APOE and KLF14 genetic variants are sex-specific for low high-density lipoprotein cholesterol identified by a genome-wide association study.

To demonstrate the loci that relate to high-density lipoprotein cholesterol (HDL-C) levels and genetic sex heterogeneity, we enrolled 41,526 participants aged between 30 and 70 years old from the Taiwan Biobank in a genome-wide association study. We applied the Manhattan plot to display the p-values estimated for the relationships between loci and low HDL-C. A total of 160 variants were significantly associated with low HDL-C. The genotype TT of rs1364422 located in the KLF14 gene has 1.30 (95% CI=1.20 - 1.42) times the risk for low-HDL compared to genotype CC in females (log(-p) =8.98). Moreover, the genes APOC1, APOE, PVRL2, and TOMM40 were associated significantly with low-HDL-C in males only. Excluding the variants with high linkage disequilibrium, we revealed the rs429358 located in APOE as the major genetic variant for lowering HDL-C, in which genotype CT has 1.24 (95% CI= 1.16 - 1.32) times the risk. In addition, we also examine 12 genes related to HDL-C in both sexes, including LPL, ABCA1, APOA5, BUD13, ZPR1, ALDH1A2, LIPC, CETP, HERPUD1, LIPG, ANGPTL8, and DOCK6. In conclusion, low-HDL-C is a genetic and sex-specific phenotype, and we discovered that the APOE and KLF14 are specific to low-HDL-C for men and women, respectively.

In vivo and in vitro growth stimulation of murine hepatoma cells by glucocorticoid.

An increased level of glucocorticoid receptors has been found in hepatoma. The aim of this study was to determine the in vivo effect of glucocorticoid on the growth of murine hepatoma cells. In vitro cell growth was determined by MTT assay, while cell cycle progression was assayed with flow cytometry. For in vivo experiments, ML-3 and Hepa 1-6 cells were implanted in BALB/c and SCID mice, respectively. Each mouse received 4 subcutaneous injections of hydrocortisone and/or RU486 after tumor implantation. We found that glucocorticoid treatment of ML-3 and Hepa 1-6 cells in vitro resulted in an increase in cell growth which was partially inhibited by RU486, a glucocorticoid antagonist. Glucocorticoid treatment enhanced the cell cycle progression of ML-3 cells. The incidence of ML-3 tumor in the hydrocortisone group was significantly higher than that of the saline, RU486, or hydrocortisone plus RU486 groups. RU486 partially blocked the hydrocortisone-stimulated growth of hepatoma. Further study showed that glucocorticoid treatment of SCID mice also stimulated Hepa 1-6 tumor growth. In conclusion, our results indicated that glucocorticoid directly stimulated hepatoma growth and this stimulation was not the result of immune suppression. Glucocorticoids may play an important role in regulating the growth of hepatoma.