Low Cholesterol due to APOB Variants: Exploring the Balance Between Liver and Cardiovascular Risk

Background & Aims: Lifelong APOB gene inactivation lowers LDL-C and cardiovascular risk, but impairs hepatic lipoprotein export, predisposing to chronic liver disease (CLD). The extent to which common steatogenic factors modulate this risk remains unclear. Moreover, the balance between long-term cardiovascular protection and CLD risk in APOB variant carriers has never been evaluated.Methods: Using UK Biobank data, we analysed 241 APOB loss-of-function (LoF) carriers and 410 721 non-carriers, stratified by steatogenic risk factors, including age, sex, diabetes, BMI, alcohol intake and the PNPLA3-rs738409 genotype. Associations with transaminase levels, CLD and cardiovascular (ASCVD) outcomes were assessed using Python and R packages.Results: APOB carriers had similar to 35% lower LDL-C and apoB levels, along with reduced total triglycerides and Lp(a) (all p < 0.001). Baseline ALT and AST were higher in carriers than in non-carriers (P-adj = 3.6 x 10(-7)), particularly among those with obesity (p <= 0.003). The prevalence and incidence of CLD were consistently higher in carriers across all risk factor categories (p <= 0.01), with the strongest association in those with diabetes and obesity over 15 years of follow-up (P-adj = 0.03). In contrast, APOB carriers as a whole had a 57% lower ASCVD risk (P-adj = 0.009), with a similar atheroprotective trend across all risk factor categories. This corresponded to an absolute risk reduction of 2.30 ASCVD events/1000 person-years (p = 0.002) and an absolute increase of 3.48 CLD events/1000 person-years (p = 0.003).Conclusions: Long-term exposure to low LDL-C levels due to APOB LoF variants has opposite consequences, reducing ASCVD risk but increasing CLD risk, especially in the presence of diabetes and obesity. These findings highlight the importance of balancing cardiovascular benefit with hepatic safety when considering apoB-targeting therapies.