Umekawa T, Kogure A, Toda H, Yoshikawa T: Relation between polymorphisms G1704T and G82S of RAGE gene and diabetic retinopathy in Japanese type 2 diabetic patients.
Intern Med

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.