Background: Endothelin-1 is a vascular growth factor involved in the pathogenesis of cardiovascular diseases and in angiogenesis accompanying malignancy. Because endothelin expression is regulated by sex hormones, variability in expression may help explain excess male susceptibility to certain neoplasms, the most striking of which is Kaposi’s sarcoma (KS). The gene encoding endothelin-1, EDN1, shows modest genetic linkage to the HLA complex, but its polymorphism has not been investigated in relation to HLA alleles or in the context of malignancy.

Methods: Subjects from the Multicenter AIDS Cohort Study included 147 men with HIV-associated KS (HIV-KS) and 147 HIV-positive controls matched for disease progression. We evaluated two EDN1 polymorphisms: a variable nucleotide tandem repeat (VNTR) and an intron 4 single nucleotide polymorphism (SNP) identified by TaqI RFLP. HLA typing data was also available. Previously HLA-typed cell lines in 60 Caucasians permitted determination of linkage distribution (LD).

Results: Neither of the single genetic variants was significantly associated with KS. A combination of allele 8 at the VNTR plus variant b of the SNP in intron 4, which are in linkage disequilibrium with each other (LD, D = 0.0105, p = 0.018), occurred in significantly lower proportion in HIV-KS than in controls (Odds ratio = 0.24, 95% confidence interval = 0.06–0.72, McNemar p = 0.009). Because no significant LD observed between EDN1 and HLA-A or -B alleles, HLA linkage to EDN1 did not explain the association.

Conclusions: A combination of two EDN1 polymorphisms in LD showed a protective effect in HIV-KS, suggesting a role for endothelin similar to that observed in other diseases characterized by endothelial pathology. The promoter region of this haplotype could be less responsive to androgenic stimulation, with reduced promoter activity in turn influencing the inordinately high male susceptibility to KS.