MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital University of Oxford, Oxford, Oxfordshire, United Kingdom.
PLoS One. 2012;7(7):e40100. doi: 10.1371/journal.pone.0040100. Epub 2012 Jul 13.
A large body of functional and epidemiological evidence have previously illustrated the impact of specific MHC class I subtypes on clinical outcome during HIV-1 infection, and these observations have recently been re-iterated in genome wide association studies (GWAS). Yet because of the complexities surrounding GWAS-based approaches and the lack of knowledge relating to the identity of rarer single nucleotide polymorphism (SNP) variants, it has proved difficult to discover independent causal variants associated with favourable immune control. This is especially true of the candidate variants within the HLA region where many of the recently proposed disease influencing SNPs appear to reflect linkage with 'protective' MHC class I alleles. Yet causal MHC-linked SNPs may exist but remain overlooked owing to the complexities associated with their identification. Here we focus on the ancestral TNFα promoter -237A variant (rs361525), shown historically to be in complete linkage disequilibrium with the 'protective' HLA-B5701 allele. Many of the ancestral SNPs within the extended TNFα promoter have been associated with both autoimmune conditions and disease outcomes, however, the direct role of these variants on TNFα expression remains controversial. Yet, because of the important role played by TNFα in HIV-1 infection, and given the proximity of the -237 SNP to the core promoter, its location within a putative repressor region previously characterized in mice, and its disruption of a methylation-susceptible CpG dinucleotide motif, we chose to carefully evaluate its impact on TNFα production. Using a variety of approaches we now demonstrate that carriage of the A SNP is associated with lower TNFα production, via a mechanism not readily explained by promoter methylation nor the binding of transcription factors or repressors. We propose that the -237A variant could represent a minor causal SNP that additionally contributes to the HLA-B5701-mediated 'protective' effect during HIV-1 infection.
大量的功能和流行病学证据以前表明，特定 MHC Ⅰ类亚型对 HIV-1 感染过程中的临床结果有影响，最近的全基因组关联研究（GWAS）也再次证实了这一点。然而，由于基于 GWAS 的方法的复杂性以及与罕见单核苷酸多态性（SNP）变体的身份相关的知识缺乏，因此很难发现与有利的免疫控制相关的独立因果变体。这在 HLA 区域内的候选变体中尤其如此，最近提出的许多影响疾病的 SNP 似乎反映了与“保护性”MHC Ⅰ类等位基因的连锁。然而，由于与它们的鉴定相关的复杂性，因果 MHC 相关 SNP 可能存在但仍未被发现。在这里，我们重点关注历史上与“保护性”HLA-B5701 等位基因完全连锁的祖先 TNFα 启动子-237A 变体（rs361525）。扩展的 TNFα 启动子内的许多祖先 SNP 与自身免疫性疾病和疾病结果有关，然而，这些变体对 TNFα 表达的直接作用仍然存在争议。然而，由于 TNFα 在 HIV-1 感染中起着重要作用，并且由于-237 SNP 靠近核心启动子，位于先前在小鼠中表征的假定抑制剂区域内，以及破坏了甲基化敏感的 CpG 二核苷酸基序，我们选择仔细评估其对 TNFα 产生的影响。现在，我们使用各种方法证明，通过一种不易用启动子甲基化或转录因子或抑制剂的结合来解释的机制，携带 A SNP 与 TNFα 产生较低有关。我们提出-237A 变体可能代表一个次要的因果 SNP，它另外有助于 HLA-B5701 介导的 HIV-1 感染中的“保护性”效应。
