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

描述（由申请人提供）：HIV相关卡波西肉瘤（HIV-KS）是一种血管增生性疾病，好发于男性。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。HIV-KS的有限遗传学研究集中在染色体6p上人类白细胞抗原（HLA）复合物的标记上。最近的工作仔细选择，匹配，基因分型，HIV-1/HHV-8感染的病例和对照未能证实以前报道的关系与HLA II类等位基因。相反，它确定了B*1402-DRB 1 *0102的作用，这是一种常见的地中海/犹太单倍型，在编码肾上腺性类固醇生物合成的21-羟化酶的CYP 21 A2中含有突变。这项研究还表明，来自染色体6p21.3 - 24.1区域的影响，该区域包含HFE的C282 Y突变，端粒到HLA，以及内皮素-1（EDN 1）的短串联重复序列（STR）多态性。这些观察结果证明了在HLA区域内寻找替代遗传解释和扩展探索影响免疫应答、血管生成和肾上腺类固醇生物合成的6p 21 -24基因的合理性。已经在研究中的KS病例和匹配对照对将增加到总共超过400对，用于HLA复合体中靶向非HLA基因的系统研究，因为它们在血管生物学（NOTCH 4和AIF 1），性类固醇合成（CYP 21 A2）和免疫应答（NFKBIL 1）中的作用。此外，HLA邻近的约20 Mb区域包含许多在HIV-KS发病机制中具有合理作用的基因：干扰素调节蛋白-4（IRF 4）、HIV-1增强子结合蛋白（HVEP 1）和癌基因（DEK），其也与HHV-8潜伏相关核抗原相互作用。 广泛的基因分型加上复杂的分析方法，连锁不平衡和单倍型效应应该发现HIV-KS遗传易感性标记在一个已经怀疑，但研究不足的地区。CYP 21 A2，特别是EDN 1的变化，其在KS发病机制中的作用和与性激素的相互作用，可能有助于解释强烈的男性易感性HIV-KS。除了对HIV-KS的影响外，这项工作还应为该基因组区域的群体遗传学提供有价值的信息。

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.