Monos D S, Kamoun M, Udalova I A, Csanky E, Cizman B, Turetskaya R L, Smirnova J B, Zharkov V G, Gasser D, Zmijewski C M
Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, USA.
Hum Immunol. 1995 Oct;44(2):70-9. doi: 10.1016/0198-8859(95)00060-h.
The TNF region within the MHC includes a number of immunologically important genes. Microsatellites TNFa and TNFb adjacent to TNF exhibit extensive polymorphism. Employing a PCR-based technique, we identified TNFab haplotypes and defined their distribution in 97 controls and 48 diabetics of Caucasoid origin in a search for other genes within the MHC potentially associated with IDDM. Twenty-five different TNFab haplotypes were identified. A significant difference (p < 0.0005) in frequency between patients and controls was found for TNFa1b5 (relative risk 53). However, no other TNFab microsatellites demonstrated significantly different frequencies. Among diabetics TNFa1b5 was found to be in linkage disequilibrium with HLA-DR3-B18, a haplotype known to be associated with IDDM. Thus the increased frequency of TNFa1b5 among diabetics could reflect a linkage disequilibrium with a gene within the TNF region or with other genes, including the HLAs, which characterize this haplotype. In both controls and diabetics TNFa2b3 and TNFa7b4 were in linkage disequilibrium with DR3-B8 and DR7, respectively. Among diabetics, TNFa2b1 and TNFa6b5 were in linkage disequilibrium with DR4-B62 and DR4-B44, respectively. It is intriguing that TNFab haplotypes, represented by a short piece of about 200 nucleotides in the untranslated region upstream of TNF beta gene, maintain strong linkage disequilibria with different HLA haplotypes extending over 1 million base pairs. The identification of TNFab microsatellites exhibiting a high polymorphic index in a region lacking known polymorphic markers may provide potentially important information regarding the association of HLA haplotypes with autoimmune diseases, as they are in close proximity to other genes of immunologic importance.
MHC内的TNF区域包含许多具有免疫重要性的基因。与TNF相邻的微卫星TNFa和TNFb表现出广泛的多态性。我们采用基于PCR的技术，在97名高加索裔对照者和48名糖尿病患者中鉴定了TNFab单倍型，并确定了它们的分布，以寻找MHC内其他可能与IDDM相关的基因。共鉴定出25种不同的TNFab单倍型。TNFa1b5在患者和对照者中的频率存在显著差异（p < 0.0005）（相对风险为53）。然而，没有其他TNFab微卫星显示出频率上的显著差异。在糖尿病患者中，发现TNFa1b5与HLA - DR3 - B18处于连锁不平衡状态，已知该单倍型与IDDM相关。因此，糖尿病患者中TNFa1b5频率增加可能反映了与TNF区域内基因或其他基因（包括构成该单倍型的HLA基因）的连锁不平衡。在对照者和糖尿病患者中，TNFa2b3和TNFa7b4分别与DR3 - B8和DR7处于连锁不平衡状态。在糖尿病患者中，TNFa2b1和TNFa6b5分别与DR4 - B62和DR4 - B44处于连锁不平衡状态。有趣的是，由TNFβ基因上游非翻译区约200个核苷酸的短片段代表的TNFab单倍型，与延伸超过100万个碱基对的不同HLA单倍型保持着强烈的连锁不平衡。在缺乏已知多态性标记的区域中鉴定出具有高多态性指数的TNFab微卫星，可能会提供有关HLA单倍型与自身免疫性疾病关联的潜在重要信息，因为它们与其他具有免疫重要性的基因紧密相邻。
