Long-range linkage on chromosome 6p of VEGF, FKBP5, HLA and TNF alleles associated with transplant rejection.

Polymorphisms in several genes on the short arm of chromosome 6 (6p), among them, VEGF, FKBP5, HLA-DR and TNF-alpha, have been associated with inflammation and transplant outcome, such as acute rejection. Independent segregation of these genes is unproven, so we investigated linkage between distant genes on 6p and the putative existence of evolutionarily conserved long-range 6p haplotypes. SNPs studied were VEGF-2578*C/A (rs69947), VEGF-1154*G/A (rs1570360) TNF-alpha-308*G/A (rs1800629) and FKBP5*C/T (rs1360780) in 206 random and 80 selected HLA-DR52 positive individuals. To simplify the analysis, the HLA-DR genotypes were collapsed to the five human ancestral supertypes, namely: HLA-DR51, DR52, DR53, DR1 and DR8. Gametic phase and linkage between paired genotypes were determined using Arlequin 3.01 software, and significance was determined by Chi-square and Fisher's exact test analysis. Significant allelic associations were evident across the 6p region examined. Two putative haplotypes were identified, associated with DR52 and DR1. Within the HLA-DR52 supertype, TNF-alpha -308*A was associated with DR3, while FKBP5*T was associated with DR6. The interval between VEGF and TNF-alpha is 12.31Mb. Therefore, allelic associations are surprising considering expected recombination and the evolutionary time (c10MY) since divergence of DR supertypes. This suggests that DR1 and DR52 haplotypes may have a survival advantage. Within the DR52 supertype, VEGF*C-DR3-TNF -308*A is a 'high inflammatory' haplotype associated with acute and chronic rejection, while the FKBP5*T-DR6 haplotype is associated with resistance to endogenous and exogenous glucocorticoids. Conversely, the DR1 haplotype is a 'low inflammatory' haplotype.