Genome-wide association study identifies and validates genetic variation in the RIG-I/MAVS signaling pathway...

Immune deficiency and infection with human herpesvirus-8 (HHV-8) are established component causes of Kaposi sarcoma (KS), but they are insufficient to cause disease in most people at risk. Therefore, we hypothesized that genetic variation may contribute to KS risk in children and adults, as well as contribute to its unique epidemiology in sub-Saharan Africa.

To test this hypothesis, we conducted a two-phase genome-wide association study (GWAS): a discovery study in perinatally HIV-infected children (45 KS cases, 91 controls), followed by validation of significant results in a sample of adults living with HIV (215 cases, 262 controls). After standard quality control, we tested single-nucleotide variants for association with KS.

In children, the top signal was a missense variant in the mitochondrial antiviral-signaling (MAVS) gene (rs7269320), which showed a suggestive allelic association with KS (OR 3.8, 95% CI 2.2 -6.7, p=9.7×10^-7). In the adult validation study, the same MAVS variant was again associated with KS, indicating a recessive inheritance pattern (OR 2.2, 95% CI 1.2 -3.9, p=0.006). MAVS is a component of the RIG-I/MAVS signaling pathway and a biologically plausible genetic variant contributing to KS oncogenesis. MAVS protein deficiency/dysfunction is known to impair the antiviral cytokine response to HHV-8 infection and enhance its reactivation.

These findings provide the first pediatric evidence of germline susceptibility to KS and suggest RIG-I/MAVS as a candidate pathway for host risk. Further replication and functional studies are needed to clarify the mechanism underlying the risk associated with MAVS and to assess whether it could be used to identify individuals at the highest risk for KS in high-burden settings and/or be leveraged as a novel therapeutic strategy.