The causality between CD8⁺NKT cells and CD16⁻CD56 on NK cells with hepatocellular carcinoma: a Mendelian randomization study

Hepatocellular carcinoma (HCC), which is featured with high morbidity and mortality worldwide, is a primary malignant tumor of the liver. Recently, there is a wealth of supporting evidence revealing that NK cell-related immune traits are strongly associated with the development of HCC, but the causality between them has not been proven.

Two-sample Mendelian randomization (MR) study was performed to probe the causal correlation between NK cell-related immune traits and HCC. Genetic variations in NK cell-related immune traits were extracted from recent genome-wide association studies (GWAS) of individuals with European blood lineage. HCC data were derived from the UK Biobank Consortium's GWAS summary count data, including a total of 372,184 female and male subjects, with 168 cases and 372,016 controls, all of whom are of European ancestry. Sensitivity analysis was mainly used for heterogeneity and pleiotropy testing.

Our research indicated the causality between NK cell-related immune traits and HCC. Importantly, CD8⁺NKT cells had protective causal effects on HCC (OR = 0.9996;95%CI,0.9993–0.9999; P = 0.0489). CD16⁻CD56 caused similar effects on NK cells (OR = 0.9997;95%CI,0.9996–0.9999; P = 0.0117) as CD8⁺NKT cells. Intercepts from Egger showed no pleiotropy and confounding factors. Furthermore, insufficient evidence was found to support the existence of heterogeneity by Cochran's Q test.

MR analysis suggested that low CD8⁺NKT cells and CD16⁻CD56 expression on NK cells were linked with a higher risk of HCC.