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: 7099622
• 负责人: Richard Alan Kaslow
• 金额: $ 26.12万
• 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/7099622
• 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，男性明显多发。所有病例均感染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 感染者都会出现 HIV-KS。由于 HHV-8 毒株之间的毒力似乎没有很大差异，因此宿主决定因素无疑在疾病的发展中发挥着重要作用。 HIV-KS 的有限遗传研究集中在 6p 染色体上人类白细胞抗原 (HLA) 复合物的标记上。最近对精心挑选、匹配、基因分型的 HIV-1/HHV-8 感染病例和对照进行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，它鉴定了 B*1402-DRB1*0102 的作用，B*1402-DRB1*0102 是一种常见的地中海/犹太单倍型，其中包含编码用于肾上腺性类固醇生物合成的 21-羟化酶的 CYP21A2 突变。这项研究还表明，染色体 6p21.3 - 24.1 区域含有 HFE、端粒到 HLA 的 C282Y 突变，以及内皮素-1 (EDN1) 的短串联重复 (STR) 多态性。这些观察结果证明在 HLA 区域内寻找替代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 基因进行扩展探索是合理的。已经在研究的 KS 病例对和匹配对照将增加到总共 400 多对，用于对 HLA 复合体中的目标非 HLA 基因进行系统研究，因为它们在血管生物学（NOTCH4 和 AIF1）、性类固醇合成中的作用（CYP21A2）和免疫反应（NFKBIL1）。此外，与 HLA 相邻的大约 20 Mb 区域包含许多在 HIV-KS 发病机制中可能发挥作用的基因：干扰素调节蛋白 4 (IRF4)、HIV-1 增强子结合蛋白 (HlVEP1) 和癌基因(DEK)，它也与 HHV-8 潜伏相关核抗原相互作用。 广泛的基因分型与连锁不平衡和单倍型效应的复杂分析方法相结合，应该可以在一个已经可疑但研究不充分的区域发现 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 的影响之外，这项工作还应该为该基因组区域的群体遗传学提供有价值的信息。