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

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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.