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Abstract ABCC6 deficiency promotes ectopic calcification; however, circumstantial evidence suggested that ABCC6 may also influence atherosclerosis. The present study addressed the role of ABCC6 in atherosclerosis using Ldlr −/− mice and pseudoxanthoma elasticum (PXE) patients. Mice lacking the Abcc6 and Ldlr genes were fed an atherogenic diet for 16 weeks before intimal calcification, aortic plaque formation and lipoprotein profile were evaluated. Cholesterol efflux and the expression of several inflammation, atherosclerosis and cholesterol homeostasis-related genes were also determined in murine liver and bone marrow-derived macrophages. Furthermore, we examined plasma lipoproteins, vascular calcification, carotid intima-media thickness and atherosclerosis in a cohort of PXE patients with ABCC6 mutations and compared results to dysmetabolic subjects with increased cardiovascular risk. We found that ABCC6 deficiency causes changes in lipoproteins, with decreased HDL cholesterol in both mice and humans, and induces atherosclerosis. However, we found that the absence of ABCC6 does not influence overall vascular mineralization induced with atherosclerosis. Decreased cholesterol efflux from macrophage cells and other molecular changes such as increased pro-inflammation seen in both humans and mice are likely contributors for the phenotype. However, it is likely that other cellular and/or molecular mechanisms are involved. Our study showed a novel physiological role for ABCC6, influencing plasma lipoproteins and atherosclerosis in a haploinsufficient manner, with significant penetrance.

Chronic hepatitis C infection is a major cause of liver cancer in the United States. Hawai'i's incidence of liver cancer consistently ranks among the highest in the US, due in part to the high prevalence of hepatitis B in the state. To better understand the factors associated with liver cancer among patients in Hawai'i with hepatitis C virus (HCV) infection, the patient database of Kaiser Permanente's Hawai'i region was used to identify a cohort of 3198 patients with a history of chronic HCV infection, of whom 159 (5%) were diagnosed with liver cancer between the years 2004-2020. Multiple logistic regression was used to identify factors independently associated with liver cancer. Male sex (AOR 2.02, 95% CI 1.34-3.06), Asian race (AOR 1.78, 1.16 - 2.74) and hepatitis B core antibody (HBCAB) positivity (AOR 1.76, 95% CI 1.25 - 2.49) emerged as independent predictors of liver cancer among patients with chronic HCV infection. A history of diabetes (AOR 1.56, 1.07 - 2.27) and older age at the time of HCV diagnosis (AOR 1.19, 1.09-1.29) also emerged as significant associations. HBCAB-positive individuals did not differ significantly from those who were HBCAB-negative in regards to demographics or 5-year survival rate. In this cohort of patients with chronic HCV, a positive HBCAB without evidence of active hepatitis B infection was associated with 1.76 increased odds of liver cancer compared to those with negative HBCAB. This finding may have important implications for screening algorithms among individuals with hepatitis C infection. [ABSTRACT FROM AUTHOR]