Abstract

A variant upstream of human leukocyte antigen C (HLA-C) shows the most significant genome-wide effect on HIV control in European Americans and is also associated with the level of HLA -C expression.

We characterized the differential cell surface expression levels of all common HLA -C allotypes and tested directly for effects of HLA -C expression on outcomes of HIV infection in 5243 individuals. Increasing HLA -C expression was associated with protection against multiple outcomes independently of individual HLA allelic effects in both African and European Americans, regardless of their distinct HLA -C frequencies and linkage relationships with HLA -B and HLA -A.

Higher HLA -C expression was correlated with increased likelihood of cytotoxic T lymphocyte responses and frequency of viral escape mutation. In contrast, high HLA -C expression had a deleterious effect in Crohn’s disease, suggesting a broader influence of HLA expression levels in human disease.