Chromosome 6p21-24 Markers in HIV-Related Kaposi Sarcoma

HIV 相关卡波西肉瘤中的染色体 6p21-24 标记

• 批准号: 6929223
• 负责人: Richard Alan Kaslow
• 金额: $ 26.75万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-27 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929223
• 关键词: AIDS; Kaposi' s sarcoma; biomarker; clinical research; dehydroepiandrosterone; disease /disorder etiology; gender difference; genetic mapping; genetic polymorphism; genetic promoter element; genetic susceptibility; histocompatibility antigens; hormone regulation /control mechanism; human genetic material tag; human herpesvirus 8; human tissue; immune response; male; molecular oncology; neoplasm /cancer epidemiology; neoplasm /cancer genetics; nuclear factor kappa beta; oxygenases; patient oriented research; steroid biosynthesis

DESCRIPTION (provided by applicant): HIV-related Kaposi sarcoma (HIV-KS) is an angioproliferative disease with a striking predilection for men. All cases are infected with Kaposi sarcoma herpes virus (human herpes virus type 8, HHV-8), but not all HHV-8-infected individuals develop HIV-KS. Because virulence does not appear to differ greatly among HHV-8 strains, host determinants undoubtedly play a prominent role in development of disease. Limited genetic investigation of HIV-KS has concentrated on markers in the human leukocyte antigen (HLA) complex on chromosome 6p. Recent work on carefully selected, matched, genotyped, HIV-1/HHV-8-infected cases and controls has failed to confirm previously reported relationships with HLA class II alleles. Rather, it identified an effect of B*1402-DRB1*0102, a common Mediterranean/Jewish haplotype that contains a mutation in CYP21A2 encoding the 21-hydroxylase enzyme for adrenal sex steroid biosynthesis. This study also suggested effects from the chromosome 6p21.3 - 24.1 region harboring the C282Y mutation of HFE, telomeric to HLA, as well as a short tandem repeat (STR) polymorphism of endothelin-1 (EDN1). These observations justify a search for alternative genetic explanations within the HLA region and an extended exploration of 6p21-24 genes that influence immune response, angiogenesis and adrenal steroid biosynthesis. Pairs of KS cases and matched controls already under study will be augmented to a total of more than 400 each for systematic study of targeted non-HLA genes within the HLA complex because of their role in vascular biology (NOTCH4 and AIF1), sex steroid synthesis (CYP21A2), and immune response (NFKBIL1). In addition, the approximately 20 Mb region adjacent to HLA contains a number of genes with plausible roles in the pathogenesis of HIV-KS: interferon regulatory protein-4 (IRF4), HIV-1 enhancer-binding protein (HlVEP1), and an oncogene (DEK), which also interacts with HHV-8 latency-associated nuclear antigen. Extensive genotyping coupled with sophisticated analytic methods for linkage disequilibrium and haplotype effects should uncover HIV-KS genetic susceptibility markers in an already suspect but inadequately studied region. Variation in CYP21A2 and especially EDN1, with its role in KS pathogenesis and interaction with sex hormones, may help account for the strong male predisposition to HIV-KS. Beyond its impact on HIV-KS, the work should contribute valuable information for population genetics of this genomic region.

描述（由申请人提供）：hiv相关的卡波西肉瘤（HIV-KS）是一种血管增生性疾病，主要发生于男性。所有病例都感染了卡波西肉瘤疱疹病毒（人类疱疹病毒8型，HHV-8），但并非所有HHV-8感染者都会发展为HIV-KS。由于HHV-8毒株之间的毒力似乎没有很大差异，宿主决定因素无疑在疾病的发展中起着重要作用。有限的HIV-KS遗传研究主要集中在6p染色体上的人类白细胞抗原（HLA）复合物的标记物上。最近对精心挑选的、匹配的、基因分型的HIV-1/ hhv -8感染病例和对照的研究未能证实先前报道的与HLA II类等位基因的关系。相反，它发现了B*1402-DRB1*0102的影响，B*1402-DRB1*0102是一种常见的地中海/犹太单倍型，含有编码肾上腺性类固醇生物合成的21-羟化酶的CYP21A2突变。该研究还提出了HFE C282Y突变的染色体6p21.3 - 24.1区域、HLA端粒以及内皮素-1 （EDN1）短串联重复（STR）多态性的影响。这些观察结果证明了在HLA区域寻找其他遗传解释和扩展探索影响免疫反应、血管生成和肾上腺类固醇生物合成的6p21-24基因是合理的。由于靶向非HLA基因在血管生物学（NOTCH4和AIF1）、性类固醇合成（CYP21A2）和免疫反应（NFKBIL1）中的作用，已经在研究中的KS病例和匹配对照将增加到总共400多个，用于HLA复合物内靶向非HLA基因的系统研究。此外，HLA附近大约20 Mb的区域包含许多在HIV-KS发病机制中可能起作用的基因：干扰素调节蛋白-4 （IRF4）、HIV-1增强子结合蛋白（HlVEP1）和致癌基因（DEK），它们也与HHV-8潜伏期相关的核抗原相互作用。广泛的基因分型结合复杂的连锁不平衡和单倍型效应分析方法，应该在已经怀疑但研究不足的区域发现HIV-KS遗传易感性标记。CYP21A2，尤其是EDN1的变异，及其在KS发病机制中的作用和与性激素的相互作用，可能有助于解释男性对HIV-KS的强烈易感性。除了对HIV-KS的影响外，这项工作还将为该基因组区域的群体遗传学提供有价值的信息。