Apolipoprotein E ε3 and ε4 are associated with a lower exposure to hepatitis E virus in American non‐Hispanic blacks
Authors: Sven Pischke, Johannes Hartl, Anne‐Marie Roque‐Afonso, Vincent Mallet
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: In a sample of more than 6000 participants, Zhang et al. reported that anti–hepatitis E virus (HEV) immunoglobulin G (IgG) seroprevalence was lower in non‐Hispanic blacks (15.3%) compared to non‐Hispanic whites (22.3%) and Mexican Americans (21.8%) in the 1988‐1994 Third National Health and Nutrition Examination Survey.1 They identified an association between low anti‐HEV IgG seropositivity and carriage of apolipoprotein E (APOE) alleles ε3 and ε4 in non‐Hispanic blacks but not in other ethnic groups. Various protective mechanisms, including modulation of the immune response against HEV, are discussed. We disagree with the methodology and with the interpretation of the results. Anti‐HEV IgG seropositivity is dependent on lifestyle factors. About one‐fourth of Muslims in the United States are African Americans (https://en.wikipedia.org/wiki/Islam_in_the_United_States). This subgroup has a specific lifestyle that could explain by itself the differences observed in the study—basically, reduced consumption of swine meat. The absence of a relation between anti‐HEV IgG seroprevalence and region of residence, poverty income ratio, and education in this subgroup is clearly in favor of a protective lifestyle. Any statistical analyses in this ethnic group should therefore be adjusted on this potential confounder. We also disagree with the interpretation of the results. Anti‐HEV seropositivity reflects a past or present immune response to HEV but is not informative about the host's response to HEV. Any genetic variant, including APOE ε3 and ε4, does not influence the anti‐HEV seroconversion rate. For example, interleukin‐28b influences the immune response to hepatitis C viral infection (spontaneous clearance versus chronic infection) but does not modify seroprevalence rates as hepatitis C viral infection mainly depends on specific lifestyles and iatrogenic factors and not on genetic factors. The majority of HEV infections take a clinically silent course (>95%).2 The Third National Health and Nutrition Examination Survey results show high rates of HEV exposure despite low numbers of reported cases of HEV infections. Any study on the potential protective effect of a genetic variant for symptomatic HEV infection should compare patients who developed a silent infection to those who developed overt HEV infection. Finally, inhibition of HEV entry due to the incorporation of APOE in the HEV envelope is discussed. HEV is a nonenveloped virus in the digestive tract. It may replicate first in the digestive tract without eliciting immunity and gain an envelope at this stage. Then, an enveloped virus reaches the liver through the bloodstream, and its entry in hepatocytes is putatively inhibited by the reported polymorphism. This is very speculative and not supported by the results. Within the last paragraph of the manuscript the authors encouraged the readers to replicate and verify their results. Hereby we suggest that we (1) determine the proportion of different APOE genotypes in patients with overt hepatitis E and (2) adjust all future genetic studies on food consumption, with special attention to swine consumption, as swine meat is a source of HEV transmission in developed countries.