University of Southern California, Los Angeles, USA.
Mol Immunol. 2009 Nov;47(1):96-100. doi: 10.1016/j.molimm.2009.01.006. Epub 2009 Feb 23.
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-2578C/A (rs69947), VEGF-1154G/A (rs1570360) TNF-alpha-308G/A (rs1800629) and FKBP5C/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 -308A was associated with DR3, while FKBP5T 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, VEGFC-DR3-TNF -308A 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.
6 号染色体短臂上的几个基因（6p）中的多态性，包括 VEGF、FKBP5、HLA-DR 和 TNF-α，与炎症和移植结果（如急性排斥反应）有关。这些基因的独立分离尚未得到证明，因此我们研究了 6p 上远距离基因之间的连锁关系以及假定存在进化上保守的长距离 6p 单倍型。在 206 名随机和 80 名选定的 HLA-DR52 阳性个体中，研究了 VEGF-2578C/A(rs69947)、VEGF-1154G/A(rs1570360)、TNF-α-308G/A(rs1800629)和 FKBP5C/T(rs1360780)的 SNP。为了简化分析，将 HLA-DR 基因型合并为五个人类祖先超型，即 HLA-DR51、DR52、DR53、DR1 和 DR8。使用 Arlequin 3.01 软件确定配对基因型的配子相位和连锁，并通过卡方和 Fisher 精确检验分析确定显著性。在检查的 6p 区域中，明显存在等位基因关联。鉴定出两个假定的单倍型，与 DR52 和 DR1 相关。在 HLA-DR52 超型中，TNF-α-308A 与 DR3 相关，而 FKBP5T 与 DR6 相关。VEGF 和 TNF-α 之间的间隔为 12.31Mb。因此，考虑到预期的重组和 DR 超型分化以来的进化时间（c10MY），等位基因关联令人惊讶。这表明 DR1 和 DR52 单倍型可能具有生存优势。在 DR52 超型中，VEGFC-DR3-TNF-α-308A 是一种与急性和慢性排斥反应相关的“高炎症”单倍型，而 FKBP5*T-DR6 单倍型与对内源性和外源性糖皮质激素的抗性相关。相反，DR1 单倍型是一种“低炎症”单倍型。
