Characterization of allelic and nucleotide variation between the RAGE gene on chromosome 6 and a homologous pseudogene sequence to its 5' regulatory region on chromosome 3: implications for polymorphic studies in diabetes.

Activation of the receptor for advanced glycation end products (RAGE) appears to be a key mechanism in the pathogenesis of diabetic vascular disease, making RAGE a candidate gene for investigation. RAGE is located in the major histocompatibility complex locus on chromosome 6, which contains a multitude of overlapping and duplicated genes involved predominantly in inflammatory and immune responses. The RAGE 5' flanking region from -505 in a 5' direction overlaps with PBX2, a gene that has a pseudogene copy on chromosome 3, making any studies of polymorphisms in this duplicated region potentially fraught with error. In this study we have addressed these issues by confirming RAGE as a predominantly single-copy gene and PBX2 to have two gene copies in the haploid human genome. We have characterized the gene:pseudogene differences between RAGE/PBX2 on chromosome 6 and PsiPBX2 on chromosome 3, which include a change from C to A at position -1139 RAGE/+2298 PBX2, previously reported as a polymorphism. Single chromosome-specific DNA amplification of the duplicated region has clarified five polymorphisms to be on chromosome 3 and one (at -1202 RAGE/+2234 PBX2) to be on chromosome 6. In conclusion, this study provides essential data for the study of RAGE and its genetics.