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: 6844803
• 负责人: Richard Alan Kaslow
• 金额: $ 26.57万
• 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 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6844803
• 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(申请人提供)：艾滋病毒相关卡波西肉瘤(HIV-KS)是一种血管增生性疾病，男性有明显的偏好。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)，但并不是所有感染HHV-8的人都会患上HIV-KS。由于HHV-8毒力株之间的毒力似乎没有太大差异，宿主决定因素无疑在疾病的发展中发挥着重要作用。对HIV-KS的遗传学研究有限，主要集中在染色体6p上人类白细胞抗原(人类白细胞抗原)复合体的标记上。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人类白细胞抗原II类等位基因的关系。相反，它发现了B*1402-DRB1*0102的影响，这是一种常见的地中海/犹太人单倍型，含有编码肾上腺性类固醇生物合成21-羟基酶的CYP21A2突变。本研究还提示染色体6p21.3-24.1区域含有HFE的C282Y突变、端粒和内皮素-1(EDN1)的短串联重复序列(STR)多态性。这些观察结果证明了在人类白细胞抗原区域内寻找可供选择的遗传解释，以及对影响免疫反应、血管生成和肾上腺类固醇生物合成的6p21-24基因的深入探索是合理的。由于在血管生物学(NOTCH4和AIF1)、性类固醇合成(CYP21A2)和免疫反应(NFKBIL1)中的作用，已经在研究中的一对KS病例和匹配的对照组将增加到总共400多对，用于系统研究人类白细胞抗原复合体中的目标非人类白细胞抗原基因。此外，在与人类白细胞抗原相邻的约20Mb区域，含有一些在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)和癌基因(Dek)，该基因也与HHV-8潜伏相关核抗原相互作用。广泛的基因分型，再加上复杂的连锁不平衡和单倍型效应分析方法，应该会在一个已经可疑但研究不足的地区发现艾滋病毒-KS遗传易感标记。CYP21A2，尤其是EDN1的变异，及其在KS发病机制中的作用以及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，这项工作还应该为这一基因组区域的群体遗传学提供有价值的信息。